Conference Organizers - Asociatia Prader Willi din Romania

Table of Contents
Table of Contents
Welcome to Cluj-Napoca, Romania
Organizing Committees
Conference Venue
Conference Information
Registration
Audio Visual Equipment for
Speakers
Messages/Information Board
Catering
Posters
Social Programs
Scientist’s Dinner
Gala Dinner
Close of PWS Conference Dinner
Entire Conference Close Dinner
General Information
Travel Agency
Cellular Phones
Emergency Medical Assistance
Pharmacy
Money Matters
Taxi/Transport Information
Beginning Romanian
General Meetings
Scientist’s Program
Scientist’s Abstracts- Oral
Presentations
Scientific Medical Poster Abstracts
Scientific Behavioral/Psychological
Poster Abstracts
Presenters and Affiliations
Caretakers Program
Association’s Day Program
Parents and Professionals Program
Presentation Summaries
Children’s Program
Rare Diseases Awareness Program
Rare Diseases Oral Presentations
Rare Diseases Poster Abstracts
Speaker Biographies
Map of Cluj-Napoca, Romania
Page Number
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13-38
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130-151
152-180
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This book has been assembled and edited by Autumn Henderson- International PWS
Conference Organizing Committee.
2
Welcome to Cluj-Napoca, Romania
On behalf of the International Prader Willi Syndrome Organisation (IPWSO), I
welcome you to Cluj Romania for the Sixth International PWS Conference.
Members of our PWS family from around the world will come together in
celebration of our passing of “Fifty Years of Progress” since identification of PWS
by Doctors Prader, Labhart, and Willi and the Fifteenth Anniversary of (IPWSO).
Following the giant footsteps of our founders, this conference strives to build upon
the knowledge we have learned and at the same time stretch our imaginations to a
better future for people with PWS. A relatively new association, RPWA, is an
inspiration, making Romania a fitting and especially exciting place to begin this
new era of optimism and hope.
Enjoy this conference, the warm hospitality of our hosts, and the opportunity to
learn and share while making new friends from many diverse cultures and realities.
Support and collaboration from our oldest to our youngest associations is vital to
our international PWS family. By connecting and collaborating, we can create a
network of overwhelming power, moving people’s hearts and enhancing the lives
of people with PWS and their families – everywhere!
Pam Eisen
President International Prader Willi Syndrome Organisation- International
PWS Conference Organizing Committee Chair
Coming to Romania, you will discover yourself, discovering others…
The Romanian Prader Willi Association (RPWA) warmly welcomes you in joining
us in Cluj-Napoca, Romania for the 6th International PWS Workshop and
Conference and the 1st Romanian Rare Diseases Awareness Conference, which has
been organized for the first time in a new EU member country.
Organizing an international conference and initiating new projects for patients with
PWS is a great challenge for RPWA and the Romanian medical department. The
most important steps in this process have been taken and at this conference, our
professionals and parents will have a chance to learn, discuss, and make plans for
the future.
The partnership among the stakeholders involved in the diagnosis and management
of PWS and rare diseases is essential in developing solutions to address the
specific needs of patients and their families.
We hope that this conference will provide us with the opportunity to make this
dream come true, to create a link between families, patients, and professionals all
over the world!
Dorica Dan
President Romanian Prader Willi Association- International PWS Conference
Organizing Committee Chair
3
Organizing Committees
Scientific Program Organizers
Anthony J. Holland, MBBS, MRCPsych, M.Phil (UK)
Suzanne B. Cassidy, MD (USA)
Scientific Advisory Committee
Daniel J. Driscoll, MD, PhD (USA)
Elisabeth M. Dykens, PhD (USA)
Anthony P. Goldstone, MA, MRCP, PhD (UK)
Bernhard Horsthemke, PhD (Germany)
Françoise Muscatelli, PhD (France)
Lenuta Popa, MD, PhD (Romania)
Caretakers Organizing Committee
Dr. Hubert Soyer- Chair (Germany)
N. Hödebeck-Stuntebeck- Chair (Germany)
Jackie Mallow- Chair (USA)
Associations Day Organizing Committee
Joan Gardner- Chair (USA)
Jackie Waters- Chair (UK)
Parents and Professionals Organizing Committee
Susanne Blichfeldt, MD- Chair (Denmark)
Dorica Dan- Chair (Romania)
Pamela Eisen- IPWSO President, Chair (USA)
Dr. Szekely Aurelia- Professional Delegate IPWSO
Rare Diseases Awareness Programme Organizers
Dorica Dan- Chair (Romania)
Christel Nourissier - Chair (France)
Prof. Dr. Maria-Julieta Puiu- Scientific Chair (Romania)
Rare Diseases Scientific Advisory Committee
Christel Nourissier - EURORDIS
Prof. Dr. Maria-Julieta Puiu – UMF Timisoara
Pr Rumen Stefanov-- Plovdiv, Bulgaria
Prof. Domenica Taruscio- Instituto Superiore di Sanita, Italy
Dr Cristina Skrypnyk- Children Hospital Oradea
Prof. Dr. Cristina Borzan – Comisia Nationala de Sanatate
Dr Min Chieh Tseng- Taiwan Foundation for Rare Disorders (TFRD)
Conference Organizers
Romanian Prader-Willi Association
International Prader-Willi Organization
S.C. Simbolife S.R.L.
Trima Events S.R.L.
4
Conference Venue
Universitatea de Medicina si Farmacie “Iuliu Hatieganu” Cluj-Napoca, Romania
Located in the center of Cluj-Napoca, close to the Botanical Gardens and the Somes River, the
University serves as an excellent facility to hold this conference. The building belongs to the
University of Medicine and Pharmacy and includes 2 large auditoriums and multiple meeting
rooms and classrooms for sessions and workshops. Conference sessions will be held in rooms
assigned on individual conference programs. Directions to each of the rooms can be found by
signs posted in the venue or by asking one of the volunteers helping at this important event.
Please refer to the individual conference programs for details of speakers, workshops, rooms, and
sessions.
Universitatea de Medicina si Farmacie “Iuliu Hatieganu”
Str. Pasteur, Nr. 6
Cluj-Napoca, Romania
Tel: 0264-594252
Conference Information
Registration
The conference registration desk is located in the General Lobby of the conference venue by the
front doors. Our registration committee and volunteers will be available for information during
the registration hours of the conference as follows:
June 20- 15.00-20.00
June 21- 8.00-17.00
June 22- 8.00-12.00
June 23- 8.00-17.00
June 24- 8.00-17.00
Audio Visual Equipment for Speakers
Speakers will be able to visit their rooms and download and/or change presentations during
registration hours by contacting the volunteers at the registration desk. Speakers should load
their presentations at the registration desk and the technology crew will disseminate the
presentations to the proper rooms through a network. Please let the technology crew know of
special needs for your presentations.
Messages/Information Board
In the General Lobby by the registration desk will be an information board posted including
program schedules, transportation information, maps, and a message board for delegates to post
messages for other participants. Please check the message board regularly.
Catering
All Coffee breaks and Lunches will be catered in the General Lobby of the Conference Venue
during specific break times for each individual program schedule (see each schedule in this
booklet). Dinners will also be in the General Lobby at specified times at the conference venue.
5
Posters
All posters will be displayed in the corridors of the first and second floors outside of the main
auditoriums. The number of your poster can be found next to your poster title in this book, and it
coincides with the place number on the display stand. Double sided tape will be provided to post
your posters on the stands. Medical posters for the Scientific Program will be displayed on the
second floor corridor and Behavioral/Psychological posters for the Scientific Program will be
displayed on the first floor corridor. All Rare Diseases Awareness posters will be displayed on
the first floor corridor.
Posters for the Scientific Program can be put up on the 20th of June during registration hours, or
in the morning of the 21st of June before the Scientific Program starts. The posters for the
Scientific Program should be taken down after the Scientific Program ends on the 22nd of June.
Rare Diseases Posters can be put up on the 23rd of June during registration hours and should be
taken down after the Rare Diseases Awareness Program ends on the 24th of June.
Social Programs
Scientist’s Dinner
On Thursday, June 21st at 19.00, there will be a dinner for everyone in the General Lobby of the
University Conference Venue.
Gala Dinner
On Friday, June 22nd at 19.00, there will be a grand dinner in the General Lobby of the
University Conference Venue including entertainment, traditional Romanian cuisine, and drinks.
Close of PWS Conference Dinner
On Saturday, June 23rd at 20.00, there will be a dinner in the General Lobby of the University
Conference Venue.
Entire Conference Close Dinner
On Sunday, June 24th at 19.00, there will be a dinner in the General Lobby of the University
Conference Venue including entertainment, traditional Romanian cuisine, and drinks.
6
General Information
Travel Agency
Simbotours is our official travel agent and will have a desk next to the registration desk for
questions and/or concerns. Simbotours will open on June 20th starting at 15.00 until 20.00 and
will be available from 8.00-17.00 on June 21-24.
Contact numbers and addresses for Hotels are listed below.
City Plaza
Sindicatelor Str. Nr.9 - 11
Tel: (+)40 264-450101
Fax: (+)40 264-450152
Hotel Belvedere
Str. Călăraşilor nr.1
Tel: (+)40 264 432071
Fax: (+)40 264 432076
Hotel Capitolina
Str. Victor Babes nr. 35
Tel: 004 - 0264 450 490,
Fax: 004 - 0264 450 497
Hotel Capitol
Str. Neagra nr. 9
Tel/ fax: 004 - 0264 450 498
Napoca Hotel
Str. Octavian Goga, nr. 1
Tel: 0264-580715
Sport Hotel
Aleea Stadionului nr.1
Tel: (+)40 264 593921
Fax: (+)40 264 595859
National/International Calling and Cellular Phones
You are kindly asked to have your cellular phone turned off while attending the conference
sessions and workshops.
Dialing within Romania from a fixed phone:
0 + three digit area code + six digit telephone # when dialing anywhere in the countryside or
0 + 21 + seven digit telephone # when dialing a number Bucharest
Three digit telephone numbers are local toll-free numbers for emergencies or businesses.
International dialing from Romania from a fixed phone:
00 + country code + area code + telephone #
Emergency Medical Assistance
Emergency: 112 (available for ambulance, police, firefighters)
Emergency Hospital (Spitalul Clinic Judetean de Urgenta Cluj-Napoca)
3/5 Clinicilor Str.
Tel: 592771
See map for location
Pharmacy
Farmacia 89 - Tel: 596523
Located at the Emergency Hospital
7
Money Matters
Romania uses the Romanian Lei. Using ATM cards is very convenient and you will usually get
a better exchange rate than in an exchange office, but you will probably be charged a small fee
by your bank so it may be about the same. The big advantage of using ATM machines is that
they eliminate the need to carry large amounts of cash as traveler’s checks are virtually useless.
If you do plan on exchanging cash be sure you have brand new bills with no cuts or marks of any
kind on them. Usually exchange houses will not take bills with bank marks or other markings on
them. Even a small tear in a bill and it will be rejected. If you are using U.S. Dollars be sure you
have only the most recent design and coloration on the bill. You will need to provide your
passport to the exchange office.
Taxi/Transport Information
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•
•
•
•
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Diesel Rapid - (0264) 946
Atlas Taxi - (0264) 969
Diesel Taxi - (0264) 953, +40-744 646663, +40-745 381532, +40-722 859093
Nova Taxi - (0264) 949
Pritax - (0264) 942, +40-744 159720, +40-788 550000
Pro Rapid - (0264) 948
Terra Fan - (0264) 944
Inside Romania: Important Phrases
Thank you - Multsumesc
Please - Va rog
Good day - Buna ziua
Where is - unde este
How much is - cat costa
ten - zece
hundred - suta
thousands -mii
one -unu
two - doi
three -trei
four - patru
five - cinci
six -sase
seven -sapte
eight - opt
nine -noua
good bye - la revedere
Good morning - Buna dimineata
Good afternoon - Buna ziua
Good evening - Buna seara
Good night - Noapte buna
General Meetings
IPWSO General Assembly- Saturday June 23rd, 17.00-19.00- First Floor Auditorium One-For
delegates and observers
Satellite Symposium of Rare Diseases- Saturday June 23rd, 14.30-15.30- Pop Room 1-For Rare
Diseases Organizations and Affiliations
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6th International Prader-Willi Syndrome Conference
Scientific Conference
Cluj-Napoca, Romania
June 21-22, 2007
Co-Organizers
Anthony J. Holland, MBBS, MRCPsych, M.Phil (UK)
Suzanne B. Cassidy, MD (USA)
Scientific Advisory Committee
Daniel J. Driscoll, MD, PhD (USA)
Elisabeth M. Dykens, PhD (USA)
Anthony P. Goldstone, MA, MRCP, PhD (UK)
Bernhard Horsthemke, PhD (Germany)
Françoise Muscatelli, PhD (France)
Lenuta Popa, MD, PhD (Romania)
----------
IPWSO and the organizers would like to thank Pfizer Worldwide Endocrine
Care for their generous support of the Scientific Conference through an
unrestricted educational grant.
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IPWSO Scientific Program
Thursday- June 21, 2007
9.00-9.15: Welcome and Announcements
9.15-12.30: Platform Session 1 (Second Floor Auditorium Two)-Characterizing and
Understanding the PWS Phenotype
Moderator: Dr. Tony Holland
9.15: INVITED SPEAKER: Daniel Driscoll, M.D., Ph.D, USA
UPDATE OF CLINICAL CORRELATIONS OF GENOTYPES IN PWS;
9.45: Grugni et al.- MORTALITY IN PRADER-WILLI SYNDROME: ROLE OF
GENOTYPE, GENDER AND GH THERAPY;
10.05: Klockaert et al. (Vogels presenting)- FERTITLITY AND INFERTILITY IN
PRADER-WILLI SYNDROME TESTICULAR HISTOLOGY IN NINE MALES WITH
CRYPTORCHIDISM;
10.25: Lindmark & Trygg-NUTRITIONAL INTAKE BY YOUNG CHILDREN WITH
PRADER WILLI SYNDROME;
10.45-11.15: COFFEE BREAK (GENERAL LOBBY)
11.15: INVITED SPEAKER: Elisabeth Dykens, Ph.D., USA
INVESTIGATING THE BEHAVIOURAL AND PSYCHIATRIC PHENOTYPE;
11.45: Woodcock et al.- THE RELATIONSHIP BETWEEN TEMPER OUTBURSTS,
REPETITIVE BEHAVIOUR AND A PREFERENCE FOR PREDICTABILITY IN
CHILDREN WITH PRADER-WILLI SYNDROME;
12.05: Bollerslev et al.- WORKING MEMORY IN ADULTS WITH PRADER-WILLI
SYNDROME. BASELINE DATA FROM A PROSPECTIVE RANDOMIZED STUDY;
12.25-13.30: LUNCH (BUFFET IN GENERAL LOBBY)
13.30-15.30: Poster Session (Medical Posters in corridor of 2nd Floor, Behavioral Posters in
corridor of 1st Floor) (Authors present)
13.30-14.30: Odd numbered authors present
14.30-15.30: Even numbered authors present
15.30-17.10: Platform Sesion 2 (Second Floor Auditorium Two)-The PWS Genotype
Moderator: Dr. Suzanne Cassidy
15.30: INVITED SPEAKER: Bernhard Horsthemke, Ph.D., Germany
CANDIDATE GENES FOR PWS;
16.00: INVITED SPEAKER: Alexander Huttenhofer, Ph.D., Austria
THE SMALL NUCLEOLAR RNAs AND THEIR POTENTIAL ROLE IN PWS;
10
16.30: Stefan et al.- A MASTER REGULATOR OF COORDINATE GENE EXPRESSION
IN PRADER-WILLI SYNDROME;
16.50: Goldstone et al.- PHENOTYPING OF ADULT MICE WITH A DELETION OF
THE PRADER-WILLI SYNDROME IMPRINTING CENTER;
17.10-17.40: COFFEE BREAK (GENERAL LOBBY)
17.40-18.30: Platform Session 3 (Second Floor Auditorium Two)-Managing PWS
Moderator: Dr. Lenuta Popa
17.40: Nagai et al.- TESTOSTERONE REPLACEMENT THERAPY IN 13 ADULTS
PATIENTS WITH PRADER-WILLI SYNDROME;
18.00: Grugni et al.-BODY COMPOSITION AND GH RESPONSE TO
GHRH+ARGININE IN ADULT PATIENTS WITH PRADER-WILLI SYNDROME;
18.20: Forster & Gourash- PHENOMENOLOGY AND MANAGEMENT OF MOOD
ACTIVATION IN PRADER-WILLI SYNDROME;
19.30: SCIENTISTS DINNER (GENERAL LOBBY OF CONFERENCE VENUE)
Friday- June 22, 2007
8.30-12.30: Platform Session 4 (Second Floor Auditorium Two)-Investigating Biological
and Environmental Mechanisms Associated with the Phenotype of PWS
Moderator: Dr. Leopold Curfs
8.30: INVITED SPEAKER: Anthony P. Goldstone, MA, MRCP, PhD., UK
NEUROENDOCRINE MECHANISMS IN PWS PHENOTYPES;
9.00: INVITED SPEAKER: Francoise Muscatelli, Ph.D., France
WHAT CAN WE LEARN FROM MOUSE MODELS TO BETTER UNDERSTAND
PWS?;
9.30: Relkovic et al. - BEHAVIOURAL ANALYSIS OF A MOUSE MODEL OF PWS;
9.50: Webb et al. - AFFECTIVE PSYCHOSIS IN PEOPLE WITH PRADER-WILLI
SYNDROME;
10.10-10.40: COFFEE BREAK (GENERAL LOBBY)
10.40: Soni et al. -THE ROLE OF FAMILY PSYCHIATRIC HISTORY IN THE
DEVELOPMENT OF PSYCHOPATHOLOGY IN PEOPLE WITH PWS;
11.00: Schwenk (Driscoll presenting) -PRADER-WILLI SYNDROME AND OTHERS
WITH EARLY-ONSET MORBID OBESITY SHARE SIMILAR STRENGTHS IN
COGNITION AND ACHIEVEMENT;
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11.20: Hawkins et al. -AN ETHNOGRAPHY OF RESIDENTIAL SERVICES FOR
ADULTS WITH PRADER-WILLI SYNDROME: THE ROLE OF THE BEHAVIOURAL
PHENOTYPE IN STAFF MEMBERS’ INTERPRETATIONS OF RESIDENTS’
BEHAVIOURS;
11.40: Whitman et al. -GROWTH HORMONE EFFECTS IN INFANTS AND TODDLERS
WITH PRADER-WILLI SYNDROME: DOES EARLY INTERVENTION MAKE A
DIFFERENCE?;
12.00-12.30: General discussion for 30 minutes
Moderators: Dr. Suzanne Cassidy and Dr. Tony Holland
12.30-13.30: LUNCH (BUFFET IN GENERAL LOBBY)
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Platform Session 1 (Second Floor Auditorium Two)-Characterizing and Understanding the
PWS Phenotype
INVITED SPEAKER: Daniel Driscoll, M.D., Ph.D, USA
UPDATE OF CLINICAL CORRELATIONS OF GENOTYPES IN PWS;
SPEAKER: Graziano Grugni, MD
MORTALITY IN PRADER-WILLI SYNDROME: ROLE OF GENOTYPE, GENDER
AND GH THERAPY;
SPEAKER: Annick Vogels, M.D., Ph.D, Belgium
FERTITLITY AND INFERTILITY IN PRADER-WILLI SYNDROME TESTICULAR
HISTOLOGY IN NINE MALES WITH CRYPTORCHIDISM;
SPEAKER: Marianne Lindmark, Nutritionist, Norway
NUTRITIONAL INTAKE BY YOUNG CHILDREN WITH PRADER WILLI
SYNDROME;
INVITED SPEAKER: Elisabeth Dykens, Ph.D., USA
INVESTIGATING THE BEHAVIOURAL AND PSYCHIATRIC PHENOTYPE;
SPEAKER: Kate A. Woodcock, Ph.D. Student, UK
THE RELATIONSHIP BETWEEN TEMPER OUTBURSTS, REPETITIVE
BEHAVIOUR AND A PREFERENCE FOR PREDICTABILITY IN CHILDREN WITH
PRADER-WILLI SYNDROME;
SPEAKER: Ulla M.V.Bollerslev, M.Ed.Psych, Norway
WORKING MEMORY IN ADULTS WITH PRADER-WILLI SYNDROME. BASELINE
DATA FROM A PROSPECTIVE RANDOMIZED STUDY;
13
UPDATE OF CLINICAL CORRELATIONS OF GENOTYPES IN PWS
Daniel J. Driscoll, M.D., Ph.D.
Pediatric Genetics, University of Florida College of Medicine, Gainesville, FL, USA
Prader-Willi syndrome (PWS) is a contiguous gene syndrome resulting from the loss of paternal
expression of 5 protein coding genes and 5 classes of box C/D small nucleolus RNA (snoRNA) genes.
The 3 main molecular classes of PWS are large deletions (4 - 4.5 Mb), maternal uniparental disomy
(UPD) 15 and imprinting defects (ID). Each molecular class has subclasses. In addition, there are rare
chromosomal rearrangements that account for <1% of cases.
Genotype-phenotype correlations have been done comparing deletions and UPDs. Significant differences
have been found (e.g., higher verbal IQ scores and increased psychiatric problems in UPD). However,
the overall differences between these 2 molecular classes are less striking than that found for Angelman
syndrome.
Recently several groups have reported differences in behavior and psychological problems in type 1 vs
type 2 deletions, but there is not complete agreement regarding the extent of the differences between these
2 main types of deletions. Furthermore, the samples sizes are still small. Adding to the difficulty in
interpreting the data is that the size of the large deletions may be more heterogeneous than previously
thought. In addition, there is some controversy as to the clinical significance of being hemizygous for the
4 non-imprinted genes (GCP5, CYFIP1, NIPA2 and NIPA1) in proximal 15q11.
Comprehensive clinical data is lacking for the ID group due to the rarity of this molecular class.
However, from the information available there does not seem to be a clinical difference between the small
imprinting center (IC) deletion patients and those with epimutations. In addition, it appears that ID
patients are very similar phenotypically to UPD patients which would be what has been found for
Angelman syndrome.
The rare chromosomal rearrangements (inversions, and balanced and unbalanced translocations) in
15q11.2 have given us insight as to the potential role of certain genes in the PWS region due to the unique
genetic material that is present and absent in these patients. Some of these individuals have classical
PWS while others have some “PWS-like” features, but are missing key classical features. These unique
rearrangements have implicated a major role for the HBII-85 snoRNA gene in the PWS phenotype while
relegating the HBII-52 snoRNA gene to a more minor role.
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MORTALITY IN PRADER-WILLI SYNDROME: ROLE OF GENOTYPE, GENDER
AND GH THERAPY
Graziano Grugni, MD1, Antonino Crinò, MD2, Laura Bosio, MD3, Andrea Corrias, MD4, Marina Cuttini,
MD2, Teresa De Toni, MD5, Eliana Di Battista, MD5, Adriana Franzese, MD6, Luigi Gargantini, MD7,
Nella Greggio,8 Lorenzo Iughetti, MD9, Chiara Livieri, MD10, Arturo Naselli, MD5, Claudio Pagano,
MD8, Giovanni Pozzan, MD8, Letizia Ragusa, MD11, Alessandro Salvatoni, MD12, Alessandro Sartorio,
MD1, Giuliana Trifirò, MD13, Roberto Vettor, MD8, Giuseppe Chiumello, MD3 (Genetic Obesità Study
Group of the Italian Society of Pediatric Endocrinology and Diabetology).
1
Italian Auxological Institute, Verbania; 2Bambino Gesù Hospital, Palidoro-Rome; 3S. Raffaele Hospital,
Milan; 4University of Turin; 5University of Genoa; 6University of Naples; 7Civic Hospital of Treviglio
(BG); 8University of Padua; 9University of Modena and Reggio Emilia; 10University of Pavia; 11Oasi
Maria S.S., Troina (EN); 12University of Varese; 13S. Giuseppe Hospital, Milan; Italy.
INTRODUCTION: Complications associated with obesity are the recognized main risk factors for death
during the entire lifespan of patients with Prader-Willi syndrome (PWS), while infectious disease seems
to be the major cause of unexpected sudden death in children below the age of 5 years. In addition, some
patients with PWS may be susceptible to additional diseases unrelated to obesity, which may compromise
health further. As far as genetic mechanisms are concerned, it has been reported that UPD15 seems to be
an independent risk factor for death in adult patients with PWS. On the other hand, no data about the
effects of gender on mortality risk of PWS are currently available. Moreover, the role of GH/IGF-I axis
dysfunction and its treatment in the poor health outcomes of PWS adults remains to be fully established,
whereas the benefits of GH therapy (GHT) were well documented both in children and in adolescents. In
spite of these beneficial effects, fatal events after the start of GHT have been reported in paediatric
patients with PWS, raising the possibility that a causal link may be present. The aim of our study was to
analyse the role of genotype, gender and GHT as factors contributing to the mortality of Italian patients
with PWS.
PATIENTS AND METHODS: In collaboration with the Italian PWS Association and in a national
collaborative study, all known cases with genetically confirmed PWS were collected. Clinicians were
asked to report genetic tests, age, sex, weight, length/height, presence or absence of GHT, dosage and
duration of GH treatment, and cases of death. Multivariate Cox proportional hazards analysis was used to
explore the factors potentially associated with survival.
RESULTS: On 30 June 2006, 425 subjects with PWS, 209 males (M) and 216 females (F), were
identified. Two hundred and thirty-eight patients had a del15, 104 subjects had a UPD15, and 4
individuals showed a translocation affecting chromosome 15q11-q13. Positive methylation test was
demonstrated in the remaining 79 patients (18.6%). The median age was 13.7 (range 0.5-45.4) for males,
and 19.0 (range 0.4-46.7) for females. One hundred and thirty (62.2%) of the males and 103 (47.7%) of
the females were below 18 years of age. The difference of age distribution between males and females
was statistically significant (p 0.03). Overall, the proportion of obesity was 62.6%. A total of 212 subjects
have performed GHT (49.9%, 106 M): 141 cases were currently receiving GHT (33.2%, 80 M), while 71
individuals have stopped the treatment (16.7%, 26 M). Eighteen patients deceased during the past 20
years. The frequency of death was higher in M than in F (12/209= 5.74% vs. 6/216= 2.77%). On the other
hand, no difference was detected between the different genotypes (del15= 4.6%; UPD15= 4.8%). Three
children (2 M) died while receiving GHT. The frequency of death during GHT was 1.41% (3/212), while
15 out of 213 patients with PWS died without GHT (7%). When the effect of GHT, obesity, genetic
defect and gender were considered together in a multivariate Cox model, only the latter showed a
marginally significant (p=0.05) relationship with survival, with a decreased risk of death for females
compared to men (OR 0.38, 95% CI 0.14-1.02).
CONCLUSIONS: 1) no correlation was found between death and UPD15; 2) mortality is higher in M
than in F. This finding may indicate random variation in small populations. Alternatively, the possibility
that, with PWS, as in general population, women outlive men cannot be excluded. However, such
variations may also suggest an increased mortality rate in M patients with PWS; 3) GHT in patients with
PWS, as a group, does not seem to rise the risk of death.
15
FERTITLITY AND INFERTILITY IN PRADER-WILLI SYNDROME
TESTICULAR HISTOLOGY IN NINE MALES WITH CRYPTORCHIDISM
K. Klockaert1, G. Bogaert1, P Moerman2, J.P. Frijns3, A.Vogels3
Department of Urology1, Department of Anathomopathology2, Department of Human Genetics3 ;
University Hospital of Leuven, Herestraat 79, 3000 Leuven, Belgium
INTRODUCTION: Hypogonadism leading to genital hypoplasia and delayed or incomplete gonadal
maturation is a central feature of the Prader-Willi syndrome (PWS). Cryptorchidism is found in 93% of
the PWS patients and is considered to be a phenotypic criterion. Infertility is also thought to be a
consistent characteristic in males with PWS. Nevertheless data on spermatogenesis are lacking. In normal
males who undergo orchidopexy for cryptorchidism, there is a correlation between prepubertal lesions on
testicular biopsies and the degree of spermatogenesis in postpubertal specimens (Nistal et al., 2000). To
predict future spermatogenesis we analysed testicular histology in 8 prepubertal boys with cryptorchidism
and a molecularly confirmed diagnosis of PWS. In addition we analysed the testicular histology in one
adult male with cryptorchidism and torsio testis.
MATERIAL AND METHODS: We describe the testicular histology in 8 boys (6 with a deletion, 2 with
uniparental maternal disomy) who underwent orchidopexy (13 testes) for cryptorchidism (age at time of
biopsy: 16 months to 14 years) and in one adult male who underwent orchidectomy for cryptorchidism
with torsio testis. On the basis of this testicular biopsy, prepubertal undescended testes were classfied
into four Nistal categories (Nistal et al., 1980) according to the mean tubular diameter (MTD) , the tubular
fertility index (TFI: the average percentage of of tubules showing germ cells) and the Sertoli cell index
(STI: number of Sertoli cells per cross-sectioned tubule): Nistal category 1: normal MTD, TFI >50%,
SCI normal; Nistal category II: slight to marked reduced MTD, TFI 30-50%, SCI normal ; Nistal category
III: MTD severe and diffuse reduced, TFI<30%, SCI severely reduced; Nistal category IV: normal MTD,
variable TFI, diffuse Sertoli cell hyperplasia.
RESULTS: Out of the eight prepubertal boys, two (25%) showed a Nistal score of I, one (12.5%)
showed a Nistal score of II and five males (62.5%) showed a Nistal score of III. The testis of the adult
male showed a Sertoli cell nodulus, vacuolised Leydig cell, peritubular hyalinisation and small tubuli.
CONCLUSION: PWS appears to be a heterogeneous disorder with respect to testicular histology.
Although a great part (62.5%) of the prepubertal boys with cryptorchidism show absence of
spermatogonia, 25% of the boys have a normal testicular histology. Future studies are necessary to
evaluate the evolution of germ cells in males with the Prader-Willi syndrome and to correlate these data
with testicular histology and spermiogram in adulthood.
References
M. Nistal, M.L. Riestra, R. Paniagua. Correlation between testicular biopsies (prepubertal and
postpubertal) and spermiogram in cryptorchid men. Hum. Pathol. 2000; 31(9):1022-30
M. Nistal, Paniagua R., Diez-Pardo J.A. Histologic classification of undescended testes. Hum. Pathol.,
1980;11(6):666-74
16
NUTRITIONAL INTAKE BY YOUNG CHILDREN WITH PRADER WILLI
SYNDROME
Marianne LindmarkA and Kerstin U. TryggB
Frambu National Centre for Rare Disorders, Siggerud, Norway, BDepartment of Nutrition, University of
Oslo, Norway
A
INTRODUCTION: Prader-Willi syndrome (PWS) is a genetic disorder associated with hyperphagia that
typically occurs from an age between 2-6 years, and without caloric restriction these children will become
obese. The families and caregivers of these children receive nutritional counselling, however limited
information is available on how families implement the dietary restriction and there is limited knowledge
of the actual nutritional intake among young children with PWS. The nutritional intake of 2-, 3- and 4
years old Norwegian children with PWS have been evaluated and compared with the results of the
national food surveys for children 2 years and 4 years in Norway.
MATERIAL AND METHODS: We have followed a group of 6 children with PWS. They constitute the
total known population of children with PWS in Norway born between 2000-2002. All children in this
study were diagnosed with PWS in there first months of life. Assessments of the food intake in the age
groups 2-3 years and 3-4 years was preformed twice a year by structured food interview with parents,
carried out by a nutritionist. All interviews were preformed by the same person. One assessment was
completed using the 24-h recall method via telephone with one of the parents. All interviews, except the
24-h recall, were translated into a typical three day food consumption for each child. For the 24-h recall
calculations are made only using information from the food consumption for the 24-hour period. In the
age group 4-5 years the parents recorded the children’s food consumption for a total of 7 days, divided
into two periods during the year, by using a precoded food-diary developed for a national food survey
among Norwegian 4 years old children. The recorded data was encoded and analyzed using a food
database and software systems developed at the Institute of Nutrition Research, University of Oslo.
RESULTS: We found a mean total caloric intake in the age group 2-3 years: 772 Kcal/day, age 3-4: 862
Kcal/day and age 4-5 years: 953 Kcal/day. This caloric intake amounted to 54 % and 65 % of average
caloric intake in the national food surveys for the 2 years and 4 years old Norwegians. When we express
the calorie intake for the children with PWS per kg, we found in the age group 2-3 years: 54 kcal/kg - 99
Kcal/kg, mean 72 Kcal/kg, median 70 kcal/kg, in the age group 3-4 years: 48 Kcal/kg – 76, Kcal/kg,
mean 65 Kcal/kg, median 68 Kcal/kg. And in the age group 4-5: 49 kcal/kg – 76 Kcal/kg, mean 64
Kcal/kg, median 67 Kcal/kg.
The mean percentage of energy from fat in group age 2-3: 25 E% (range 15-39 E%), age 3-4: 24 E%
(range 19-32 E%) and age 4-5: 25 E% (range 20-30 E%).
The mean percentage of energy from sugars in the group age 2-3: 4,3 E% (range 0,6-20,4 E%), age 3-4:
2,6 E % (range 0,5 -6,4 E%) and age 4-5: 4,9 E% (range 0,5-13,4 E%). In the national surveys the mean
percentage of energy from sugars where found to be 11,7 E% and 15,1 E% among the 2 years and 4 years
old.
CONCLUSION: Children with PWS consume fewer calories than reference values for age and gender,
even though a variation in calorie consumption is seen within the PWS group. Children with PWS
consume less fat and less sugars than the average among other Norwegian children their age and with few
exceptions their intake of fat and sugars are within the general recommendations of max 30 E% from fat
and max 10 E % from sugars. An evaluation of the children’s intake of micronutrients is required to make
sure their nutritional intake is optimal for growth and development.
17
CORRELATES OF BEHAVIORAL PROBLEMS AND STRENGTHS IN PERSONS
WITH PRADER-WILLI SYNDROME
Elisabeth M. Dykens, Ph.D
Associate Director, Vanderbilt Kennedy Center for Research on Human Development; Director,
Vanderbilt Kennedy University Center of Excellence on Developmental Disabilities; Professor,
Psychology and Human Development, Nashville, TN 37203
This talk presents three sets of findings from an ongoing program of phenotypic research on Prader-Willi
syndrome (PWS).
First, we compare several behavioral domains (adaptive and maladaptive behavior, compulsivity,
cognitive profiles) across persons with the three major genetic subtypes of PWS: Type I paternal deletion,
Type II paternal deletion, and maternal UPD. We also report how these groups fare on our new measure
of hyperphagic drive, behavior, and severity, and on ERP studies using food stimuli.
Second, we offer highlights from our studies of mothers and fathers of offspring with PWS, including
both the stressful and positive aspects of raising children with this syndrome. We compare maternal
coping, stress, cortisol levels, and positive parental perceptions to mothers of children with other
disabilities, and to how mothers interact with their offspring with PWS in a food-related task.
Third, we describe two understudied areas of strength in PWS: a desire to physically care-take others,
including pets; and remarkable skills with jigsaw puzzles and word search puzzles that seem based
primarily on shape recognition and memory. We compare these strengths to other groups with and
without disabilities, and show how they relate to age, genetic subtypes, and specific neuropeptides (e.g.,
oxytocin, ghrelin).
The talk highlights the need for interdisciplinary research on genetic, neurological, and environmental
factors that promote optimal outcomes in persons with PWS and their families.
18
THE RELATIONSHIP BETWEEN TEMPER OUTBURSTS, REPETITIVE
BEHAVIOUR AND A PREFERENCE FOR PREDICTABILITY IN CHILDREN WITH
PRADER-WILLI SYNDROME
Kate A. Woodcock, Chris Oliver and Glyn W. Humphreys
School of Psychology, University of Birmingham, UK.
INTRODUCTION: Children with Prader-Willi syndrome (PWS) often show ‘temper outbursts’ and
certain types of repetitive behaviour. Some of these behaviours may be related to executive dysfunction.
This study aims to describe the profile of executive functioning in children with PWS and explore
potential relationships between this profile and aspects of the behavioural phenotype.
METHODS: 28 children with PWS (12 male; mean age 161m) and 28 typically developing children (11
male; mean age 103m) completed measures of executive attention including a computer task that can
assess attentional switching. Carers of these children rated the frequency of repetitive behaviours on two
informant report questionnaires. Carers of 46 children with PWS were interviewed about the
environmental context of repetitive behaviour shown by their child
RESULTS: Group differences in developmental and chronological age were controlled for statistically.
A mixed factor ANCOVA of reaction times in the computer task showed a significant interaction between
group and switching (F(1,52)=9.24, p=0.004), with PWS children showing greater switching costs.
Compared to typically developing children, children with PWS also showed significantly more preference
for predictability, repetitive questioning, completing behaviour and persistent habits. Interviews showed
that of the 80% of carers who reported temper outbursts, 91.9% reported that unpredictability occurred
antecedent to these outbursts. Of 93.5% of carers who reported repetitive questions, 83.7% reported that
these increased following unpredictability. A standard score of switch cost was significantly correlated to
ratings of children’s preference for predictability, but, interestingly, not to any other of the common
repetitive behaviours.
DISCUSSION: Children with PWS show a deficit in switching attention that may underlie a preference
for predictability that appears to be related to some challenging behaviours.
19
WORKING MEMORY IN ADULTS WITH PRADER-WILLI SYNDROME.
BASELINE DATA FROM A PROSPECTIVE, RANDOMIZED STUDY
Ulla M.V.Bollerslev, M.Ed.Psych.1,2, Marina Falleti, M.Sc3, Kai F. Rabben, MD2, Jens Bollerslev, MD,
DMedSc4
1
The Institute for Educational Research, University of Oslo, Norway, 2Frambu Competence Center,
Norway, 3CogState, Melbourne, Australia, 4Section of Endocrinology, National University Hospital,
University of Oslo, Norway
INTRODUCTION: The Prader-Willi syndrome is a rare, complex, and genetically determined neurodevelopmental disorder. The subjects have their own individual characteristics; however share in common
particular physical features and specific cognitive strengths and weaknesses. These characteristics change
across the lifespan and make up the physical and behavioural “phenotype” of the syndrome. With age,
certain behaviours become more evident, for instance repetitive and ritualistic behaviour in older children
and adults. According to the literature, subjects score moderate to high on subscales measuring
compulsory behaviour. Learning difficulties are common and range the whole spectrum, from mild to
severe. Most subjects find reading, spelling and especially mathematics very difficult. By means of a
computer based cognitive test (CogState), the aim of the present study was, on a cross-sectional basis, to
analyse aspects of the adults working memory.
METHODS: Twenty individuals (mean age 28.3 years, range 21-37 years, 7 men) with genetically
verified PWS included in the Nordic Prader-Willi study were investigated with selected parts of the
CogState battery and compared with normative data and the findings were related to data on
anthropometry. According to the definition by WHOM of overweight and obesity in normal subjects, 4
individuals had a normal weight, 3 were overweight and the rest obese. The mean Body Mass Index
(BMI) was 33.5 k/m2 (SD = 10.6). The genetic background was a deletion in most of the patients as only
one individual had verified UPD.
RESULTS: Nineteen subjects were able to perform the computer based test. We found that adults with
PWS have significantly decreased elements of working memory compared to normative data. In general,
the subjects had median scores within two standard deviations below the normal mean, however with
large differences between the cognitive tests performed. Moreover, extensive inter-individual ranges were
observed. Females did significantly better than males in some of the items. Related to BMI, obese
subjects performed slightly better in working memory than the less obese.
DISCUSSION: Adults with PWS were both positive and corporative in this time limited, motivating, and
visual based cognitive test situation. In general, our population had markedly decreased working memory,
as detected with the CogState battery. The impairment for all items was of major magnitude, however the
impairment of visual memory was less pronounced. This should be taking into account, when teaching
strategies and learning are considered. The visual pathway is obviously the best functioning and should be
used in educational settings and when giving general information.
20
Platform Sesion 2 (Second Floor Auditorium Two)-The PWS Genotype
INVITED SPEAKER: Bernhard Horsthemke, Ph.D., Germany
CANDIDATE GENES FOR PWS;
INVITED SPEAKER: Alexander Huttenhofer, Ph.D., Austria
THE SMALL NUCLEOLAR RNAs AND THEIR POTENTIAL ROLE IN PWS;
SPEAKER: Mihaela Stefan, PhD, USA
A MASTER REGULATOR OF COORDINATE GENE EXPRESSION IN PRADERWILLI SYNDROME;
INVITED SPEAKER: Anthony P. Goldstone, MA MRCP PhD., UK
PHENOTYPING OF ADULT MICE WITH A DELETION OF THE PRADER-WILLI
SYNDROME IMPRINTING CENTER;
21
CANDIDATE GENES FOR PRADER-WILLI SYNDROME
Bernhard Horsthemke, PhD, Karin Buiting, PhD
Institut für Humangenetik, Universitätsklinikum Essen, Germany
The proximal long arm of human chromosome 15 (15q11-q13) contains a cluster of imprinted genes
which are under the control of a bipartite imprinting centre. MKRN3, MAGEL2, NDN, SNURF-SNRPN
and several snoRNA genes are expressed from the paternal chromosome only. In 2000, we identified an
intronless gene (C15orf2) between NDN and SNURF-SNRPN, which encodes an 1156-amino-acid protein
of unknown function. By Northern blot analysis we had found that C15orf2 is exclusively expressed in
testis. Biallelic expression of C15orf2 in adult testis correlated with the absence of methylation of a 250
bp CpG island. C15orf2 appears to be primate-specific and under strong positive selection. Recently, we
have identified two novel genes (prader-willi region non-protein-coding RNA 1 and 2; PWRN1 and
PWRN2) between NDN and C15orf2. By data base search we found five partially duplicated copies, of
which only one copy each appears to be active. PWRN2 is only expressed in testis and biallelic.
PWRN1transcripts are most abundant in testis, but present in other tissues, also. It is is biallelically
expressed in testis and kidney, but monoallelically in fetal brain. Methylation analysis of a CpG island 15
kb upstream of exon 1 showed absence of methylation in spermatozoa, but methylated and unmethylated
alleles in fetal brain. Reinvestigation of C15orf2 revealed that this gene is also expressed in fetal brain
and that expression in this tissue is monoallelic.
Each of the above mentioned genes may play a role in PWS. There is no evidence that a mutation in a
single gene causes the full phenotype of PWS. Atypical deletions in humans as well as mouse models
may help to elucidate the contribution of each of these genes to PWS.
22
THE SMALL NUCLEOLAR RNAs AND THEIR POTENTIAL ROLE IN PWS
Alexander Hüttenhofer, M.D., Ph.D.
Innsbruck Biocentre, Division of Genomics and RNomics, Medical University Innsbruck, Innsbruck,
Austria
In our quest to identify novel non-coding RNAs (ncRNAs) in model organisms (an approach for which
we coined the term RNomics), we have identified three brain-specific ncRNAs, designated as HBII-13,
HBII-52 and HBII-85 from a mouse brain cDNA library. We have isolated the human orthologs of the
three ncRNAs and mapped them between the SNRPN and UBE3A genes on chromosome 15q11-q13. The
region containing the three ncRNA genes has been implicated in the etiology of the Prader-Willi
syndrome. Two of the ncRNA genes, HBII-52 and HBII-85, are encoded in tandemly repeated arrays of
47 or 27 units, respectively. Interestingly, these RNAs were absent from a PWS patient cortex and from a
PWS mouse model, demonstrating their paternal imprinting status and pointing to their potential role in
the etiology of PWS. By a bioinformatical approach, we were able to identify three additional ncRNA
genes within the same locus, designated as HBII-436, HBII-438A and HBII-438B, which are also subject
to imprinting and are predominately expressed in the brain.
Due to conserved sequence and structure motifs, the six ncRNAs can be assigned to the class of small
nucleolar RNAs (snoRNAs). This class of RNA molecules has previously been shown to target ribosomal
RNAs by a short antisense element located within snoRNAs. By this mechanism, ribosomal RNAs are
targeted for modification at the site of complementarity to snoRNAs. All six brain-specific snoRNAs
from the PWS region lack complementarity to ribosomal RNAs. In one case, the HBII-52 snoRNA, we
could show a potential interaction with a brain-specific mRNA, the serotonin receptor mRNA 5-HT2C at a
site where the mRNA is regulated by alternative splicing and editing. We could demonstrate that the
HBII-52 snoRNA is able to regulate gene expression of the serotonin receptor 5-HT2C by modification of
the mRNA. This implies novel biological function for this class of ncRNAs and points to their potential
role in the etiology of PWS.
23
A MASTER REGULATOR OF COORDINATE GENE EXPRESSION IN PRADERWILLI SYNDROME
1
2
3
Mihaela Stefan, PhD , Tohru Ohta, MD, PhD , Kentaro Yamasaki, MD, PhD and Robert D. Nicholls,
DPhil
1
1
2
Children’s Hospital of Pittsburgh, Pittsburgh, PA; Health Science University of Hokkaido, Japan;
3
University of Pennsylvania, Philadelphia, PA.
Genetic defects in Prader-Willi syndrome (PWS) lead to loss of function of a unique set of imprinted,
paternally-expressed genes in chromosome 15q11.2 that encode proteins, snoRNAs and, in the mouse,
microRNAs. PWS genes have enriched expression in neurons with most predicted to regulate other
RNAs. However, the mechanistic relationships between imprinting, somatic expression of PWS genes
and the phenotypic basis are unknown. Bioinformatic analyses of mammalian genome sequences using
permutations of Nuclear Respiratory Factor-1 (NRF-1) consensus motifs revealed an unexpected high
number of potential NRF-1 sites within the PWS imprinted region. In mouse, a total of 18
phylogenetically conserved NRF-1 motifs were identified within the Ndn promoter, U1 promoters, SnurfSnrpn promoter and enhancer, a mini-CpG island between Mkrn3 and Magel2 and a cluster of four
adjacent NRF-1 binding sites within Mirh1 intron 2. Using chromatin immunoprecipitation we found that
NRF-1 binds to open chromatin [acetylated H4 and di-methylated H3 (K4) histones] and unmethylated
CpG regions containing NRF-1 sites of the active, paternally-derived allele in mouse brain and human
neuroblastoma (NB) cells. However, NRF-1 was not associated with inactive chromatin at the sites
located in the intergenic region between Mkrn3 and Magel2, Mirh1 intron 2 (NRF-1 cluster) and U1
promoters in mouse fibroblasts suggesting a neuronal specific function for these elements. To assess the
significance of NRF-1 for the activity of PWS regulatory regions, mutations in NRF-1 binding sites were
analyzed using dual-luciferase reporter assays. Luciferase (Luc) gene transcription under the control of
the Ndn, Snurf-Snrpn and U1 minimal promoters was significantly reduced in the absence of NRF-1
binding sites. Interestingly, NRF-1 confers promoter activity in vitro for both the intergenic
Mkrn3/Magel2 mini-CpG island and Mirh1 intron 2 NRF-1 cluster despite the fact that these structures
are not promoters in vivo. Moreover, when cloned in the enhancer position of the pGL3-basic vector, the
NRF-1 cluster dramatically increased promoter activity of Ndn and Mirh1 in NB cells suggesting a
broader regulatory role for this element. To demonstrate that NRF-1 is a master regulator of PWS-region
genes, we used vector-mediated small interfering RNA (siRNA) to examine the effect of down-regulation
of NRF-1 expression on the transcription of PWS imprinted genes in NB cells. Knockdown of NRF-1
expression with an average fold of 0.48 ± 0.04 resulted in significantly reduced mRNA levels of all PWS
genes analyzed by regular and quantitative RT-PCR analysis. Intriguingly, down-regulation of NRF-1
also decreases transcription of PWS genes that don’t possess NRF-1 binding sites within 5’ regulatory
regions (eg. Mkrn3, Mirh1). These results demonstrate that NRF-1 acts as a master transcription factor for
PWS somatic expression. Further studies aim to identify long-range regulatory mechanisms mediated by
NRF-1 in the PWS region by visualizing interactions between distant PWS regulatory regions.
24
PHENOTYPING OF ADULT MICE WITH A DELETION OF THE PRADER-WILLI
SYNDROME IMPRINTING CENTER
Anthony P. Goldstone 1*, Karen A. Johnstone 2, Christopher R. Futtner 2, Xeve Silver 3, Clive Wasserfall
4
, Margaret L. Stoll 5, Roger L. Reep 5, Mark A. Atkinson 4, Jim L. Resnick 2 & Daniel J. Driscoll 1,2
1
Division of Pediatric Genetics, 2 Dept. of Molecular Genetics, 3 AMRIS Facility, McKnight Brain
Institute, 4 Dept. of Pathology, University of Florida; 5 Dept. of Physiological Sciences, University of
Florida College of Veterinary Medicine; Gainesville, USA. *Current address: MRC Clinical Sciences
Centre, Imperial College, Hammersmith Hospital, London, UK
INTRODUCTION: PWS is caused by the loss of imprinted gene expression on chr 15q11-q13. The
PWS-imprinting center (PWS-IC) is a positive regulatory element required for bidirectional activation of
a number of paternally expressed genes in this region. Until recently, all mouse models of PWS were
post-natally lethal, precluding them from studies of late onset phenotypes, such as obesity. We have
established a strain-specific survival model of PWS through paternally inherited deletion of the PWS-IC
on an FVB-B6 F1 background.
METHODS: PWS-IC+/del mice were compared to wild-type littermates. Mice were housed in groups by
sex and genotype. Body weight and food intake were measured twice weekly from weaning at 3 weeks
until 22 weeks, and then weekly until 48 weeks. At 50 weeks, after a 6 hour fast, organs were removed for
histology, and blood taken for measurement of insulin, leptin, ghrelin and IGF-1. Adult mice had in vivo
brain (11 Tesla) and ex vivo whole body (4.7 Tesla) magnetic resonance imaging (MRI) to examine brain
and body composition.
RESULTS AND DISCUSSION: Body weights for both male and female PWS-IC+/del mice remained
reduced compared to wild-type mice throughout the post-weaning period into adulthood (n = 10-16 per
group). Compared to wild-type littermates, the body weight of male PWS-IC+/del mice was 54% at 3
weeks and 52% at 48 weeks (mean ± SEM: 29.5 ± 0.8 vs. 55.8 ± 1.8g, P<0.001), and of female PWSIC+/del mice was 55% at 3 weeks and 63% at 48 weeks (21.5 ± 0.6 vs. 39.2 ± 3.1g, P<0.001). Female
PWS-IC+/del mice had delayed vaginal opening compared to wild-type females (39 vs. 27 days, n = 7,
P<0.001).
Both sexes of adult PWS-IC+/del mice had a large reduction in inguinal adipose tissue weight (by 45-83%
at 50 weeks of age), and fat content was visibly reduced on MRI. PWS-IC+/del mice had significantly
reduced plasma insulin, leptin and IGF-1 levels compared to wild-type littermates, but no significant
difference in plasma ghrelin (n = 6-12 per group). Post-weaning food intake (corrected for body weight)
was in fact reduced in male PWS-IC+/del mice up to 14 weeks of age, and in female PWS-IC+/del mice up to
the 48 week point.
At 50 weeks of age, PWS-IC+/del mice had reduced body length (by 9-10%, P<0.001), reduced brain, liver,
stomach, kidney and testes weights (by 10-54%, P<0.02) compared to wild-type mice. No histological
abnormalities in the liver, stomach, duodenum, pancreas, kidney, salivary gland, ovary or testis were seen
in PWS-IC+/del mice on hematoxylin and eosin staining. No gross brain defects were seen in adult PWSIC+/del mice using MRI except for mild ventriculomegaly (n = 4 of each sex, aged 54 to 77 weeks), nor
with thionine or myelin staining (n = 7 of each sex, aged 48 to 109 weeks).
CONCLUSION: As in humans with PWS, PWS-IC+/del mice display pre-weaning failure-to-thrive and
growth retardation which persist into adulthood. However, by contrast these mice do not develop
hyperphagia, obesity or infertility. In fact, adult PWS-IC+/del mice are resistant to the development of agerelated adiposity. Current studies are addressing abnormalities in brain morphology or behavior, as they
are observed in humans with PWS.
25
Platform Session 3 (Second Floor Auditorium Two)-Managing PWS
SPEAKER: Toshiro Nagai, MD, Japan
TESTOSTERONE REPLACEMENT THERAPY IN 13 ADULTS PATIENTS WITH
PRADER-WILLI SYNDROME;
SPEAKER: Graziano Grugni, MD, Italy
BODY COMPOSITION AND GH RESPONSE TO GHRH+ARGININE IN ADULT
PATIENTS WITH PRADER-WILLI SYNDROME;
SPEAKER: Janice L. Forster, MD, USA
PHENOMENOLOGY AND MANAGEMENT OF MOOD ACTIVATION IN PRADERWILLI SYNDROME;
26
TESTOSTERONE REPLACEMENT THERAPY IN 13 ADULTS PATIENTS WITH
PRADER-WILLI SYNDROME
Toshiro Nagai, MD, Kazuo Obata, MD, Takayoshi Tsuchiya, MD, Yuriko Tanaka, MD, Yuuzou Tomita,
MD, Ryoichi Sakuta, MD, Nobuyuki Murakami, MD
Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan
BACKGROUND: Males with PWS show various degrees of hypogonadism and it causes decrease of
bone and muscle mass. However, testosterone replacement therapy has been controversial due to
anecdotal concerns that testosterone might cause inappropriately aggressive behavior or worsen other
behavioral problems.
PURPOSE: To evaluate the effect of testosterone on behavioral problems, muscle volume, bone mineral
density (BMD), body composition, blood IGF1, and body mass index (BMI) in PWS.
SUBJECTS & METHODS: Thirteen male patients (age ranging from 19 to 51 y/o, chromosome 15q
deletion in all 13 pts, duration of therapy 1.0 to 8.8 years, mean 3.9 years) who have been treated with
testosterone (125 mg depot testosterone I.M. once monthly) were evaluated for the following issues;
behavior (monthly examination and interview from the patients and their parents), paravertebral muscle
volume (CT scan), BMD of lumbar spines(DEXA), %fat in the truncal area (DEXA), serum IGF1 level,
and BMI.
RESULTS: None showed worsening of behavioral problems and 2 patients showed improvement of their
irritability. Two of them showed erection of penis and one experienced sperm ejaculation about once
monthly. Paravertebral muscle volume did not change statistically. BMD increased and %fat decreased
significantly (p=0.0038 and p=0.011, respectively). Serum IGF1 levels and BMI did not change during
the treatment.
DISCUSSION: Testosterone replacement therapy did not worsen their behavioral problems and rather
improved aggressive behavior in 2 patients. Muscle volume and BMI did not improve, but BMD and
body composition improved. Serum IGF1 level did not increase during the therapy.
CONCLUSION: Testosterone replacement therapy in male adults with PWS is a safe and useful
treatment.
27
BODY COMPOSITION AND GH RESPONSE TO GHRH+ARGININE IN ADULT
PATIENTS WITH PRADER-WILLI SYNDROME
Graziano Grugni, MD1, Antonino Crinò, MD4, Paride Bertocco, MD2, Paolo Marzullo, MD3.
1
Department of Auxology, 2Department of Physical Medicine and Rehabilitation and 3Department of
Internal Medicine, Italian Auxological Institute Foundation, Verbania, Italy; 4Unit of Autoimmune
Endocrine Diseases, Bambino Gesù Children’s Hospital, Palidoro-Rome; Italy.
INTRODUCTION: The complications associated with obesity seem to be the main risk factors for death
in the older subjects with Prader-Willi syndrome (PWS). On the other hand, an awareness is rising that
poor health outcomes of PWS subjects may not be entirely caused by obesity alone. It is currently unclear
whether risks of critical illnesses of PWS are influenced by GH deficiency (GHD). However, a GH/IGFI-mediated control of cardiac risk in PWS has been recently found (Marzullo et al., J Clin Endocrinol
Metab 2005). In this context, we have recently reported a reduced GH secretion in PWS adults when
compared with a control group with similar BMI (Grugni et al., Clin Endocrinol 2006). Nevertheless,
BMI is not an exact measure of adiposity in PWS as it underestimates % of body fat (Goldstone et al.,
Am J Clin Nutr 2002; Kennedy et al., Int J Obes 2006). In fact, PWS harbour a higher fat mass than
simple obesity, under the same degree of weight excess, both in children and in adults (Brambilla et al.,
Am J Clin Nutr 1997; Theodoro et al., Obesity 2006). The aim of this study was to examine the role of
body composition in the blunted GH secretion in PWS adults.
PATIENTS AND METHODS: 8 patients with PWS (2M/6F, 6 del15/2 UPD15, age 28.0+2.2 yrs, BMI=
44.1+2 kg/m2; mean+SEM) were included in the study. Dual-energy x-ray absorptiometry (GE-Lunar,
Madison, WI) was used for measurements of fat mass (FM%= 54.5+1.5). A control group of 8 obese
subjects (SO) (1M/7F, age 29.5+2.7 yrs, BMI= 42.7+0.43 kg/m2) with comparable body composition
(FM%= 52.2+1; p=0.2) was enrolled. In all patients the pituitary GH secretion was analyzed by dynamic
testing with GHRH+arginine. GH responses were evaluated either as mean peak values (ng/ml), or as the
area under the curve (AUC, ng/ml/h) and the net incremental area under the curve (nAUC, ng/ml/h). In
addition, the baseline IGF-I levels were determined.
RESULTS: Both GH responses to GHRH+arginine test and IGF-I levels were significantly lower in
PWS subjects, in comparison to SO patients (table 1). According to the literature (Corneli et al., Eur J
Endocrinol 2005), 3 PWS individuals (37.5%) could be defined as severe GHD, as well as one SO (GH
peak <4.2 ng/ml). Seven PWS and 3 SO had subnormal IGF-I levels (normal values: 182-782 ng/ml).
Table 1
GH peak
PWS
7.0+1.3
GH
(ng/ml/h)
405+75
SO
p=
21.9+4.7
0.009
1325+315
0.013
(ng/ml)
AUC
GH nAUC (ng/ml/h)
IGF-I
367+75
104+18
1294+313
0.012
256+37
0.003
(ng/ml)
CONCLUSIONS: Our findings seem to demonstrate that the differences in stimulated GH levels
between our PWS and SO are not related to body FM%. These data suggest that GHD in PWS is not
merely secondary to altered body composition.
28
PHENOMENOLOGY AND MANAGEMENT OF MOOD ACTIVATION IN PRADERWILLI SYNDROME
Janice L. Forster, MD and Linda M. Gourash, MD
Pittsburgh Partnership, Pittsburgh, PA, USA
INTRODUCTION: Mood disorders with or without psychotic features have been reported in PraderWilli syndrome (PWS). Leibenluft et al (2003) characterize symptoms of mania in juvenile onset bipolar
disorder as narrow phenotype (elation, grandiosity, episodicity) or broad phenotype (irritability, emotional
reactivity, chronicity). The authors review the phenomenology and management of mood activation in
PWS, characterize symptoms of mania, and comment on predisposing, precipitating and perpetuating
factors.
METHODS: The authors collect from their clinical experience with PWS a cohort of individuals with
mood activation with or without psychosis.
RESULTS: Mood activation was observed in one third of individuals with PWS referred for psychiatric
evaluation and treatment. The cohort includes 38 children and adults, ages 8-39 years; there is no gender
bias, and the genotypic frequency reflects the accepted occurrence rates of deletion and UPD conditions.
Within the cohort, there was no genotypic bias among those presenting with the narrow phenotype. All of
these patients were psychotic, and almost all of them required mood stabilizers and antipsychotic agents
to resolve their symptoms. Those presenting with the broad phenotype were more likely to have the
deletion condition. Only half of these patients were psychotic, and they required less pharmacotherapy.
Among the developmental cohort, more children with the deletion condition than UPD present with
psychotic mood disturbance; after the developmental period, the ratio reverses. The major precipitating
factor for mood activation among all groups of patients was pharmacotherapy with selective serotonin
reuptake inhibitors (SSRI’s). Symptoms did not remit until the SSRI was discontinued, even in the
presence of environmental management.
DISCUSSION: Mood activation is a serious, poorly recognized problem among individuals with PWS
resulting in referral for psychiatric evaluation. For the most part, mood activation is an iatrogenic problem
arising from the use of SSRI medications. If the symptoms of mood disorder persist after the
discontinuation of the SSRI, then anticonvulsant mood stabilizers and lithium can be used effectively in
concert with environmental interventions. In these cases, mood activation may uncover an underlying
diathesis for Bipolar I Disorder which is usually associated with the narrow phenotype of mania.
Surprisingly, individuals with UPD were not the most likely persons in this cohort to experience the
narrow phenotype of mood activation. However, individuals with deletion condition were more likely to
present with the broad phenotype, especially among the youngest cohort. Symptoms of mood disorder in
PWS are effectively managed with mood stabilizers in concert with environmental interventions when
mood activating agents are discontinued.
29
Platform Session 4 (Second Floor Auditorium Two)-Investigating Biological and
Environmental Mechanisms Associated with the Phenotype of PWS
INVITED SPEAKER: Anthony P. Goldstone, MA MRCP PhD., UK
NEUROENDOCRINE MECHANISMS IN PWS PHENOTYPES;
INVITED SPEAKER: Francoise Muscatelli, Ph.D., France
WHAT CAN WE LEARN FROM MOUSE MODELS TO BETTER UNDERSTAND
PWS?;
SPEAKER: Dinko Relkovic, Italy
BEHAVIOURAL ANALYSIS OF A MOUSE MODEL OF PWS;
SPEAKER: Tessa Webb, UK
AFFECTIVE PSYCHOSIS IN PEOPLE WITH PRADER-WILLI SYNDROME;
SPEAKER: Sarita Soni
THE ROLE OF FAMILY PSYCHIATRIC HISTORY IN THE DEVELOPMENT OF
PSYCHOPATHOLOGY IN PEOPLE WITH PWS;
INVITED SPEAKER: Daniel Driscoll, M.D., Ph.D, USA
PRADER-WILLI SYNDROME AND OTHERS WITH EARLY-ONSET MORBID
OBESITY SHARE SIMILAR STRENGTHS IN COGNITION AND ACHIEVEMENT;
SPEAKER: Rebecca Hawkins, UK
AN ETHNOGRAPHY OF RESIDENTIAL SERVICES FOR ADULTS WITH PRADERWILLI SYNDROME: THE ROLE OF THE BEHAVIOURAL PHENOTYPE IN STAFF
MEMBERS’ INTERPRETATIONS OF RESIDENTS’ BEHAVIOURS;
SPEAKER: Barbara Y. Whitman, Ph.D, USA
GROWTH HORMONE EFFECTS IN INFANTS AND TODDLERS WITH PRADERWILLI SYNDROME: DOES EARLY INTERVENTION MAKE A DIFFERENCE?;
30
NEUROENDOCRINE MECHANISMS IN PWS PHENOTYPES
Anthony P. Goldstone, MA MRCP PhD
Consultant Endocrinologist, Metabolic and Molecular Imaging Group, MRC Clinical Sciences Centre,
Imperial College, Hammersmith Hospital, London, UK
Many of the characteristic PWS phenotypes have a neuroendocrine basis, including genital hypoplasia at
birth; childhood development of obesity and then profound hyperphagia (between ages of 1 and 6 years)
leading to progressive morbid obesity into adulthood; short stature due to GH deficiency and
(predominantly hypothalamic) hypogonadism with incomplete delayed puberty and infertility;
developmental delay with mild to moderate mental retardation, abnormal sleep patterns and
hypersomnolence.
PWS subjects have delayed meal termination and earlier meal initiation and return of hunger after the
previous meal. Given free access to food, PWS subjects will consume approximately three times that of
control subjects. The reduced satiation in PWS occurs despite delayed gastric emptying which would be
expected to produce the opposite effect.
Subjects with PWS may have marked elevations in the appetite-stimulating stomach-derived hormone
ghrelin, for their obesity, though plasma levels do fall appropriately after food. This appears at least partly
explained by their preserved insulin sensitivity and relative hypoinsulinaemia, related to reduced visceral
adiposity. A role for hyperghrelinaemia in the hyperphagia of PWS has yet to be proven. Acute
normalisation of ghrelin levels with somatostatin does not reduce food intake in PWS, and chronic studies
with longer-acting analogues are ongoing.
For their obesity, subjects with PWS have normal fasting and post-prandial plasma levels of the
anorexigenic hormones leptin, PYY, GLP-1 and CCK, and other gut hormones, such as gastrin and GIP.
This suggests the absence of a global defect in gut hormone secretion or autonomic efferents to end
organs. However, fasting and post-prandial levels of the anorexigenic hormone pancreatic polypeptide
(PP) are reduced in PWS.
In addition to these hormonal abnormalities that might contribute to hyperphagia in PWS
(hyperghrelinaemia, PP deficiency and hypoinsulinaemia), there are likely to be overriding brain defects,
particularly hypothalamic, which lead to disordered appetite. The volume and number of oxytocin
neurons of the paraventricular nucleus is decreased in post-mortem hypothalami from patient with PWS.
No abnormalities in neuropeptide Y, agouti-related protein, pro-opiomelanocortin, growth hormonereleasing hormone, melanin-concentrating hormone receptor 1, or orexin neurons have yet been found
that could explain PWS phenotypes
Recent functional neuroimaging techniques such as positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI) in PWS have revealed abnormal brain activation patterns in
corticolimbic structures, such as the amygdala, pre-frontal, orbitofrontal and insula cortex, at rest or in
response to food stimuli. These suggest abnormal reward and motivational responses to food that may
also contribute to the hyperphagia in PWS. Detailed MR scanning including techniques such as diffusion
tensor imaging are also revealing neuroanatomical abnormalities within extra-hypothalamic brain
structures in PWS that may play a role in cognitive, behavioural and neuroendocrine phenotypes.
The presence of relative rather than absolute resistance to peripheral satiety signals, and defects within
extra-hypothalamic brain structures raises the intriguing possibility of novel therapeutic avenues for PWS,
particularly in reducing hyperphagia in PWS.
31
WHAT CAN WE LEARN FROM MOUSE MODELS TO BETTER UNDERSTAND
PWS?
Françoise Muscatelli1, PhD, Françoise Watrin1, PhD Sandrine Geib1, PhD, Sebastien Zanella2, PhD,
Gérard Hilaire2.
1
Institut de Biologie du développement de Marseille Luminy, Université de Luminy, Marseille, France.
CNRS, Maturation, Plasticity, Physiology and Pathology of Respiration, UMR 6153, 280 boulevard
Sainte Marguerite, 13009 Marseilles France.
2
INTRODUCTION: Mouse model is a powerful force in elucidating the genetic basis of human disease
and in analysing the mechanisms of this disease at the physiological, cellular and molecular levels.
PWS is a complex disease resulting from a lack of expression of several genes located in the 15q11-q13
region. Because there is no reported PWS patient with a normal paternal copy of 15q11-q13 and an
inheritance consistent with a single mutated gene, it is assumed that PWS is a multigenic syndrome. PWS
results from the loss of expression of several paternally expressed genes including SNURF-SNRPN,
NDN, MAGEL2, MKRN3, C15ORF, the C/D-box small nucleolar RNAs (snosRNAs) and some other
non coding transcripts. The mouse 7C chromosomal region has conserved synteny with the human 15q11q13 region: the genes, their organization and their imprinted regulation are conserved. Thus, mouse
appears a good model to study the regulation and function of those genes, in regard to PWS.
RESULTS: Two types of mouse models have been generated. The first type is characterized by a global
deficiency of paternal gene expression in the 7C chromosomal region. Four such potential mouse models,
have so far been reported as PWS model. In all cases, the main feature of the observed phenotype is
lethality during the first post-natal week, associated with various degrees of poor feeding, hypotonia and
growth retardation. These observations are consistent with the feeding difficulties and failure to thrive
that characterize PWS infants. Such models do not allow us to determinate the role of each gene in the
PWS phenotype. The second type of mouse models is defined by specific inactivation of each candidate
gene separately, in order to determine the role of each gene in the aetiology of PWS. Among all knockout mouse models created, Necdin knock-out mouse models show postnatal respiratory distress leading to
lethality in a fraction of pups at birth. Surviving Necdin-KO mice present phenotypic characteristics such
as respiratory defects, a high level of scraping, a particular cognitive profile, sensory-motor defects which
reveal striking parallels with some of the phenotypic manifestations in PWS patients. The Necdin-KO
model is consequently a good model for specific symptoms of PWS. The physiological and cellular
defects leading to these symptoms will be discussed.
DISCUSSION: The foreseeable consequences of such studies on mouse models will be to associate the
clinical symptoms of PWS with specific genes and signalling pathways that are deficient in PWS and to
suggest appropriate therapies for PWS or other pathologies that share symptoms with PWS (obesity,
compulsive behavior…).
32
BEHAVIOURAL ANALYSIS OF A MOUSE MODEL OF PWS
Dinko Relkovic1,2, Trevor Humby2, Karen A. Johnstone3, Jim L. Resnick3, Anthony J. Holland4,
Lawrence S. Wilkinson2 and Anthony R. Isles2,4
1
The Babraham Institute, Cambridge, UK; 2Behavioural Genetics Group, Psychological Medicine, Cardiff
University, Cardiff, UK 3Department of Molecular Genetics and Microbiology, Center for Mammalian
Genetics, University of Florida, Gainesville, USA; 4Developmental Psychiatry, University of Cambridge,
Cambridge, UK
INTRODUCTION: Prader-Willi syndrome (PWS) is a developmental disorder characterized by the lack
of expression of maternally imprinted genes on chromosome 15q11-q13 either through paternally
inherited deletion, chromosome 15 maternal uniparental disomy (mUPD) or imprinting centre (IC)
mutations. Individuals are prone to a number of neuropsychiatric problems, including obsessive
compulsive behaviour, mood instability, non-psychotic depression and psychosis. Exactly which genes in
the PWS interval contribute to these behavioural phenotypes is not clear, and indeed the finding that those
PWS patients with either IC mutation or mUPD are more likely to develop psychotic illness than deletion
subtypes suggests that some psychiatric problems may not be due to loss of maternally imprinted gene
expression, but the over-expression of paternally imprinted genes in or close to the PWS interval (Boer et
al. 2001).
METHODS: We are using an established mouse model (PWS-ICdel) which recapitulates the molecular
features of the IC mutation PWS genetic subtype. The work is focused on examining behavioural
endophenotypes of relevance to PWS, including sensorimotor gating (prepulse inhibition and acoustic
startle), reactivity to novel and fear inducing environments (locomotor activity and open field) and
cognitive aspects of psychosis, such as preservation (reversal learning).
RESULTS: Gene expression analysis of brain samples confirms the absence of maternally imprinted
gene expression in the PWS-ICdel mice. Additionally there is a relative over-expression of the paternally
imprinted gene Ube3a and differences in the relative abundance of functional 5Ht2cr splice variants.
PWS-ICdel mice were generally hypolocomotor compared to wild type littermates, but also showed greater
motoric skill on the rotarod test. There were no apparent difference in sensory motor gating, nor were
there any differences in emotional behaviour in the open field test. Cognitive testing using a Y-maze
based task indicated that PWS-ICdel mice made less errors-to-criteria in reversal learning. Analysis of
latency data also suggested that during initial acquisition of the task the PWS-ICdel were quicker at key
decision points of the task.
DISCUSSION: For the first time we have examined behavioural endophenotypes of relevance to the
neuropsychiatric problems seen in PWS in a mouse model. The PWS-ICdel mice show specific differences
in aspects of locomotor function, particularly a general hypolocomotor phenotype, something that is
consistent with the condition. Furthermore we have demonstrated a cognitive difference in that the PWSICdel mice actually perform a Y-maze reversal learning task better than wild-type littermates. We suggest
this may be due to altered motivational processes with respect to the food reinforcer in the PWS-ICdel
mice.
33
AFFECTIVE PSYCHOSIS IN PEOPLE WITH PRADER-WILLI SYNDROME
Tessa Webb1, Esther Maina2, Sarita Soni3, Joyce Whittington3, Harm Boer4, David Clarke5, Anthony
Holland3
1
Institute of Biomedical Research, Medical School, University of Birmingham, UK; 2Department of
Cancer Studies, Medical School, University of Birmingham, UK; 3Department of Developmental
Psychiatry, University of Cambridge, UK; 4Janet Shaw Clinic, North Warwickshire NHS Trust, UK; 5Lea
Castle Hospital, North Warwickshire NHS Trust, UK.
Affective psychosis associated with PWS occurs mainly in people with UPD(15)mat rather than those
with 15q11q13del.This suggests that it is related to the presence of two active copies of a gene(s) located
in the distal half of the PWS/ASCR (Prader-Willi/Angelman syndrome critical region) where some genes
are paternally imprinted but maternally active and whose loss of expression results in Angelman
syndrome (AS).
A large population study of PWS within the UK identified 12 people with a deletion in 15q11q13 who
had suffered a psychotic episode and four people over 30 years of age with UPD(15)mat who so far had
not.
These people were investigated using a series of microsatellite markers located within the PWS/ASCR.
It was found that the 12 people with 15q11q13del who had suffered psychotic episodes, despite having
the same deletion breakpoints as the remainder of the study participants with 15q11q13del, demonstrated
two maternally derived copies at loci lying between D15S975 and D15S661 making them effectively
disomic for this small region of the ASCR. When a series of 25 people with 15q11q13del who were not
psychotic were studied with the same microsatellite markers, they all demonstrated a single allele at each
of these loci. So, with only the four exceptions mentioned previously, all of the people with PWS
accompanied by psychotic episodes had two active copies of any putative imprinted genes or transcripts
lying within this small region while non-psychotic people, including a series of control individuals, had
only one. The four people with PWS due to UPD(15)mat but without affective psychosis were also found
to have two maternally derived alleles at loci between D15S975 and D15S661 with no paternal copy, so
segmental UPD had not occurred in them.
As D15S975 is located within IVS3-4 of the GABRG3 gene and D15S661 lies within the 5’UTR of the
OCA2 gene, neither of which is believed to be imprinted, real-time expression studies were carried out on
six ESTs (expressed sequence tags) and three possible scan genes (theoretical genes) identified from
database searches of the region. The results obtained suggest that it may not be simple over-expression of
a causative imprinted gene present in two active copies that permits the manifestation of psychotic
symptoms in PWS people with UPD(15)mat, but an epigenetic dysregulation of gene expression.
34
THE ROLE OF FAMILY PSYCHIATRIC HISTORY IN THE DEVELOPMENT OF
PSYCHOPATHOLOGY IN PEOPLE WITH PWS
Sarita Soni1, Joyce Whittington1, Anthony J. Holland1, Tessa Webb2, Harm Boer3, David Clarke4
1
Section of Developmental Psychiatry, Department of Psychiatry, University of Cambridge, Cambridge,
UK; 2Institute of Biomedical Research, Medical School, University of Birmingham, Birmingham, UK;
3
Janet Shaw Clinic, Birmingham, UK; 4Lea Castle Centre, Kidderminster, UK.
INTRODUCTION: From a UK-wide study, we showed that psychotic illness was significantly more
prevalent in those with the chromosome 15 uniparental maternal disomy (UPD) genetic subtype (62%)
than in those with a 15q11-q13 deletion (17%). As a result, we initially hypothesised that the etiology of
psychosis in those with UPD was the result of the specific arrangement of imprinted genes at 15q11-q13,
whereas the etiology of psychosis in those with a deletion was influenced by the same bio-psycho-social
factors that mediate psychosis in the general population. However, our finding that the phenomenology of
psychotic illness was similar in both genetic subtypes suggested that the mechanisms of development of
psychosis in both genetic subtypes might be the same. We investigated the presence of psychopathology
in first-degree relatives (FDRs) of people with PWS and were able to develop hypothetical models that
encompassed the above apparently conflicting findings. The clinical findings were supported and
strengthened by genetic investigation.
METHOD: We recruited 119 individuals with genetically-confirmed PWS (85 deletion, 34 UPD). A full
clinical and family psychiatric history was taken using a battery of tests including the Family History
Research Diagnostic Criteria (using the Family history method). A blood sample was taken from each
individual for genetic analysis.
RESULTS: Depressive illness is more common in FDRs of probands with a deletion with psychosis than
probands with UPD with psychosis. Probands with a deletion with psychosis had a significantly greater
rate of family history of depression than probands with a deletion without psychosis; this difference did
not hold for probands with UPD. Where affective illness was present in parents of probands with a
deletion with psychosis in this sample, that parent was inevitably the mother.
DISCUSSION: These findings suggest that the risk for developing psychosis in those with a deletion
may be inherited via the maternal line. That is, depression in mothers may be caused by the overexpression of a paternally imprinted/maternally expressed gene, which when transmitted to their offspring
with a 15q11-q13 deletion manifests as an affective psychotic disorder. Psychotic illness in those with
UPD may also be the result of over-expression of a paternally imprinted/maternally expressed gene, but
this abnormality is inherent in the UPD genotype and is not inherited.
35
PRADER-WILLI SYNDROME AND OTHERS WITH EARLY-ONSET MORBID
OBESITY SHARE SIMILAR STRENGTHS IN COGNITION AND ACHIEVEMENT
Krista A. Schwenk1,2, Jennifer Miller2, John H. Kranzler1, and Daniel J. Driscoll2
1
College of Education and 2Department of Pediatrics, University of Florida
INTRODUCTION: Individuals with PWS have been described as having mild to moderate mental
retardation and multiple severe learning disabilities with relative weaknesses in short-term memory and
mathematical skills and relative strengths in reading skills and on tasks that assess attention to visual
detail, visual-motor coordination, perceptual planning, and spatial organization. Dykens and colleagues
(J. Am. Acad. Child Adolesc. Psychiatry, 1992) found that the mean level of achievement for individuals
with PWS was approximately 2 years above their IQ. However, Whittington et al. (J. of Intellectual
Disability Research, 2004) reported that levels of achievement were lower than what was predicted based
on IQ among individuals with PWS. Furthermore, our group (Miller et al., J. Peds, 2006) has recently
demonstrated that individuals in general with early-onset morbid obesity have significantly lower general
intellectual ability and lower achievement than a normal sibling control group.
METHODS: The Woodcock-Johnson Tests of Cognitive Abilities, Third Edition (WJIII-Cog) and the
Woodcock-Johnson Tests of Achievement, Third Edition (WJIII-TA) were used to determine the extent to
which individuals with PWS (n=17; age range 6-39 years), early-onset morbid obesity (EMO) of
unknown etiology (n=19; ages 6-22 years), and their normal control siblings (n=18; ages 5-27 years)
reached the attainments predicted by their IQ. In addition, the relative strengths and weaknesses of the 3
groups (PWS, EMO, and controls) were investigated. Extensive genetic testing was conducted on both
the PWS (12 with deletions and 5 with UPD) and EMO subjects.
RESULTS: All 3 groups scored higher on their overall achievement score (TIA) than their IQ, but the
difference between these scores was only significant (p<.05) for the PWS group (PWS: TIA = 67 and IQ
= 63; EMO: TIA = 79 and IQ = 75; and Control: TIA = 109 and IQ = 108). The PWS and EMO groups
did not score significantly different from each other on the Cognitive Efficiency and Phonemic
Awareness clusters. The PWS and EMO groups scored significantly higher on their Verbal Ability,
Thinking Ability, and Phonemic Awareness cluster scores (PWS: p<.001, p<.01, and p<.001,
respectively and EMO: p<.01, p<.05, and p<.001, respectively) of the WJIII-Cog than would have been
predicted from their overall IQ.
In terms of the WJIII-TA, the PWS and EMO groups did not score significantly different from each other
on their TIA and Academic Skills cluster score. In addition, both the PWS and EMO groups scored
significantly higher on their Oral Language and Academic Skills cluster scores (PWS: p<.05 and p<.01,
respectively and EMO: p<.001 and p<.001, respectively) of the WJIII-TA than their TIA.
CONCLUSIONS: We found that individuals with PWS and EMO shared many similarities on their
cognitive abilities and achievement scores. In particular, both groups scored significantly higher on their
Phonemic Awareness cluster score compared to their IQ and on their Oral Language cluster score
compared to their TIA. Our results indicate that the PWS and EMO groups have relative strengths in
linguistic competency, listening ability, and comprehension. We are currently performing very detailed
anatomic measurements of brain morphology from head MRIs to better understand the etiology of the
strengths and weaknesses in cognition and achievement in the PWS and EMO groups with particular
attention to the auditory/speech cortex.
36
AN ETHNOGRAPHY OF RESIDENTIAL SERVICES FOR ADULTS WITH PRADERWILLI SYNDROME: THE ROLE OF THE BEHAVIOURAL PHENOTYPE IN STAFF
MEMBERS’ INTERPRETATIONS OF RESIDENTS’ BEHAVIOURS.
Rebecca Hawkins, Tony Holland, Marcus Redley.
The Learning Disabilities Research Group, Section of Developmental Psychiatry, University of
Cambridge, UK.
The behavioural phenotype associated with Prader-Willi syndrome (PWS) has been largely accepted by
those involved in the provision of services. This presentation will explore the role of the behavioural
phenotype in the care practices adopted by specialist residential homes that provide services for adults
diagnosed with PWS.
The staff members’ understanding of the behavioural phenotype, in particular the idea that the eating
behaviour and challenging behaviours are genetically determined, was central to the design of the
residential settings (e.g. locks on kitchen doors), the daily routines (e.g. strict mealtimes) and the training
provided for new support workers (e.g. teaching of restraint techniques). In this talk particular attention
will be paid to support workers’ and managers’ interpretations of residents’ behaviours and the role that
their understanding of the behavioural phenotype played in the support they offered residents. The data
discussed in this presentation is taken from a qualitative ethnographic study, which involved ten months
of observation in two specialist residential homes, interviews with staff members and residents and the
analysis of institutional documents.
The support workers and managers used the concept of the behavioural phenotype to make sense of
residents’ eating behaviour and challenging behaviours however, when used alone this interpretation was
not sufficient. They also understood these behaviours as being both learnt, from previous care placements,
and self determined. At different points in time therefore, the same behaviour could be understood as
being genetically determined, learnt and self determined. To view these apparently contradictory
interpretations as being due to support workers’ and managers’ misunderstanding of the behavioural
phenotype however, would fail to take into account the role these interpretations played in the provision
of services. The ability to make flexible interpretations of residents’ behaviours facilitated support
workers in managing residents’ dependencies and behaviours. For instance, constructing a resident’s
challenging behaviour as being self determined allowed support workers to encourage the resident to take
responsibility for their actions and lessened the need for physical restraint. Furthermore, these
interpretations enabled both support workers and managers to (re)produce care relationships between
support workers and residents. For instance, perceiving a resident’s past violent behaviour as being
genetically determined or learnt meant support workers did not blame the resident for their behaviour.
The complex and flexible constructions of residents’ behaviours made by support workers and managers
therefore enabled them to carry out subtle work that resulted in the provision of good care.
37
GROWTH HORMONE EFFECTS IN INFANTS AND TODDLERS WITH PRADERWILLI SYNDROME:
DOES EARLY INTERVENTION MAKE A DIFFERENCE?
Barbara Y. Whitman, Ph.D.1, Sue Myers, M.D.1, Aaron Carrel, MD2, David Allen, MD2
1
St. Louis University Department of Pediatrics, 2University of Wisconsin - Madison
INTRODUCTION: Infants with PWS display decreased muscle mass, hypotonia, and abnormally
increased fat mass as assessed by DEXA scan prior to excessive weight gain, or hyperphagia. Growth
hormone (GH) administration to children with PWS improves, but does not normalize, body composition,
energy expenditure, and strength and agility. This study investigates whether GH therapy in infants with
PWS can ameliorate hypotonia and prevent deterioration in body composition. We compare a subset of
these children, now treated for four years, starting in infancy, with the youngest subset of a previous study
for whom growth hormone replacement was not initiated until age four and above.
METHODS: Twenty-nine infants and toddlers with genetically confirmed PWS (ages 4-37 months) were
randomized to GH treatment (1mg/m2/day) or control (no treatment) for 1 year. During years 1-2, control
subjects were treated with GH (1.5mg/m2/day), while previously treated subjects continued on
1mg/m2/day. Sixteen of these children now between the ages of 48 to 72 months and enrolled in the study
for 4 years are compared with the youngest subset of a previous GH study. Comparisons are made
between the 4 year values of those enrolled in the infant study and the baseline values of the children
starting GH replacement between 48 and 72 months.
RESULTS: Children treated since infancy had significantly improved standardized height scores (0.96 vs
-1.2, p<.0001), had significantly better BMI’s (19.2 vs. 25, p<.005); body composition by DEXA
indicated that the early treated groups had significantly less body fat (36.0 vs. 43.5, p<.04). In addition,
the early treated group talked significantly earlier (14.5 mo vs. 21.5 mo., p<.01) and more normalized
head circumference (1.22 vs. -0.25).
DISCUSSION: This comparison of a group of children receiving GH replacement therapy from infancy
to an untreated group of approximately the same age suggests that early GH hormone therapy has a broad
ranging impact in this population beyond simply increased height. The positive changes in both body
composition and neuro-developmental areas are intriguing and deserve long term follow-up.
38
Poster Session – Medical (2ND FLOOR CORRIDOR)
1.
Andreghetto et al. (Hladnic presenting): ADULT PRADER – WILLI SYNDROME PATIENTS
THERAPEUTIC CYCLES
2.
Bianco et al.: EFFECTS ON SCOLIOSIS IN FOUR PATIENTS WITH PRADER-WILLI
SYNDROME TREATED WITH GROWTH HORMONE FOR FIVE YEARS
3.
Collin et al.,: A BOY WITH KLINEFELTER SYNDROME AND PRADER-WILLI
SYNDROME: A CLINICAL REPORT
4.
Crinò et al.: MULTIFORM HYPOGONADISM IN MALE PATIENTS WITH PRADERWILLI SYNDROME.
5.
Diene et al.: MULTIDISCIPLINARY MANAGEMENT OF CHILDREN WITH PRADERWILLI SYNDROME IN THE FRENCH DATABASE OF PWS
6.
DiGiorgio et al. (Crinò presenting): EVALUATION OF OSTEOPOROSIS IN WOMEN WITH
PRADER-WILLI SYNDROME.
7.
Dudley & Muscatelli: CROSS-CULTURAL COMPARISONS OF OBESITY AND
SPONTANEOUS GROWTH IN FRANCE, GERMANY, USA AND UK
8.
Fanari et al.: POLYSOMNOGRAPHY IN ADULT INDIVIDUALS WITH PRADER-WILLI
SYNDROME TREATED WITH GH
9.
Herzovich et al. (Vaiani presenting): CENTRAL HYPOTHYROIDISM (CH) IN PATIENTS
WITH PRADER WILLI SYNDROME DURING THE FIRST 2 YEARS OF POSTNATAL LIFE
10.
Holland et al.: THE EUROPEAN PRADER WILLI SYNDROME CLINICAL RESEARCH
DATABASE
11.
Kodra et al. (Taruscio presenting): ASSESSMENT OF ACCESSIBILITY TO AND QUALITY
OF HEALTH AND SOCIAL SERVICES FOR PATIENTS WITH PRADER WILLI SYNDROME IN
ITALY AND ROMANIA
12.
Loughnan et al.: HORMONE REPLACEMENT IN ADOLESCENTS AND ADULTS
WITH PRADER-WILLI SYNDROME
13.
Murakami et al.: GROWTH HORMONE EFFECT ON MUSCLE VOLUME AND SCOLIOSIS
IN PRADER-WILLI SYNDROME
14.
Popa et al.: SOMATIC AND BEHAVIORAL DIFFERENCES IN CHILDREN WITH PRADERWILLI SYNDROME
15.
Priano et al.: PAIN THRESHOLD IMPAIRMENT IN PRADER WILLI SYNDROME:
A NEUROPHYSIOLOGICAL STUDY
16.
Schulze et al.: GASTRIC NECROSIS IS ASSOCIATED WITH NORMAL BMI IN PRADERWILLI SYNDROME
17.
Sinnema et al. (Curfs presenting): AGEING IN PEOPLE WITH PRADER WILLI SYNDROME
(PWS)
39
18.
Skrypnyk et al.: IMPORTANCE OF THE MINOR CRITERIA FOR A POSITIVE CLINICAL
DIAGNOSIS OF PRADER WILLI SYNDROME PATIENTS
19.
Tsuchiya et al.: BENEFICIAL EFFECT OF EARLY USE OF GROWTH HORMONE IN
PATIENTS WITH PRADER-WILLI SYNDROME
20.
Varlan et al.: NURSING OF ADULT PATIENTS WITH PRADER-WILLI SYNDROME
21.
Vismara et al. (Grugni presenting): GAIT ANALYSIS IN ADULT PATIENTS WITH PRADERWILLI SYNDROME: A CROSS-SECTIONAL COMPARATIVE STUDY
22.
Whitman: SEXUAL BEHAVIOR IN ADOLESCENTS AND ADULTS WITH
PRADER-WILLI SYNDROME
23.
Zandona et al. (Hladnic presenting): DNA EXTRACTION FROM DRIED BLOOD SPOTS
AND METHYLATION TEST FOR DIAGNOSIS OF PRADER-WILLI SYNDROME PATIENTS
40
ADULT PRADER-WILLI SYNDROME PATIENTS THERAPEUTIC CYCLES
G. Andrighetto, P. Parmigiani, U. Hladnik
Baschirotto Institute for Rare Diseases Foundation onlus, Costozza di Longare, Vicenza, Italy
Prader-Willi syndrome (PWS) is a complex genetic disease that arises from lack of expression of
paternally inherited imprinting controlled genes on chromosome 15q11-q13. The frequency is between
1/10000 and 1/30000. Life expectancy of the patients is getting longer and nowadays it is common to see
patients with PWS above the 5th decade.
The B.I.R.D. Foundation is committed to offer clinical and molecular diagnosis, genetic counselling and
guidelines to parents with affected children but also several therapeutic cycles for adults with PWS.
The major concerns with the PWS adults are obesity and behavior. Growth hormone therapy is helping
PWS patients develop a better muscular tonicity and achieve a taller stature but hyperphagia is constantly
present.
4 - 6 therapeutic cycles for 2 - 4 weeks are organized for adults with PWS every year. During these cycles
a team of specialists helps the PWS patients reduce their body weight. Knowing the complexity of the
psychological effect of their condition on most of the PWS patients the cycle is structured in a way to
resemble a gathering of friends that share the same problem. The basis of these cycles is the occupational
therapy and the daily activities of the participants are structured in order to be as entertaining as possible
to help them distract from food. There are 5 hypocaloric meals a day on a strictly fixed timetable as we
know that being able to plan their daily meals helps PWS patients control their hunger. Among the
activities are various sports, music, drawing, trips to nearby locations, social games. During the stay the
participants live inside the structures of the foundation and are always watched over by the staff. A strict
control is needed to help them follow the dietary rules. The patients’ health is constantly controlled by
medical specialists and a complete clinical evaluation is made before and after the therapeutic cycle.
The B.I.R.D. Foundation has done 21 cycles since 2002 with this multispecialist approach of medical
doctors, nurses, psychologists, educators as well as students and volunteers. On average the participants
lose between 6 to 9 kg of body weight and consider their stay as a pleasant one.
The importance of these cycles is to help the PWS patients reduce their body weight, socialise with other
PWS patients and, not last, to offer some relief to the families.
41
EFFECTS ON SCOLIOSIS IN FOUR PATIENTS WITH PRADER-WILLI SYNDROME
TREATED WITH GROWTH HORMONE FOR FIVE YEARS
M. Bianco, L. Ragusa, F. La Barbera, I. Cardillo, D.Greco, F. Calì*, P.Bosco*, P. Occhipinti,
F.Scannella, A. Costanzo, S. Buono, C. Romano
Dept. For Mental Retardation, *Dept. of Laboratories, Oasi Institute (I.R.C.C.S.), Via Conte Ruggero, 7394018 Troina (EN)-ITALY
INTRODUCTION: Prader-Willi Syndrome (PWS) is a genetic disease with an average incidence rate of
1/25.000, which is due to a common genetic defect that abolishes the expression of imprinted paternal
genes in the 15q11-q13 chromosomal region. It is characterized by severe hypotonia, obesity, short
stature, small hands and feet, hypogonadism, and feeding disorders.
The objective of our study is to examine orthopedic aspects of PWS, as well as to evaluate how
growth hormone (GH) intake might affect the trend of scoliotic bend.
METHODS: We examined 14 PWS patients (9 females and 5 males), aged 2 to 23 years, diagnosed with
a methylation test and FISH. All patients received the Adam’s Forward Bend Test. The amplitude of the
scoliosis curvature was evaluated using the Cobb’s method and MEHTA index, and the degree of skeletal
maturity using Risser’s index.
RESULTS: Only 71.43% (namely, 10) out of the above-mentioned sample presented with primary
idiopathic scoliosis and no other orthopaedic complication. Over a period of 5 years, the characteristics of
scoliosis in GH off-treatment PWS patients remained stable, as evaluated with Cobbs method and
MEHTA index.
DISCUSSION: The scoliosis in PWS patients overlaps with the clinical features encountered in
idiopathic scoliosis. It is present from an early age and remains stable during childood, but progresses in
15 to 20% of cases during adolescence. GH treatment in PWS normalizes height and increases lean body
mass, which is beneficial to weight management. In our sample there was no significant difference in
scoliosis progression and spine curve measurements with Cobbs angle method and MEHTA index during
the GH treatment.
42
A BOY WITH KLINEFELTER SYNDROME AND PRADER-WILLI SYNDROME: A
CLINICAL REPORT.
Philippe J.L. Collin, M.D. 1,2, Harm Boer, M.D., Ph.D. 3, Annick Vogels, M.D., Ph.D. 4, Leopold M.G.
Curfs, Ph.D. 2,5
1
2
3
4
5
Department of Child and Adolescent Psychiatry, Koraal Groep, Sittard, The Netherlands.
The Research Institute Growth & Development (GROW) Maastricht University, The Netherlands.
The Janet Shaw Clinic, Brooklands, Birmingham, United Kingdom.
Department of Clinical Genetics of the Catholic University of Louvain, Belgium.
Department of Clinical Genetics, Academic Hospital Maastricht, The Netherlands.
INTRODUCTION: A number of X and Y chromosome abnormalities have been reported in children
with Prader-Willi syndrome (PWS). This report describes a 16-year-old boy with 47, XXY, UPD 15,
karyotype and a Prader-Willi syndrome (PWS) phenotype. He was admitted to the outpatient service of
our multidisciplinary clinic for children with mental retardation and psychiatric and behavioural problems
with worsening behavioural problems. We compared the phenotype of our patient to that of other patients
in the literature for whom detailed phenotypic information was available and against the clinical criteria
for PWS and Klinefelter syndrome (KS).
METHODS: In this descriptive and mainly retrospective case study, we describe a 16-year-old boy with
Klinefelter syndrome and Prader-Willi syndrome. The patient underwent psychiatric assessment by a
psychiatrist who was skilled in assessment of children with intellectual disabilities. Symptomatology was
collected on basis of clinical interview, clinical observation, family and carer informants, medical records
and psychiatric reports.
RESULTS: This boy was born after 36 weeks gestation. Klinefelter syndrome was diagnosed on prenatal
amniocentesis. As an infant, he was hypotonic and demonstrated a poor suck. He had delayed milestones.
By parental report, he had a history of eating behaviors typical for PWS. He had been diagnosed as
suffering from Prader-Willi syndrome at the age of three years and genetic studies confirmed a maternal
uniparental disomy. At 13 years, there were behavioral problems, with episodes of temper tantrums,
obsessions and compulsions. A variety of behavioural disturbances that have been reported (stubbornness,
temper-tantrums, skin picking, obsessive-compulsive behaviour and internalising emotional problems),
conformed to the criteria of the behavioural phenotype of PWS.
DISCUSSION: We reported a patient with PWS and KS and describe the difficulties with the clinical
diagnosis of these conditions when they coexist. For the clinical point of view, the affected individual is
expected to have a PWS phenotype. The chromosome X and 15 events commonly occur in different
parents and pre- and post-conception, thus the mechanism are likely distinct and coincidental. These two
conditions would be expected to occur together, by chance alone, in 1 in 20 million live births. While
some speculate the frequency of these reports alone suggests that the events are not coincidental, we are
hesitant to attribute this specific combination to a concordant etiology. On the other hand, most of those
cases include non-disjunction events that are associated with advanced maternal age; thus it may not be
unexpected to see the concordance of UPD 15 with sex chromosome aneusomy.
43
MULTIFORM HYPOGONADISM IN MALE PATIENTS WITH PRADER-WILLI
SYNDROME.
Antonino Crinò¹, Girolamo Di Giorgio¹, Graziano Grugni², Emanuela De Marco³, Emanuela Cama³,
Antonella Anzuini³, Sabrina Spera¹, Gaetano Carducci1, Guido Castelli Gattinara¹, Andrea Lenzi³,
Antonio Francesco Radicioni³
¹Paediatric and Autoimmune Endocrine Diseases Unit, Bambino Gesù Hospital, Research Institute,
Palidoro (Rome); ²Italian Auxological Institute Foundation, Piancavallo (Verbania); ³Department of
Medical Pathophysiology, Sapienza University of Rome - ITALY
INTRODUCTION: Hypogonadism leading to hypogenitalism and early pubertal arrest is a main feature
of PWS and is generally attributed to hypothalamic dysfunction, but data are not univocal. The aim of this
study is to investigate the cause of the hypothalamic-pituitary-gonadal axis dysfunction in male subjects
with PWS.
METHODS: We studied 36 patients with genetically confirmed diagnosis age from 1.2-42.7 yrs
(median:16.6 yrs). All subjects had history of cryptorchidism and have spontaneously started their
pubertal development, but they had an arrest of gonadal development at a maximum pubertal stage of G3.
Basal gonadotropin (FSH, LH), testosterone (T) and Inhibin B (InhB) levels were measured. 150 normal
subjects, divided in pre-pubertal (50 pts, age: 0.8-10.5 yrs, pubertal stage: G1) and pubertal (100 pts, age:
9.7-17.8 yrs, pubertal stage: G2-G5) were used as a control group.
RESULTS: The 4 different patterns of gonadotropins levels by pubertal stage are shown in the table:
G1 (n = 13)
G2 (n=14)
G3 (n=9)
Age 1.2-32.3
Age 9.6-42.7
Age 15.3-33.3
normal FSH and LH
23 % (n=3)
7 % (n=1)
22 % (n=2)
high FSH - normal LH
46 % (n=6)
72 % (n=10)
56 % (n=5)
low FSH and LH
23 % (n=3)
7 % (n=1)
11 % (n=1)
normal FSH - low LH
8 % (n=1)
14 % (n=2)
11 % (n=1)
T levels (range: 0.13-6.9 ng/ml) were below the normal range for age and pubertal stage in 27/36 (75%)
patients and normal in 9/36 (25%). Serum InhB was undetectable in 14/36 (39%) patients. In pre-pubertal
group (G1) InhB was undetectable in 4/13 patients (31%), low in 9/13 (69%, range 18.5-56.4 pg/ml)
compared to pre-pubertal control group (InhB levels: 56.5-145.8 pg/mL). In pubertal group (G2-G3) (23
pts, age: 9.6-42.7) InhB was undetectable in 10/23 patients (43%), low in 12/23 (53%, range 5.2-64.3
pg/ml) and normal in 1/23 patients (4%,104 pg/ml) compared to pubertal control group (InhB levels:
68.6-322.7 pg/mL). In the subgroup of patients with high FSH (n=21), the linear correlation analysis
showed an inverse relation between InhB and both FSH (r =-0.4652, r²=0.22, p=0.0388) and age (r =0.5503, r²=0.3029, p=0.0119), while FSH correlated positively with age (r=0.6431, r²= 0.4136, p=0.0022)
independently to pubertal stage.
DISCUSSION: Low InhB with high FSH levels suggest a damage of Sertoli cells displaying a
hypergonadotropic hypogonadism that seems to be already present in early childhood (46% of pts with
high FSH in G1 were aged 1.2-9.4 yrs) and that become more evident in older age. On the other hand we
noticed that 18/27 (66%) pts with normal LH levels had low T levels. This suggests both a hypothalamic
and Leydig cells damage displaying a combined hypogonadism pattern. In conclusion, our results confirm
that PWS male patients have a multiform hypogonadism that could be of central, peripheral or combined
origin detectable already in early age.
44
MULTIDISCIPLINARY MANAGEMENT OF CHILDREN WITH PRADER-WILLI
SYNDROME IN THE FRENCH DATABASE OF PWS
G Diene1, S Caula1, C Molinas1, L Cazals1, M Glattard1, P. Barat2, S Boulard2, M. Colle2, F. Dallavalle3,
P. Garnier4, C. Jeandel3, M. Jésuran-Pérelroizen5, A. Lienhardt6, JC. Mas7, A. Moncla8, M. Nicolino9, O.
Puel2, G. Simonin8, MA Voelckel8, K. Wagner7, M Tauber1
1
CHU Toulouse 2CHU Bordeaux 3CHU Montpellier 4CHU Grenoble 5Toulouse 6CHU Limoges 7CHU
Nice 8CHU Marseille 9CHU Lyon FRANCE
INTRODUCTION: The reference centre for Prader-Willi syndrome, set-up by the health ministry in
November 2004, involves 6 regions of the South of France with a coordination team in Toulouse. One of
the objectives of the centre is to set-up a database starting with children and adolescents containing
medical and psychosocial data. This database is partially supported by Pfizer Inc.
METHODS: One hundred and forty eight children (81 male, 67 female) were included in the database
with a median chronological age at inclusion of 7.3 years [0.21-23.25]. Median age at diagnosis was 3
months [0.1-144] with 64% deletion and 24% uniparental disomy. The objective of the study was to
evaluate the multidisciplinary management of these patients (nutritional management, physiotherapy,
psychomotricity, speech and language management) at different ages (younger than 6 years, between 6
and 12 years and older than 12 years). Data were collected at the entry in the database and yearly. We
only present baseline data. Case report forms were filled by the paediatric endocrinologists and sent to our
centre, which enters the data. The questions asked were if there was an active therapy or if the therapy
was stopped or never proposed.
RESULTS:
Nutritional management
by a dietician (N=137)
Yes, active
Yes, stopped
No, never proposed
Physiotherapy (N=137)
Yes, active
Yes, stopped
No, never proposed
Psychomotricity (N=135)
Yes, active
Yes, stopped
No, never proposed
Speech and language
management (N=139)
Yes, active
Yes, stopped
No, never proposed
All
< 6 years
> 6 and <12 years
> 12 years
66.4%
6.6%
27%
78.6%
1.8%
19.6%
62.2%
6.7%
31.1%
52.8%
13.9%
33.3%
52.5%
38.7%
8.8%
64.3%
30.3%
5.4%
44.4%
44.4%
11.2%
44.4%
44.4%
11.2%
52.6%
23%
24.4%
65.5%
3.6%
30.9%
59%
25%
16%
25%
50%
25%
82.1%
0%
17.9%
88.9%
8.9%
2.2%
50%
42.1%
7.9%
75.5%
14.4%
10.1%
CONCLUSION: to our surprise, 27% of the patients did not have nutritional management by a dietician
and 10% did not undergo speech and language therapy. More detailed analyses of these data are in
progress. We could use this database to understand the difficulties of multidisciplinary management and
to optimize it.
45
EVALUATION OF OSTEOPOROSIS IN WOMEN WITH PRADER-WILLI
SYNDROME
Girolamo Di Giorgio¹, Graziano Grugni², Maria Grazia Ubertini³, Rossana Fiori³, Sabrina Spera¹, Marco
Cappa³, Guido Castelli Gattinara¹, Antonino Crinò¹
¹Paediatric and Autoimmune Endocrine Diseases Unit, Bambino Gesù Hospital, Research Institute,
Palidoro (Rome); ²Italian Auxological Institute Foundation, Piancavallo (Verbania); ³Endocrinology Unit,
Bambino Gesù Hospital, Research Institute, Palidoro (Rome) - ITALY
INTRODUCTION: In Prader-Willi Syndrome (PWS) hypothalamic dysfunction is the cause of some
clinical findings like growth hormone deficiency (GHD), hypogonadism. Both hypogonadism and GHD
lead to an alteration of body composition with increased fat mass, reduction of lean mass and increased
risk of osteoporosis. The aim of this study is to investigate the presence of osteoporosis in PWS women.
PATIENTS and METHODS: We studied 15 women, age 26.49±4.47 (range 20-35 yrs), BMI 51.67±13
kg/m² (range 30.8-71.4) with genetically confirmed PWS. A deletion of chromosome 15q (FISH) was
found in 9/15 (60%). Nine pts had primary amenorrhea (group A) and 6 were menstruated (group B).
Seven patients were treated with GH during childhood, 4/9 (44%) in group A and 3/5 (60%) in group B.
None had history of treatment with estrogens or other therapy that could affect bone metabolism. Dual
Energy X-ray Absorptiometry (DXA) (Hologic Delphi 70400) was performed in all patients and bone
mineral density (BMD) of lumbar spine (expressed also as T score and Z score), Fat %, Fat mass (kg),
Lean mass (kg) were calculated. Basal FSH, LH and 17β-estradiol were measured. Data are expressed as
mean±SEM.
RESULTS: Basal LH (0.72±0.21UI/L) and FSH (2.22±0.56 UI/L) revealed a hypogonadotropic
hypogonadism in all patients. In group A BMD of lumbar spine was 0.86±0.04 g/cm², T score -1.69±0.32,
Z score -1.62±0.31, fat % 50.5±1.2, fat mass 62.6±7.9 kg, lean mass 52.3±3.4 kg. Two patients out of 9
(22%) had osteoporosis (T and Z score<-2.5 SD); 5/9 patients (56%) had osteopenia (T and Z score <-1
and >-2.5 SD), 2/9 patients (22%) had normal BMD. In group B BMD of lumbar spine was 0.90±0.06
g/cm², T score -1.3±0.5, Z score -1.2±0.5, fat % 48.5±1.1, fat mass 53.3±6.5 kg, lean mass 54±5.2 kg.
One patient out of 6 (16%) had osteoporosis, 3/6 patients (50%) had osteopenia, 2/6 patients (34%) had
normal BMD. No significant difference was found between group A and B in BMD, fat %, fat mass, lean
mass, BMI, age and gonadotropin levels. Meanwhile group B showed higher 17β-estradiol levels than
group A (63.37±11.65 vs 29.16±5.3, p=0.0128). The linear regression analysis showed a significant
positive correlation between 17β-estradiol levels and BMD in group A (r²=0.531, r=0.729, p=0.0402). No
significant correlation was found in group B. Furthermore, in both groups BMD was similar in GH
treated subjects in comparison to patients without GH therapy.
CONCLUSION: In our study a high prevalence of osteoporosis (22 % in amenorrheic and 16% in
women with menses) and osteopenia (56% and 50% respectively) was found independently from the
presence or absence of menses. Furthermore, BMD doesn’t seem to be preserved by GH therapy.
However, wider studies on amenorrheic and/or menstruated PWS woman as well as a comparison with a
group of amenorrheic PWS treated with oestrogen are needed.
46
CROSS-CULTURAL COMPARISONS OF OBESITY AND SPONTANEOUS GROWTH
IN FRANCE, GERMANY, USA, AND UK
Oenone Dudley, Dip Clin Psych1, Françoise Muscatelli, PhD2
1,2
Institut de biologie développementale moléculaire de Luminy (IBDML), Marseille, France
INTRODUCTION: Prader-Willi syndrome (PWS) is a complex disorder with phenotypic variability.
Obesity, however, is a universal feature of the syndrome. Certain variations between countries have been
reported regarding the evolution of height and weight in PWS which have been attributed by some
authors to cultural differences in the host populations, and by others to clinical management resulting
from early diagnosis. We present here the first standardized growth curves for French children with the
syndrome up to the age of 20 years and we compare the evolution of obesity in this French population
against children with the syndrome living in the USA, the UK and Germany.
METHODS: A nationwide French cohort study using a combined cross-sectional longitudinal design of
158 children and adults with PWS excluding data post GHT (growth hormone therapy). Data from health
records were collected for weight and height for each individual at 6 months, 12 months, 18 months, 2
years, 5 years, 10 years, 15 years, 20 years and currently.
RESULTS: A significantly higher rate of adult obesity is found in the French male Prader-Willi
population compared to the USA (χ² = 4.06, P = 0.04) and the UK (χ² = 3.83, P = 0.05). Similar trends are
observed for females but these fail to reach significance. This is in contrast to non PWS population trends
in France, and is not apparent in the French children with PWS, who are lighter and taller than their
American counterparts. Compared to the German population of children with PWS, weight evolution is
similar for French and German boys with PWS up to the age of 15 years, but French males with PWS are
heavier than German males with PWS at 20 years. Height, on the other hand, is similar. For females,
French girls are lighter than German girls, but height is similar. The progression of obesity in French
children with PWS who are currently under 15 years is slower than those currently 15 years and over.
Age of diagnosis is significantly positively correlated with body mass index at 2, 5 and 10 years (r = 0.33,
P = < 0.001; r = 0.28, P = 0.003; r = 0.3, P = 0.01 respectively). No genetic subtype differences for
obesity were found between mUPD and DEL.
DISCUSSION: Generational differences in levels of obesity and the positive correlation between age of
diagnosis and BMI suggest that early diagnosis has a significant impact on obesity management in PWS,
regardless of growth hormone therapy, as suggested by Vogels (2004). This is particularly important in
view of the fact that at the present time there is no medical treatment for obesity in Prader-Willi
syndrome. This may also suggest potential benefit of early (preschool) dietary intervention programmes
to tackle the obesity epidemic in the non PWS population.
Acknowledgements:
UK data supplied by Joyce Whittington, Dept Developmental Psychiatry, Cambridge, UK
US data supplied by Barbara McManus, PWSAUSA, USA
47
POLYSOMNOGRAPHY IN ADULT INDIVIDUALS WITH PRADER-WILLI
SYNDROME TREATED WITH GH
Paolo Fanari, MD1, Graziano Grugni, MD2, Lorenzo Priano, MD3, Emanuela Giacomotti, MD1; Franco
Codecasa MD1, Alberto Salvadori, MD1.
1
Department of Pulmonary Rehabilitation; 2Department of Neurology; 3Department of Auxology, IRCCS
Istituto Auxologico Italiano, Piancavallo (VB), Italy.
INTRODUCTION: Patients with Prader-Willi Syndrome (PWS) are at risk of a variety of abnormalities
of breathing during sleep, such as obstructive and central sleep apnea (OSAS) and abnormal ventilatory
responses to hypoxia and hypercapnia. A respiratory dysfunction sometimes concomitant with the
treatment with GH has been reported as a possible cause of sudden unexpected death in PWS young
subjects. We studied a group of adult PWS subjects who performed repeated complete sleep studies
during GH treatment (IGF-1 basal value mcg/l: 94 ± 13 and 305 ± 39 p< 0.0001 and 328 ± 32 p< 0.0001
after 6 and 12 months respectively).
METHODS: 13 PWS patients, 11 del15 and 2 UPD, 6 females and 7 males, aged 26.9 ±1.2 years, treated
with hormonal replacement (mean dosage 0.064 ± 0.004 mcg/kg/week) were recruited for the study. All
patients underwent an adaptation night and then a full-night polysomnography (PSG). Parameter
registered were EEG EOG; ECG; respiratory effort by thoracic and abdominal strain gauges, nasal airflow, snoring nose, oxyhaemoglobin (SaO2) using a pulse oximeter with finger probe; Macrostructure of
sleep analysis (Sleep Stages) according to Rechtschaffen and Kales’ criteria was performed. Respiratory
parameters included: apnea/hypopnea index (AHI), basal oxygen saturation (basal SaO2), lowest oxygen
saturation (lowest SaO2), time % spent at oxygen saturation below 90%, average minimum SaO2 during
desaturations. The sleep studies were performed before hormonal treatment and after 6 months and 1 year
of treatment.
RESULTS: 4 subjects (2f/2m) resulted positive for OSAS at the basal polysomnography and the two
males were treated with CPAP. BMI was unchanged after 6 months and 1 year (basal: 46.3 and 46.4 and
45.8 after 6 and 12 months respectively). AHI was unchanged in 11/12 subjects after 6 and 12 months
(basal 7.03, 6 months 7.06 and 12 months 6.7), increased in one subject after 12 months (1.9 Æ 17.65
p<0.001). Average minimum SaO2 during desaturations remained unchanged. On the contrary, lowest
SaO2 progressively lowered (76.8% Æ 68.3%, p < 0.05) and the time % spent at oxygen saturation below
90% increased after 12 months (24.7 Æ 35.6, p < 0.05).
CONCLUSIONS: A one year’s GH treatment does not seem to be associated with a worsening of AHI in
adult PWS subjects. Furthers observations may be suitable to confirm the registered SaO2 alterations. Our
data suggest the opportunity of periodical saturimetric nocturnal respiratory controls both in PDW OSAS
and non OSAS adult subjects.
48
CENTRAL HYPOTHYROIDISM (CH) IN PATIENTS WITH PRADER WILLI
SYNDROME DURING THE FIRST 2 YEARS OF POSTNATAL LIFE
Herzovich V(1), Vaiani E(1), Chertkoff (2), Iorcansky S(1), Chaler E(1), Belgorosky A(1), Torrado M(2)
.
(1)Department of Endocrinology and (2) Department of Genetic of Hospital de Pediatria Prof Dr.J.P.
Garrahan .Buenos Aires .Argentina
INTRODUCTION: Prader Willi syndrome (PWS) is a genetic disorder with a well characterized
phenotype, mostly related to hypothalamic dysfunction. Features during the first 2 years (y) of life are a
moderate intra-uterine and post-natal growth delay, general muscular hypotonia, feeding difficulties, and
delayed psychomotor development. Endocrine disorders such as growth hormone deficiency and
hypogonadism have been described. However, in infant affected patients, thyroid function has not been
well studied. The aim of this study was to analyze hypothalamo-pituitary-thyroid function during the first
2 years of life in PWS patients.
METHODS AND DESIGN: 11 patients (9 males, 2 females) with fulfilled clinical criteria for PWS
diagnosis and confirmed molecular analysis were included. Birth weight (BW) and TSH neonatal
screening (NS) was evaluated. At PWS diagnosis, auxological parameters, bone age (BA), basal serum
thyroid stimulating hormone (TSH), total(t) thyroxine (T4) and free(f) T4 levels were determined. Mean
(±SD) hormone values were compared with age-and gender- matched healthy control subjects.
RESULTS: 10/11 had normal BW for gestational age .TSH NS was normal in 11/11. At PWS diagnosis,
all patients had adequate weight for height. Mean chronological age (CA): 0.66 ±0.51y(range 0.08-1.56
y), mean BA delayed (5/11) CA-BA: 0.52 ±0.3y, mean height SDS: –1.62 ±1.11 were found. TSH levels
were within normal range: 2.39± 1.6 µg UI/ml. tT4: 7.23 ±1.15 µg/ml and fT4: 0.72 ±0.08 ng /dl were
significantly lower than age match control and below the lower limit of 95 % confidence interval of the
normal population reference.
We CONCLUDE that central hypothyroidism is a common feature in PWS patients during infancy.
TSH NS alone is not an accurate tool to be applied in PWS. Pediatricians should be aware of the need to
evaluate central hypothyroidism in PWS in this critical period of thyroid action on neurological
development. In the presence of CH we might propose that early thyroxine replacement therapy could
improve severe early features and morbidity.
49
THE EUROPEAN PRADER WILLI SYNDROME CLINICAL RESEARCH DATABASE
Tony Holland1, Olivier Cohen2; Michael Boasis2, Leopold Curfs3, Oenone Dudley4, Bernhard
Horsthemke5, Ann-Christin Lindgren6, Christel Nourissier4; Annick Vogels7, and Joyce Whittington1,
1
Cambridge University, Cambridge, UK; 2HC Forum, Grenoble, France; 3University Maastricht,
Maastricht, the Netherlands; 4French PWSA and CNRS, Marseille, France; 5Institut fur Humangenetik,
Essen, Germany; 6Karolinska Institute, Stockholm, Sweden; 7University of Leuven, Leuven, Belgium.
INTRODUCTION: PWS is a rare disorder and for this reason clinical research that aims to investigate
influences on development over the lifespan can be limited by the inability to recruit sufficient people
with PWS of different ages, genetic sub-types and of both genders in any one country. Similarly studies in
any one country alone do not readily allow the effects of different cultural influences, social policies
and/or clinical practices to be investigated.
METHODS: a combined clinical and basic science PWS research consortium has been established
funded under the EU 6th Framework. Clinical researchers and computer scientists have been developing
an internet-based secure PWS research database. The structure and content of the database was informed
by existing research databases and developed and refined by an interdisciplinary group all involved in
clinical PWS research and practice. The prime aim was to enable the structured collection of clinical data
in different countries in a secure and confidential manner compatible with EU law. The data can be
analysed by the individual countries and also combined in a manner that protects confidentiality but also
enables larger studies between countries.
RESULTS: the database is divided into six ‘index sections’ under the following headings: 1)
Demographic, diagnostic, early development; 2) Context (living circumstances etc); 3) Physical health; 4)
Mental health and behaviour; 5) Cognition and function; 6) Investigations and treatments. These sections
are further sub-divided into panels, sub-panels and fields. Data on health is structured around the different
organ systems of the body.
DISCUSSION: data is collected and stored in different ways using varied interview schedules and
structured assessments both within and between individual countries. The use of similar assessments in
different languages raises concerns about compatibility, reliability and validity. Different disciplines have
different priorities and there is a tension as to whether the database is primarily for clinical practice or
research. These issues have had to be considered and compromises made.
50
ASSESSMENT OF ACCESSIBILITY TO AND QUALITY OF HEALTH AND SOCIAL
SERVICES FOR PATIENTS WITH PRADER WILLI SYNDROME IN ITALY AND
ROMANIA
Kodra Y1, Trama A1, Dan D2, Ricci MA3, Taruscio D1
1National Centre Rare Diseases, Istituto Superiore di Sanità, Rome, Italy; 2Romanian Prader Willi
Association. Romania; 3Federazione delle Associazioni Italiane per l'aiuto ai soggetti con sindrome
Prader Willi. Italy.
INTRODUCTION: People suffering from rare diseases often experience the same problems: failure or
delay in diagnosis, scarcity of health information, lack of referral to specialized professionals, lack of
support for integration into work. Within the NEPHIRD project (Network of Public Health Institutions on
Rare Diseases in Europe), a pilot study was carried out to assess accessibility to and quality of health and
social services in patients affected by Prader Willi Syndrome (PWS) in Italy and Romania.
METHODOLOGY: The survey was carried out in Italy and in Romania in collaboration with PWS
patients’ associations: 1) La Federazione delle Associazioni Italiane per l'aiuto ai soggetti con sindrome
Prader Willi (Federation of Italian Prader Willi Associations), Italy and Romanian Prader Willi
Association, Romania. The questionnaire asks how often patients or caregivers had both negative and
positive experiences about the quality of and the accessibility to health and social services on a 5-level
scales.
RESULTS: In total 66 questionnaires for PWS were filled in (30 in Italy, 36 in Romania). In Romania,
the most negative opinions expressed by the patients were on the following topics: integration of services
(65%); diagnostic examination (36%); drug therapies (31%); or rehabilitation (21%). In Italy the major
complains follow: vocational training (82%); information about the diseases (68%); information on laws
and rights (66%).
CONCLUSIONS: Romanian patients placed access to and quality of health care at the top of their list of
what makes them dissatisfied, probably due to the difficulty in diagnosing PWS. Italian patients had
negative opinions on information and social care. Further studies are needed to better explore and
understand such a difference.
51
HORMONE REPLACEMENT IN ADOLESCENTS AND ADULTS
WITH PRADER-WILLI SYNDROME
Georgina Loughnan1, Janet Franklin1, Kate Steinbeck, MD1
1
Metabolism & Obesity Services, Endocrinology Department, Royal Prince Alfred Hospital,
Camperdown, NSW, Australia.
INTRODUCTION: Hypogonadism is present almost universally in males with Prader-Willi syndrome
(PWS) and in the majority of females. Anecdotally testosterone replacement in males and oestrogen
replacement in females are under-prescribed due to the concerns about behavioural change and
interactions with other co-morbidities. Hormone replacement therapy (HRT) has a positive effect on bone
mineral density (BMD), may be cardio-protective and may produce a physical appearance closer to peers.
The lowered BMD seen in males and females with PWS demands attention, due to increasing longevity
and fracture risk in this population.
AIMS & METHODS: The PWS clinic for adolescents and adults, at a major public teaching hospital in
Sydney, Australia, has enrolled 64 clients over the past 16 years. Thirty eight people attend regularly,
from within and outside the metropolitan area. The aim of this retrospective study was to look at
endocrine function, BMD and HRT use in this clinical cohort and compare the difference between those
on and those not on HRT and the reasons behind decisions regarding the use of HRT.
RESULTS & DISCUSSION: Fifteen clients, 8 male, 5 female receive HRT and have had BMD studies.
The genotype split is 10 with deletion and 4 with UPD, and 1 non-deleted. Mean age of the treated cohort
at their first BMD was 21 years and baseline BMD T scores range from -0.8 to
- 3.0 standard deviations. There was no difference in age at baseline between the treated group and non
treatment group of 12 clients (6 male, 6 female), with similar baseline data available. The T scores for the
non treated group ranged from 0.9 to -3.8 standard deviations. Baseline testosterone and oestrogen levels
for both groups were in the hypogonadal range.
Clinically significant improvements in spinal BMD were seen in all but 2 of the HRT patients after
treatment but clinically significant improvements in hip BMD were only seen in 3 HRT clients.
One client has demonstrated adverse affects to testosterone after 2 separate attempts to treat, each
resulting in cessation of treatment. HRT treatment schedules appear to be influenced by attendance rates,
parent and carer attitudes and the geographical distance from our service. Regular adult clinical care of
patients with PWS is continually encouraged to ensure consistent use of HRT and prolonged
improvement in BMD.
52
GROWTH HORMONE EFFECT ON MUSCLE VOLUME AND SCOLIOSIS IN
PRADER-WILLI SYNDROME
Nobuyuki Murakami, MD,PhD, Kazuo Obata, MD,PhD, Yoshitaka Tsuchiya, MD,
Yuriko Tanaka, MD, Yuzo Tomita, MD, Ryoichi Sakuta, MD,PhD, Toshiro Nagai, MD,PhD
Department of pediatrics, Dokkyo Medical University, Koshigaya Hospital, Saitama, Japan.
INTRODUCTION: Decreased muscle volume and hypotonia are the crucial findings in Prader-Willi
syndrome (PWS). Growth hormone (GH) has been anecdotally known to increase muscle strength.
However there are no published data showing the increased muscle volume by GH therapy. To evaluate
the effect of GH therapy, we examined the increase in muscle volume and whether there is any
relationship between the increase in muscle volume and scoliosis.
SUBJECTS & METHODS: Twelve patients (5 males and 7 females, age from to 15 y/o. deletion 8 and
UPD 4) were evaluated. Durations of this study on muscle volume using CT were from 6 mo to 36 mo,
mean 21 mo. One slice of the CT scan was taken at navel level every 6 months during GH therapy.
Cross-sectional areas of paravertebral muscles were measured. Cobb angles were measured
simultaneously. 4 patients had scoliosis during the evaluation. Scoliosis improved in 2 patients (Cobb
angle: 25°to <10°, 40°to 28°) and progressed in 2 patients (Cobb angle: 20°to 42°, <10°to 23°) during the
evaluation.
RESULTS: Muscle volume increased by means of 26.4 %/year (from 5.4 %/year to 61.3 %/year) during
GH therapy. In patients with improved scoliosis, muscle volumes increased as well (58.4 %/year and
31.7 %/year). Muscle volumes increased poorly in patients with progressed scoliosis (14.5 %/year and
5.4 %/year).
DISCUSSION: Scoliosis is one of the problems when GH therapy is applied to patients with PWS
because GH therapy has been considered to develop or progress scoliosis. Muscle weakness and
hypotonia of the trunk are thought to be factors resulting in developing or progressing scoliosis in PWS.
Muscle volume increased more in patients with improved scoliosis than in those with progressed
scoliosis. Therefore the improvement of muscle volume and hypotonia could prevent the development or
progression of scoliosis in PWS.
53
SOMATIC AND BEHAVIORAL DIFFERENCES IN CHILDREN WITH PRADERWILLI SYNDROME
Lenuta Popa MD, PhD1, Octavia Costin PhD1., Cristea Alexandru MD, PhD2, Popa Virgil 3
1
Department of Pediatrics, University Iuliu Hatieganu Cluj – Napoca, Romania
Department of Pediatric Neurology, University Iuliu Hatieganu Cluj – Napoca, Romania
3
Biochemical Laboratory, Children’s Emergency Hospital Cluj – Napoca, Romania
2
INTRODUCTION: Phenotypic differences among patients with Prader–Willi syndrome are based on
their genetic background. These differences may be somatic or behavioral and may have important
implications for the disease’s outcome.
OBJECTIVE: To compare clinical features and behavioural characteristics of two patients with Prader–
Willi syndrome
PATIENTS AND METHODS: Two patients, an 8 year and 7 months old boy and a 16 year old girl at
the age of the diagnosis, previously considered as having idiopathic encephalopathy, were clinically
evaluated. Methods of evaluation consist of history, physical examination, anthropometric and metabolic
assessment with plasma glucose, total cholesterol and triglyceride measurement by enzymatic methods,
and blood gases measurement, ECG recording and psychological evaluation.
RESULTS: Diagnosis was based on the consensus clinical criteria with a weighted score of 14 for the
male and 11 for the female patient. The common diagnostic features were: neonatal and infantile
hypotonia, feeding problems and failure to thrive followed by excessive weight gain after three years of
age, mental retardation, compulsive hyperphagia and characteristic facial features. Both patients had an
increased body mass index (BMI) of 40.26 kg/m2 and 42.12 kg/m2, the measure of severe progressive
obesity. Short stature, small hands and feet, learning disability, behavioral problems as minor criteria
were also present in both cases. Hypogonadism, longer period of infantile hypotonia and tube feeding,
more severe speech articulation defects, more complex obsessive – compulsive disorders with skin
picking and severe obesity were present in the male patient. The family had no control on his food intake.
Obstructive sleep apnea and hypoventilation syndrome, achanthosis nigricans and other components of
the metabolic syndrome were associated at the age of ten in this patient with a lethal outcome.
Oligomenorrhea and dyslipidemia were present and short stature and acromicria were more evident in the
girl patient, with comparable BMI but at a different age and with better learning performance.
CONCLUSIONS: In both our patients’ diagnosis was based on consensus clinical criteria. Severe
obesity in the younger child was associated with increased number of life – threatening comorbidities.
Some characteristic somatic features of Prader–Willi syndrome became evident with age. The difference
between the symptoms’ severity in the two cases may be genetic and even environmentally determined.
54
PAIN THRESHOLD IMPAIRMENT IN PRADER WILLI SYNDROME:
A NEUROPHYSIOLOGICAL STUDY
Lorenzo Priano¹, Giacinta Miscio¹, Graziano Grugni², Silvia Baudo¹, Alessandro Mauro¹,³
¹ Department of Neurology, Istituto Auxologico Italiano, IRCCS, Piancavallo (VB), Italy; ² Department
of Auxology, Istituto Auxologico Italiano, IRCCS, Piancavallo (VB), Italy; ³ Department of
Neurosciences, University of Turin, Italy.
RATIONALE: The neurophysiology of Prader-Willi syndrome (PWS) has been poorly investigated,
although the central nervous system is one of the main targets of the underlying genetic defect. A
hypothalamic involvement has been proposed to explain altered pain perception, but no
neurophysiological demonstration has been given yet. The present study was undertaken to analyse and
objectively investigate the sensory pathway functioning, with the aim of identifying a possible site
responsible for the altered pain perception.
PATIENTS AND METHODS: 14 PWS patients, 10 obese non-diabetic people and 19 age-matched
controls, underwent: a) MNCS (median, ulnar, peroneal, tibial) and SNCS (median, ulnar, sural); b)
somatosensory evoked potentials (SSEP) from upper and lower limbs; c) Quantitative sensory testing to
measure sensory threshold for vibration, warm and cold sensation (WS-CS), heat and cold-induced pain
(HP-CP); d) blood sample analysis to evaluate glucose and insulin levels and calculate the quantitative
insulin-sensitivity check index (QUICKI). All the PWS patients had a deletion at chromosome 15.
RESULTS: Electroneurography was in the normal range in PWS, although PWS patients like obese
people showed significantly decreased C-MAP amplitude of the tibial and peroneal nerves, and decreased
SAP amplitude of the sural nerve. The SSEP wave latencies were all within normal limits. In the whole
PWS group, thermal and pain thresholds but not vibratory were significantly higher than in healthy and
obese people. Most of the sensory thresholds were altered in PWS people. Insulin serum levels were
significantly increased and QUIKI decreased but less than in obese people. The sensory threshold did not
correlate either with BMI or with insulinemia levels or with QUIKI index.
CONCLUSIONS: Our preliminary data suggest that a significantly impaired thermal and pain stimulus
perception, much more evident than in our obese group, is present in PWS, but it does not seem
attributable to peripheral nerve derangement and is not related to hyperinsulinemia and insulin sensitivity.
In particular, the high pain threshold might suggest a hypothalamic dysfunction or complex derangement
of the neurotransmitter balance, as described in PWS.
55
GASTRIC NECROSIS IS ASSOCIATED WITH NORMAL BMI IN
PRADER-WILLI SYNDROME
Astrid Schulze (1) Annie Vesterby (2), Henrik Kiaer(3), Karen Broendum-Nielsen (4)
(1) Department of Neurology, Odense University Hospital (2) Institute of Forensic Medicine, Aarhus
University, (3) Department of Pathology, Sygehus Fyn Svendborg (4) Department of Genetics, Kennedy
Institute, Glostrup, Denmark
INTRODUCTION: Gastric necrosis and rupture is a rare and life threatening complication of a number
of predisposing conditions. Gastric necrosis is caused by vascular insufficiency secondary to gastric
dilatation and increased intra-gastric pressure. Gastric dilatation is associated with emptying delay and
includes symptoms such as abdominal distension, tenderness and vomiting. This requires immediate
attention including decompression. Where gastric necrosis or rupture is suspected, surgical intervention
is unavoidable. In PWS, Wharton (1997) reported 6 individuals with gastric distension, 3 developed
gastric necrosis. Schrander-Stumpel (2004) reported two adults with PWS with similar gastric findings.
The natural history of gastric dilatation and necrosis in PWS is still poorly understood. High pain
threshold and lack of vomiting in PWS are contributing factors, but probably not the only predisposing
factors in PWS.
OBSERVATION: We report three adults with clinical PWS, all with documented gastric necrosis and
rupture. In two of them, a 26 year old female and a 32 year old male, the diagnosis of PWS was
confirmed by post mortem molecular testing. The third individual, a 36 year old female, had a normal
post-mortem molecular test result – this information came as a surprise. The PWS-like condition and
behaviour of this woman is most likely due to a childhood-acquired hypothalamic dysfunction following
meningitis and subsequent hydrocephaly requiring shunting. None of the individuals had binge eating
behaviour during the days prior to death. All three individuals had been grossly overweight until started
on a nutritional regime for PWS individuals. Their BMIs had since been within the normal range. None
of them had received growth hormone treatment.
DISCUSSION: People with PWS and PWS like hypothalamic dysfunction seem to be at risk of
developing gastric emptying problems, gastric necrosis and rupture. This risk appears at least partly to be
due to weight loss. The risk seems to increase in those with BMI below 25.
To prevent this health hazard from occurring, individuals with PWS and PWS-like conditions should be
allowed a BMI of not less than 25. Slimming below this margin should be avoided until the predisposing
mechanisms are clarified in more detail and tools are available that would help to optimise and monitor
the nutritional state and body composition in individuals with PWS or PWS-like hypothalamic
dysregulation.
References
Wharton RH et al. Acute idiopathic gastric dilatation with gastric necrosis in individuals with PraderWilli syndrome. Am J Med Genet 1997: 73, 437-41
Schrander Stumpel CT et al. Prader-Willi syndrome: causes of death in an international series of 27 cases.
Am J M Genet A. 2004 .124, 333-8
56
AGEING IN PEOPLE WITH PRADER WILLI SYNDROME (PWS)
M. Sinnema1, M.A. Maaskant2,4,5, H.M.J. van Schrojenstein Lantman-de Valk3,4,5, C.T.R.M. SchranderStumpel1, L.M.G. Curfs1,5
1 Department of Clinical Genetics, Academic Hospital Maastricht; Research Institute Growth &
Development (GROW), Maastricht University
2 Maastricht University, Cluster Health Care Studies
3 Maastricht University, Department of General Practice
4 Stichting Pepijn en Paulus, Echt
5 Maastricht University, Governor Kremers Centre
AIM: In general, the ageing process in people with intellectual disabilities (ID) starts rather early
compared to people without ID. However, there still is hardly any information about the ageing process in
people with specific etiologies of ID (e.g., Prader-Willi syndrome), except for those with Down
syndrome. The characteristic morbidity in people with PWS (e.g., obesity, scoliosis, psychoses) may lead
to specific co-morbidity patterns in older age.
METHODS: We performed a descriptive study of morbidity, skills and behaviour in people with PWS in
relation to ageing. We obtained data through a postal interview from adult (18+) members with PWS of
the Dutch PWS-network (N=74).
RESULTS: In general, adults with PWS seemed to be reasonably healthy, although perceived health
decreases with age. The majority of persons were obese, especially in the age group 30-39 years. Diabetes
mellitus, hypertension, skin problems, sleep apnoea and hormonal problems like osteoporosis and
hypothyroidism were common. The prevalence of diabetes mellitus was related to age. Psychiatric
problems were frequent, especially in the persons with UPD. Growth hormone seemed to be associated
with a lower BMI.
CONCLUSION: This pilot study gave more insight into the functional status of adult persons with PWS.
However, the data are based on cross-sectional data, derived via questionnaires. Further longitudinal
research is necessary for a better understanding of the ageing process in PWS.
57
IMPORTANCE OF THE MINOR CRITERIA FOR A POSITIVE CLINICAL
DIAGNOSIS OF PRADER WILLI SYNDROME PATIENTS
C. Skrypnyk1, M. Bembea1, V. Belengeanu2, E. Tomescu3, P. Grigorescu Sido4, I. Pascanu5, M. Covic6.
1.
University of Oradea, Faculty of Medicine, Genetics Department, Oradea, Romania.
University of Medicine and Pharmacy, Genetics Unit, Timisoara, Romania. 3. Institute for Mother and
Child Care, Genetics Unit, Bucharest, Romania. 4. University of Medicine and Pharmacy, Pediatric Unit I,
Cluj Napoca, Romania. 5. University of Medicine and Pharmacy, genetics Unit, Targu Mures, Romania. 6.
University of Medicine and Pharmacy, Genetics Unit, Iasi, Romania.
2.
INTRODUCTION: Prader-Willi syndrome (PWS), a genetic disorder that involves chromosome 15, is
the most common form of obesity caused by a genetic syndrome. Diagnosis often is delayed until early
childhood because the clinical findings are relatively nonspecific, particularly in infancy, and the
dysmorphism often is subtle.
MATERIALS AND METHODS: We evaluated 16 patients with age between 8 month and 27 years old,
clinically diagnosed with PWS following the consensus major and minor criteria. All patients had a
positive clinical score for PWS, having dysmorphic features, obesity associated with childhood
hyperphagia, hypogonadism and mental retardation.
RESULTS: All patients had unrelated healthy parents and resulted from a physiological pregnancy, with
normal birth weight and normal Apgar score. The medium age of diagnosis was 8 years old, based on the
suggestive phenotype. The main reasons for a genetic evaluation were neonatal hypotonia, obesity and
mental retardation. The minor criteria had a variable frequency. Decreased fetal movement and infantile
lethargy were found in only 4/16 (25%) anfd 3/16 (18.75%) of patients, respectively. Small hands and
feet characterized all patients. Short stature (compared with family members) and hair hypopigmentation
had a low frequency being found in 3/16 (18.75%) cases. 9/16 (56.25%) of patients had high pain
threshold and 40% of patients had skin picking and sleep disturbance. Sleep apnea characterized 7/16
(43.75%) of patients and was correlated with the weight gain. A distinctive behavioral phenotype were
found in 11/16 (68.75 %) of cases.
DISCUSSION: Sensitivities of the minor criteria ranges from 18.75% (infantile lethargy) to 100% (small
hands and feet). The minor criteria can sometimes reveal the diagnosis before a major sign, and their
association with the major criteria, allow a positive diagnosis of PWS. The minor criteria can be
important to avoid over diagnosis and to make a correct selection for the molecular diagnostic tests.
58
BENEFICIAL EFFECT OF EARLY USE OF GROWTH HORMONE IN PATIENTS
WITH PRADER-WILLI SYNDROME
Takayoshi Tsuchiya, MD, Nobuyuki Murakami, MD,PhD, Yuriko Tanaka, MD, Yuzo Tomita, MD,
Kazuo Obata, MD,PhD, Ryoichi Sakuta, MD,PhD, Toshiro Nagai, MD,PhD
Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Saitama, Japan.
INTRODUCTION: Growth hormone (GH) treatment for Prader-Willi syndrome (PWS) has been started
worldwide, however, an ideal starting age of GH has not been identified. This study was designed to
determine whether we should start GH before or after 2 years old.
METHODS: GH was started before 2 years of age in 11 patients in one group (8 males and 3 females,
age ranged from 8 mo to 1 y 9 mo) and after 2 years in 11 patients in the other group (6 males and 5
females, age ranged from 3 y 6 mo to 11 y 7 mo). We compared GH effect for height SDS, %fat of body
composition by dual energy X-ray absorptiometry (DEXA), and gross motor development between these
2 groups.
RESULTS: The gain of height SDS during the first year of treatment was 0.61 SDS and 0.55 SDS,
respectively, showing no statistical difference (p=0.57). The %fat improved during the first year of
treatment from 40.4 % to 24.0 % in the early starting group and from 37.0 % to 24.4 % in the other group
and there was no statistical difference (p=0.67). Concerning gross motor developmental milestones such
as head controlling, rolling over, and sitting up, the early starting group showed a definite delay compared
to the other group. However the duration from attaining head control to sitting up showed no difference in
2 groups. (Table)
DISCUSSION: Our study showed that the early start of GH is not mandatory for improving height SDS
and %fat. The reason for the delay of gross motor development in the early starting group is probably due
to the fact that the early starting group was definitely more delayed in their development than the other
group even before GH was started. The lack of difference in the duration from attaining head control to
sitting indicates that GH therapy probably improved gross motor development. Early use of GH for PWS
is beneficial for improving gross motor development.
head control
roll over
sit up
duration from head
control to roll over
GH starting before 2 y/o
(months)
6-18
11-21
12-25
2-14
GH starting after 2 y/o
(months)
5-16
6-24
7-24
0-12
p
<0.05
<0.05
<0.05
NS
59
NURSING OF ADULT PATIENTS WITH PRADER-WILLI SYNDROME
Tina Varlan, GN, Franca Pera, HN, Alessandro Sartorio, MD, Graziano Grugni, MD.
Department of Auxology, Italian Auxological Institute Foundation, Verbania, Italy.
Our Department hospitalizes adult patients with Prader-Willi syndrome for a one-month rehabilitation
program, involving dietary intervention and physical therapy. The goal is to reduce obesity and to prevent
its complications. In order to optimize our intervention, we classify PWS patients according to the
severity of their clinical picture. For this purpose we have elaborated the following chart:
yes
no
degree
Independence level regarding personal hygiene
Independence level regarding mobility (orientation, time
conception)
Independence level regarding money management
Tendency to ingest uneatable objects
Tendency to steal (money, things)
Aggressiveness (auto/hetero)
Sexual activity
Daytime sleepiness
Compliance to physical activity
General compliance to hospitalization
Information about behaviour with other patients (hidden conflict)
Psychiatric therapy
Smoke
Rehabilitation program at home
Management of crisis: motherhood of fatherhood care?
Subsequently, specific nursing strategies are performed on the basis of the individual clinical expression.
To obtain better results, nursing of PWS adults during hospitalization requires:
1. a special attention to any source of food, keeping locked the kitchen of the Department;
2. a strict supervision of food intake during meals;
3. a strict control of standardized physical activity (walk, gymnasium, physiotherapy);
4. a special competence to administrate peculiar drugs, such as rhGH;
5. as far as violent outbursts and other behavioural abnormalities are concerned, we generally wait their
end without any coercive measures that might aggravate the situation. Thus, administration of sedative
drugs is uncommon.
60
GAIT ANALYSIS IN ADULT PATIENTS WITH PRADER- WILLI SYNDROME: A
CROSS-SECTIONAL COMPARATIVE STUDY
Luca Vismara,1-4 Marianna Romei3, Manuela Galli3, Angelo Montesano, MD1, Gabriele Baccalaro, MD1,
Marcello Crivellini3, Graziano Grugni, MD2.
1
Physical Medicine and Rehabilitation Unit and 2Department of Auxology, Italian Auxological Institute,
Verbania, Italy; 3Bioengineering Department, Politecnico di Milano, Italy; 4SOMA - School of
Osteopathic Manipulation, Milano, Italy.
INTRODUCTION: Obesity is a pathological condition associated with an impairment in skeletal statics
and dynamics. Excess weight is able to induce negative effects on several common daily movements,
such as standing up, bending, walking and running. As far as obese adult patients are concerned, obese
males display a gait pattern similar to healthy subjects but some of the temporal and angular components
seem different from those observed in non obese individuals, mainly because of the excessive adipose
tissue inside their thighs [Spyropoulos et al, Arch Phys Med Rehabil 1991; 72:1065-1070]. Severe
overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). Other typical PWS
characteristics that may interfere with gait pattern include muscular hypotonia, short stature, small hands
and/or feet and scoliosis. Hypotonia is nearly uniformly present and gradually improves with age.
Nevertheless, adults remain mildly hypotonic with decreased fat free mass. Taking into consideration the
peculiar clinical picture of patients with PWS, the aim of our study was to characterize the gait pattern of
these subjects by using 3D-Gait Analysis. The results were compared with those obtained in a group of
healthy obese patients (OB) and in a group of healthy subjects (HS).
PATIENTS AND METHODS: Nineteen patients with PWS (11M/8F, 13 del15/6 UPD15, age 25.7+6.1
yrs, BMI: 41.3+6.0 kg/m2, mean+SD), 14 OB (5M/9F, age 29.4+7.9 yrs, BMI: 39.2+3.25 kg/m2) and 20
HS (10M/10F, age 30.2+5.2 yrs, BMI: 21.4+ 2.2 kg/m2) were admitted to the study. All the subjects
performed a three-dimensional Gait Analysis (GA) assessment. Kinematic and kinetic parameters were
assessed by an optoelectronic system with 6 cameras (460 Vicon, UK) working at 100 Hz and two force
platforms (Kistler, CH). Twenty-three passive markers were placed on the subject’s body according to the
Davis protocol [Davis RB et al, Hum Mov Sci 1991; 10: 575-587].
RESULTS: PWS subjects walked with a 5% reduced cadence, with a 6.3% longer stance phase duration,
a 10% reduced single support phase, with a 16.25% shorter normalized stride length and at a 19% slower
normalized velocity, compared to HS. Moreover, PWS patients had a 3% reduced cadence, their stance
phase lasted 2% more, their single support was 5% reduced, the normalized stride length was 11.8%
shorter and normalized walking speed was 14% reduced, compared to OB. Furthermore, cadence of OB
was 1.9% lower than that of normal, stance duration lasted 3.6% more than normal, the reduction of
normalized stride length was 5% and they walked with a 6.4% reduced normalized velocity, compared to
HS. Joint kinematic parameters revealed significant differences between PWS patients and control groups
in Range of Motion (ROM) at knee and ankle parameters, with the exception of ROM at hip. In
particular, PWS patients showed statistically significant reduced sagittal plane ROM at knee and ankle in
comparison both with OB and HS (knee: PWS 56.11°+8.24° vs OB 60.12°+6.10° vs HS 61.23°+4.02°:
p<0.0001; ankle: PWS 25.06°+3.65° vs OB 29.81°+6.88° vs HS 31.90°+4.81°; p<0.001).
CONCLUSIONS: PWS gait pattern is significantly different from obese patients, despite both groups
having similar BMI. We suggest that PWS gait alterations may be related to the abnormalities in the
development of motor skills in childhood, due to precocious obesity. A tailored rehabilitation program is
needed to start in early childhood of PWS patients in order to prevent gait pattern changes.
61
SEXUAL BEHAVIOR IN ADOLESCENTS AND ADULTS WITH
PRADER-WILLI SYNDROME
Barbara Y. Whitman, Ph.D.
Saint Louis University Department of Pediatrics, St. Louis, MO. USA
INTRODUCTION: Since first described, immature genitalia, and endocrine deficiencies precluding
normal growth and sexual maturation have been cardinal features of Prader-Willi syndrome (PWS
[Hauffa, 2000]). Early and consistent data regarding these abnormalities has led to an assumption of
universal infertility (Katcher et. al., 1977; Bray, 1983; Butler, 1986; Eiholzer & Lee, 2006), despite
normal to premature adrenarche (Schmidt et al, 2001; L’Allemand et al., 2002). Further, the combined
impact of sex hormone deficiencies and cognitive/social deficits have led to a clinical assumption that
sexual understanding, interest and activity rarely, if ever, exceeded that noted in non-affected preadolescents. Behaviorally, except for the rare female who has exchanged sex for food, or aggressive
sexual behavior among males treated with testosterone replacement, most clinicians have viewed affected
individuals as essentially “asexual.” While many affected youngsters talk about dating, getting married
and having babies, this has been seen as learned socio-cultural behavior, not sexual, an understanding in
part supported by earlier data (Greenswag,1987). Three coalescing factors demand a reassessment of
these previously held beliefs: (1) recent reports of at least three successful pregnancies; (2) the author’s
experience with three previously sexually abused adults, two females and one male, who now
demonstrate indiscriminate and predatory like sexual behavior; and (3) an apparent “cross-over” effect of
growth hormone replace therapy (GHRT) on sexual maturation. This presentation reports initial survey
data from parents and community-based residential providers regarding sexual behavior in adolescents
and adults with PWS, the relation of this behavior to supplemental hormone therapy or psychotropic
medications, and the sexual policies and sex education training programs of group homes.
METHODS: The study is surveying parents and direct care providers of adolescents and adults with
PWS using two “informant” questionnaires: (1) the Sexual Behavior Questionnaire and (2) the Aberrant
Behavior Checklist. In addition, group homes are being asked to provide copies of their policies regarding
client’s sexuality and sexual relationships. For those adults in group home/supported living care,
information is being sought from both parents and care-staff.
RESULTS: At the time of this writing, the survey process has just begun. Results will be summarized
and distributed at the time of the presentation.
DISCUSSION: Multiple factors demand a better understanding of “normal” or “baseline” sexual
behavior in those with PWS including: (1) improved strategies for managing the obesity resulting in many
adults living into their 50’s and 60’s; (2) the use of growth and sex hormone replacement therapy in both
sexes; (3) the impact of increased estrogenization from selective serotonin reuptake inhibitors used as
behavior management adjuncts; (4) the recently reported pregnancies; and (5) a shift in adult living from
institutions to a “normalized” community integration model combined with concurrent “disabilities
rights” legislation and advocacy groups actively promoting the sexual activity rights of cognitively
handicapped adults. The results will be critical for designing and delivering the appropriate sex education
services for this population, an effort that currently is hampered by the limited empirical data regarding
the nature and frequency of sexual behaviors in this population.
62
DNA EXTRACTION FROM DRIED BLOOD SPOTS AND METHYLATION TEST
FOR DIAGNOSIS OF PRADER-WILLI SYNDROME PATIENTS
G. Zandonà, A. Pasqualin, E. Fanin, E. Peotta, U. Hladnik
Baschirotto Institute for Rare Diseases Foundation onlus, Costozza di Longare, Vicenza, Italy
Prader-Willi syndrome (PWS) is a complex genetic disease that arises from lack of expression of
paternally inherited imprinting controlled genes on chromosome 15q11-q13. The frequency is between
1/10000 and 1/30000. An early molecular diagnosis of the syndrome can help not only the correct
treatment of the condition but can help the family to begin an optimal lifestyle for the PWS patients since
an early age.
The B.I.R.D. Foundation developed a cost effective diagnostic procedure for PWS starting from dried
blood spots on filter paper. In particular, a methylation test in the Prader-Willi chromosome region
(PWCR) is performed. It consists of a chemical modification with sodium bisulphite which involves the
addition of a methyl group to the carbon-5 of the cytosine pyrimidine ring. Cytosine converts to uracil,
except when it is methylated because 5-methylcytosine is resistant to sodium bisulphite. In a normal
person, sodium bisulphite modifies the paternal genes of PWCR and not the maternal genes that are
methylated. In PWS patients only methylated DNA is present in the PWCR either because there is a
deletion in the paternal DNA or there is UPD or even other rearrangements or imprinting defects.
Subsequently we amplified the sodium bisulphite treated PWCR with a methylation-specific PCR with
two pairs of primers that give amplicons of different sizes. By gel electrophoresis it is possible to see two
bands if there are both the methylated and non methylated fragment and a single band if only the
methylated band is present, permitting us to diagnose the PWS with a sensitivity of 99%.
The B.I.R.D. Foundation, in collaboration with the IPWSO, is today able to offer the diagnosis for PWS
free of charge to anyone who requires it. The test is performed on DNA extracted from dried blood spots
that represent an easy and low cost way to transport samples. The test performed allows a quick diagnosis
that takes not more than a week. Fast results are essential in order to begin the therapy with growth
hormone (GH) as soon as possible since the treatment can radically change the clinical phenotype of
PWS.
63
Poster Session – Behavioral/Psychological (1st FLOOR CORRIDOR)
24.
Abraldes et al.: CORRELATION STUDY OF COGNITIVE PROFILE AND ADAPTATIVE
BEHAVIOR IN PRADER WILLI SYNDROME PATIENTS ACCORDING TO ETIOLOGY
25.
Buono et al.: PSYCHOPATHOLOGIC DISORDERS AND SELF INJURY IN PRADER-WILLI
SYNDROME
26.
Collin et al.: PSYCHOSIS IN CHILDREN WITH PRADER-SYNDROME: A CASE STUDY.
27.
Curfs et al.: INDIVIDUALS WITH PRADER-WILLI SYNDROME AND THEIR
PERCEPTION OF SKIN PICKING
28.
Grayson & Hamilton (Hamilton presenting): EXAMINING THE NATURE OF FUNCTIONAL
ARCHITECTURE SUPPORT FOR VISUO SPATIAL WORKING MEMORY TASK PERFORMANCE
IN PRADER-WILLI SYNDROME
29.
Greco et al.: CLINICAL FEATURES and PSYCHOLOGICAL PROFILES OF PRADERWILLI SYNDROME: COMPARISON OF GENETIC SUBTYPES IN 18 PATIENTS
30.
Hasegawa: COGNITIVE BEHAVIOR THERAPY (CBT) FOR A YOUNG MAN WITH PWS
31.
Honey: BEHAVIOURAL PROBLEMS IN INDIVIDUALS WITH PRADER-WILLI
SYNDROME
32.
Landau et al. (Bennaroch presenting): PARENT – CHILD RELATIONSHIP IN PRADERWILLI SYNDROME: A NARRATIVE STUDY
33.
Mori et al.: QUALITY OF LIFE AND PSYCHOLOGICAL WELL-BEING IN GH-TREATED,
ADULT PWS PATIENTS: A LONGITUDINAL
34.
Rosell-Raga et al.: AUTISTIC SYMPTOMATOLOGY, PWS AND ITS DERIVATIONS FOR
TREATMENT
35.
Semensa et al. (Ceriani presenting): MATH ABILITIES IN PRADER-WILLI SYNDROME
36.
Tregay et al.: REPETITIVE BEHAVIOUR AND EXECUTIVE FUNCTIONS IN PRADERWILLI SYNDROME AND IN AUTISM SPECTRUM DISORDERS
37.
Viardot et al.: HAS GUT-DERIVED HORMONE PYY 3-36 A CAUSATIVE ROLE IN
HYPERPHAGIA AND OBESITY IN PWS?
38.
Whittington et al.: RELATIONSHIP BETWEEN PRADER-WILLI SYNDROME (PWS) AND
SIBLING ABILITY (IQ)
64
CORRELATION STUDY OF COGNITIVE PROFILE AND ADAPTATIVE BEHAVIOR
IN PRADER WILLI SYNDROME PATIENTS ACCORDING TO ETIOLOGY
Abraldes K; Torrado, M; Bin,L; Chertkoff,L; Dr Baialardo,E; Dr Waisburg,H
Hospital Pediatria J.P. Garrahan. Argentina. Servicios de Clinicas Interdisciplinarias y Genetica.
INTRODUCTION: Prader-Willi syndrome (PWS) is a complex multisystem disorder with many
manifestations related to hypothalamic insufficiency, mental deficiency, and behavioral problems. The
aim of this study was to establish correlations of cognitive profile and adaptive behavior amongst PWS
patients, according to etiology, grouped as: (1) deletion of the 15q11-q13 region of the maternally derived
chromosome (DEL), and (2) Uniparental maternal disomy (DUPm)
.
METHOD AND MATERIALS: Patients (aged 4 through 19 years) were diagnosed at our hospital using
the methylation test; etiology identification was through FISH technique and 5 polymorphic markers.
Intellectual skills were established using Weschler scales (WIPSI, WISCIII, WAIS) determining Full
Scale IQ, Verbal IQ, and all subtests in 27 patients: 15 from Group 1 and 12 from Group 2. Adaptive
behaviour was determined with the VABS using the overall index and the following subdomains:
communication, everyday life skills and socialization, on 32 patients, 21 from Group 1 and 11 from
Group 2.
RESULTS: The evaluation of intellectual skills (see Table) show the existence of significant differences
in FSIQ and Verbal IQ, with better performance obtained by the DUP group.
With the Weschler scales we also observed significance in Arithmetic (p=0,0168) and Digit Retention
(p=0,027), with the DUP group showing the best performance.
X DEL
X DUP
P=0,05
FSIQ
53
58
0,028
Verbal IQ
55
67
0,018
CI ejecutor
56
54
0,847
In adaptive behaviour we did not observe any significance in the compound scores or in the
communication and socialization domains. In the everyday life skills domain the scores of group 2 were
significantly higher (p=0.032).
CONCLUSION: This study showed better performance in the disomic group, which could
be explained by differences in gene expression in the CNS according to etiology.
65
PSYCHOPATHOLOGIC DISORDERS AND SELF INJURY IN PRADER-WILLI
SYNDROME
S. Buono, D. Greco, B. Palmigiano, F. Scannella, P. Occhipinti, L. Ragusa, A. Costanzo, C. Romano
Department for Mental Retardation , Oasi Institute (IRCCS),Via Conte Ruggero,73 - 94018 Troina
(EN)- ITALY
INTRODUCTION: Prader-Willi syndrome (PWS) is a genetic disorder. Three different genetic
mechanisms can lead to PWS, which is due to a genetic defect that abolishes the expression of imprinted
paternal genes in the 15q11-q13 chromosomal region. The major genetic mechanism is a paternal
deletion that occurs in approximately 70% of the cases, while 25% have maternal disomy (UPD), and the
remaining 2% to 5% have imprinting defects. PWS is characterized by: neonatal hypotonia with poorsucking and failure to thrive in the post-natal period, usually delayed psychomotor development,
behavioral and emotional problems and hyperphagia in early childhood resulting in severe obesity.
The data in the literature indicate an association between PWS and psychopathological features. Persons
with PWS can present a generalized developmental delay, together with cognitive deficits. During their
development behavioral problems emerge. In almost all cases, self injurious behaviors (skin-picking), as
well as stubbornness and repetitive behaviors, are present. Frequently, there are problems linked to the
emotional affective sphere: for instance, there is a significant emotional liability consisting in irascibility
and scarce tolerance to frustrations. Rigidity in thought processes may also be present, consisting at times
in manipulative modalities expressed in interpersonal relationships, as well as in polemical and
oppositional attitudes. Furthermore, frequent compulsive and self injurious behaviors, as well as
considerable difficulty in anxiety management, have been reported.
METHODS: Our work examines a sample composed of 18 persons with PWS, whose ages range from 2
to 29 years. IQ was evaluated by Wechsler scales. Psychopathological disorders were diagnosed by
personal history and clinical evaluation. A specifically built card was developed for revealing self
injurious behaviors (SIB), and administered in interview form to the families of PWS individuals.
RESULTS: The patients show differing levels of intellectual disability: normal intelligence (6%),
borderline intellectual functioning (6%), mild mental retardation (45%), moderate mental retardation
(11%), NOS mental retardation (16%), psychomotor delay (16%). 54% of individuals present
psychopathological behavior, 15% of these individuals have a psychiatric diagnosis and 61% of these
individuals present emotional disorders or mood instability. All PWS individuals in our sample present
obsessive-compulsive traits. SIB is present in 73% of cases.
DISCUSSIONS: Our results demonstrate that PWS individuals have a higher probability of developing
psychopathology, as also shown by Watanabe et al., 1997, and Clarke et al., 1995. The emotional
problems are already present at an early age in the major part of our sample, and the diagnosis of
psychosis reached an incidence of 15% in our sample, consistent with the results reported by Vogel et al.,
2004.
66
PSYCHOSIS IN CHILDREN WITH PRADER-SYNDROME: A CASE STUDY.
Philippe J.L. Collin, M.D. 1,2, Harm Boer, M.D., Ph.D. 3, Annick Vogels, M.D., Ph.D. 4, Leopold M.G.
Curfs, Ph.D. 2,5
1
2
3
4
5
Department of Child and Adolescent Psychiatry, Koraal Groep, Sittard, The Netherlands.
The Research Institute Growth & Development (GROW) Maastricht University, The Netherlands.
The Janet Shaw Clinic, Brooklands, Birmingham, United Kingdom.
Department of Clinical Genetics of the Catholic University of Louvain, Belgium.
Department of Clinical Genetics, Academic Hospital Maastricht, The Netherlands.
INTRODUCTION: Boer et al. (2002) suggested that the Prader-Willi syndrome (PWS) is associated
with a high rate of psychotic disorders and they found an association between chromosome 15 maternal
uniparental disomy and adult psychotic illness. This study, together with other studies (Verhoeven et al.,
2003; Vogels et al., 2003, 2004), made it likely that the hypothesis that there is a non-chance relationship
between PWS and psychosis is correct. It would therefore seem that the high prevalence rate of psychosis
in people with PWS is not simply due to having a learning disability, but may represent an increased risk
specific to this syndrome. Whittington and Holland (2004) suggested that the affective and psychotic
illness associated with PWS starts in adult life, and previous studies did not describe young children with
PWS and a psychotic disorder. In this case study we describe three young children with PWS who
developed psychotic symptoms.
METHODS: These three patients underwent psychiatric assessment by a psychiatrist who was skilled in
assessment of children with intellectual disabilities. Symptomatology was collected on basis of clinical
interview, clinical observation of patients before, during and after psychotic episodes, family and carer
informants, medical records and psychiatric reports.
RESULTS: Two out of the three children in this case study had a maternal uniparental disomy (UPD)
and the third a paternal deletion. The psychiatric symptomatology - observed in our three cases - included
emotional turmoil, anxiety, irritability, confusion, mood swings with depressive episodes, hallucinatory
experiences and paranoid ideation, with a variable intensity and sub-acute onset. The high level of anxiety
observed in our sample of children with PWS and psychosis is consistent with other studies of childhood
psychosis (Biederman et al., 2004).
DISCUSSION: Prader-Willi syndrome (PWS) is associated with psychotic disorders. Previous research
gives an age of onset as 13 years or over. In this case study we describe three children with PWS who
developed psychotic symptoms before the age of eight years. Our case reports reveal that psychosis does
occur in young children with PWS, with a symptomatology similar to that in children without intellectual
disabilities. The PWS constellation (UPD), expressed in our sample, may index a more generally
vulnerable child at risk for psychosis. This case study highlights the relationship between psychosis and
PWS and is consistent with a model (Nicolson et al., 1999) in which a childhood onset psychosis is due to
a greater impairment of neurodevelopment secondary to the interaction of a number of factors,
particularly genetic ones.
67
INDIVIDUALS WITH PRADER-WILLI SYNDROME AND THEIR PERCEPTION OF
SKIN PICKING
Leopold M.G. Curfs¹ ², R. van Os³, I.M.Proot, C.T.R.M. Schrander-Stumpel¹ , R. Didden³
¹Department of Clinical Genetics, Academic Hospital Maastricht, ²Maastricht University, Governor
Kremers Centre, ³Radboud University, Nymegen
INTRODUCTION: Self-injurious skin picking is a distinctive feature of Prader-Willi syndrome. Little is
known about how individuals with PWS experience this type of behavior and what impact skin-picking
has on their lives.
METHOD: This paper reports on a first exploratory study into the perspectives of individuals with PWS
pertaining to their skin-picking behavior. Semi-structured interviews were conducted with 10 PWS adults.
The qualitative research method based on grounded theory was used to explore the impact and
perceptions of self-injurious skin-picking in individuals with PWS.
RESULTS: The interviews indicate that individuals with PWS are able to provide clues to why they
exhibit this behavior and what impact it has on their quality of life.
DISCUSSION: Unfortunately our knowledge of effective treatment of skin picking is very limited.
Several suggestions of possible effective approaches will be presented.
68
EXAMINING THE NATURE OF FUNCTIONAL ARCHITECTURE SUPPORT FOR
VISUO SPATIAL WORKING MEMORY TASK PERFORMANCE IN PRADER-WILLI
SYNDROME
Laura E Grayson and Colin J Hamilton
Cognition and Communications Research Centre, School of Psychology and Sports Sciences,
Northumbria University, Newcastle upon Tyne, NE1 8ST
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder. In 70% of cases, it occurs due to a
deleted region of Chromosome 15. PWS is characterised by moderate learning difficulties and with IQ’s
ranging from 45-95 (Borghgraef, 1990). Research has suggested strengths on tasks that assess attention to
visual detail and spatial organization (Dykens et al 1992; Gabel et al 1986; Whittington et al 2004). An
initial working memory study with individuals with PWS suggests that indeed there may be Visuo Spatial
Working Memory (VSWM) competency in children and young adults in visual and spatial memory
(McCafferty & Hamilton, 2005). This VSWM task competency was in contrast with concurrent
impairment in visuospatial executive task performance, a task demanding dual task executive resources.
Within a normative context these executive resources would typically support VSWM task performance
(Thompson et al, 2006). Thus, individuals with PWS appear to exhibit a VSWM functional architecture
which differs from the normative population, where these tasks are supported by executive resources
(Hamilton et al, 2003; Vandierendonck et al, 2004; Rudkin et al, 2006) However, it may be the case that
in PWS, task performance may be scaffolded by other executive resources. The present case study
examined the competency of a range of executive processes in an individual with PWS. The choice of
executive tasks was derived from the work of Miyake et al (2001) who identified three further executive
functions; monitoring and updating, set-shifting and inhibition. In addition a range of Speed of Processing
(SOP) tasks was employed. A thirty year old woman with suspected deletion of the 15th chromosome
participated. Controls were drawn from chronological and mental age groups. The results will be
discussed with reference to the proposal that SOP and executive resourcing are key elements of the
functional architecture underlying VSWM task performance.
69
CLINICAL FEATURES and PSYCHOLOGICAL PROFILES OF PRADER-WILLI
SYNDROME: COMPARISON OF GENETIC SUBTYPES IN 18 PATIENTS
D. Greco, S. Buono, P. Occhipinti, A. Costanzo, L. Ragusa, F. Scannella, F. Calì*, P. Bosco*, C.
Romano.
Dept. for Mental Retardation and *Dept. of Laboratories
Oasi Institute (IRCCS), Via Conte Ruggero,73 - 94018 Troina (EN)- ITALY
INTRODUCTION: Prader-Willi syndrome (PWS) can result from a 15q11-q13 paternal deletion,
maternal uniparental disomy (UPD) or mutations of the so-called Imprinting Center (IC). Advances in
genetics have led to an increased understanding of the role of the genotype on psychological functioning,
in particular regarding cognitive and behavioural phenotype.
Besides it is important to study the phenotypes associated with the two genetic subtypes, deletion and
maternal uniparental disomy. Phenotypic differences associated to these main genetic subtypes have been
reported, including lower birth weight in deletion group, shorter birth length in males with UPD and
shorter course of gavage feeding and later onset of hyperphagia in females with UPD. Besides, other
features previously reported with UPD were: less typical facial appearance, mild hypotonia, minor genital
hypoplasia, skill with puzzles, high threshold of pain, and delay in diagnosis.
Roof et al.(2000) and Thompson (2002) have examined differences in intellectual functioning related to
the two genetic subtypes. They have reported that the subjects with UPD had significantly higher verbal
IQ scores than those with deletion, while performance IQ scores did not differ between the two PWS
genetic subtypes.
Butler et al (2004) reported difficulties in reading and math skills as well as visual-motor integration, and
more behavioral and psychological problems in individuals with deletion.
Two major types are found within 95% of the patients with a 15q11-q13 paternal deletion. The
breakpoints of type I deletion are BP1 (proximal) and BP3 (distal), while those of type II deletion are BP2
(proximal) and BP3 (distal). Varela et al. (2005) did not detect significant phenotypic differences among
type I and type II deletions, but they showed that seizures were six times more common in patient with a
deletion than in those with UPD.
METHODS: The study includes18 patients with PWS (10 females and 8 males with age range 2 - 29
years). Diagnosis for all patients in our laboratory was performed by methylation testing. The deletion
was detected by FISH or MLPA, the individuals with UPD were identified by polymorphic STRmicrosatellites.
RESULTS: The PWS deletion group consists of 12 patients (4 males and 8 females), whereas the PWS
UPD group consists of 5 patients (2 males and 3 females). Only one patient is compatible with an IC
mutation. An investigation of the proximal and distal breakpoints will be carried out in 12 patients with a
15q11-q13 paternal deletion.
DISCUSSION: The phenotypic and behavioral features have been evaluated in 18 patients.
The purpose of this study is to correlate these evaluations with the genetic subtypes in our sample, and
compare our results with those already reported.
70
COGNITIVE BEHAVIOR THERAPY (CBT) FOR A YOUNG MAN WITH PWS
Tomoko Hasegawa
Genetic Support and Consultation Office, Tokyo, JAPAN
INTRODUCTION: The main behavior problems of PWS are thought to be developmental and cognitive
disorders, and impulse control disorders involving OCD behavior. With further investigations of their
causes and mechanisms, decisions about treatment strategy can be expected in the near future. On a
practical basis, effective behavior management is necessary, and many approaches have been tried. The
most effective management may be to provide people with PWS with an adequate home and social
environment to protect them against the temptation of food. For this purpose, approaches such as living in
appropriate group homes, and not being allowed to go out without caregivers can yield good results. In
Japan, however, and especially in urban areas, it is difficult to dissociate people with PWS from
neighborhood convenience stores or fast food restaurants. Also, setting up group homes takes a lot of
time. Therefore we have considered that cognitive behavior therapy (CBT) might be an effective strategy
against the inappropriate behavior associated with PWS. CBT is a term used to describe
psychotherapeutic interventions that aim to reduce psychological distress and maladaptive behavior by
altering the cognitive process*. Here we describe CBT for a male PWS patient aged 24 who suffered from
many behavior problems and wished to reduce his compulsion to eat.
PATIENTS and METHODS: The patient was suspected to have PWS at birth, but the condition was
definitively diagnosed at the age of 8 by high-resolution G-banding chromosome analysis. At that time
the boy’s mother had told him that he had PWS. Behavior problems had first become manifested at
preschool age, when he took food from a classmate’s lunchbox. Thereafter, he repeated stealing food, and
also money to buy food. As the patient was highly functional, he attended ordinary school classes. After
graduating from high school, he entered a vocational school for welfare, but dropped out because
schoolwork became too difficult for him. At high school, his weight was 59 kg, but afterwards he gained
weight, reaching 92 kg, and a final height of 153 cm. He is currently working at a firm of his own choice,
after being dismissed from several other firms. His mother has understood his condition very well, and
has socially educated him since his teens, but his repeated behavior problems have been stressful to her.
On the basis of collaboration with the patient and his mother, CBT was performed.
RESULTS and CONCLUSIONS: The first step of CBT is thought monitoring, focusing on negative
automatic thoughts such as “I have a short temper”, “Nobody trusts what I say”, “I am a loser because
even small matters irritate me”, and “It’s better if I’m not here”. To reduce the likelihood of becoming
trapped in a negative spiral, I tried to externalize the problems caused by PWS. I created two
“characters”: the “PWS-devil” and the “PWS-angel”. Since the PWS-devil likes “bad” behavior, the
patient was instructed to deprive the PWS-devil of his power by using “magic words” he could devise
himself. This would empower the PWS-angel, and give him a dominant advantage. After 13 sessions, the
patient is able to use these “magic words” and this gives him a better degree of self-control. CBT is said
to be the most effective approach for tackling behavior problems, and we consider that it can also improve
the negative behavior and negative mindset of people with PWS.
* Paul Stallard : Think Good – Feel Good, A Cognitive Behaviour Therapy Workbook for Children and Young People ( Wiley )
71
BEHAVIOURAL PROBLEMS IN INDIVIDUALS WITH PRADER-WILLI SYNDROME
Engela M. Honey
Department of Genetics, Division Human Genetics, University of Pretoria, Pretoria, South Africa
INTRODUCTION: The evidence of a characteristic behaviour profile in individuals with Prader-Willi
syndrome (PWS) has become evident in recent studies and apart from the abnormal eating behaviour,
temper tantrums, stubbornness, manipulative and controlling behavior, obsessive compulsive features and
difficulty with change in routines might become an additional handicap and should be addressed already
at an early age. In approximately 5-10% of adults with PWS there is evidence of a psychotic disorder
which might interfere with the quality of life and are a frequent cause of hospitalization and medication
use.
METHODS: Individuals diagnosed with PWS in South Africa showed behavioural disturbances and data
from patient files were collected.
RESULTS: Some individuals showed severely abnormal behaviour which included eating nonfood
items, obsessions, social withdrawal from the family and refusal to leave the house. Apathy and daytime
sleepiness in one case was managed with CPAP which caused partial reversal of symptoms.
CONCLUSION: The management consists of behavioural modification and sometimes pharmacotherapy
but the success depends on the exclusion of underlying medical problems and early identification.
72
PARENT – CHILD RELATIONSHIP IN PRADER-WILLI SYNDROME: A
NARRATIVE STUDY
Yael E. Landau1, Rivka Tuval-Mashiach2, Fortu Benarroch1, Varda Gross-Tsur1
1
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem, Israel; 2Department of Psychology, Bar
Ilan University, Israel.
INTRODUCTION: Parent-child relationship are influenced by both the child's personality and cognitive
abilities as well as by parental care giving, sensitivity, psychological processes, beliefs and expectations.
Among these interactions, feeding relationships in the first years of the child's life are, as Winnicott
(1964) formulates "…a putting into practice of love relationship between two human beings". Moreover,
the impact of the feeding relationship on child's subsequent development and firmness of attachment have
been well documented.
Children with Prader-Willi syndrome (PWS) have severe feeding and food related problems.
Paradoxically, in early infancy the feeding problems are characterized by ineffective suck and failure to
thrive, while hyperphagia, a result of hypothalamic abnormality resulting in lack of satiety, begins
between the ages of 1-6 years. Parents know that the hyperphagia can be harmful, toxic and induce
premature mortality and that they can never satisfy their child's hunger.
Our working hypothesis was that the conflict between the wish to nourish versus the negative
ramifications of eating in children with PWS will perturb the dyadic interaction of the child and his
parents. We documented the subjective experience of raising a child with PWS and assessed the impact of
food and feeding in the evolving parent-child relationship.
METHOD: Twenty two parents (10 couples and 2 mothers) of twelve children, five boys and seven girls,
ages 10-78 months, were interviewed. All parents were interviewed in a semi-structured interview,
recorded, transcribed and content analyzed by two researchers (YEL and RTM) for main themes.
RESULTS: Four main themes evolved from the interviews were:
1. Parental experiences were described in extremes and the description of their experience varied
pre- and post-diagnosis.
2. Parents viewed their children at five different domains: As a normal child; As a sick child; As a
child with PWS; as an individual; as a sibling.
3. Parents didn’t seem to be willing to confront future issues believing that their child is “different”.
4. All parents described food and feeding habits in excessive details, both of the child with PWS and
of the family. Moreover, food and feeding were a constant and major concern for most and were
also expressed in internal conflicts and conflicts with the environment.
CONCLUSION: The subjective experience of raising a child with PWS is a definite challenge to the
evolving parent-child relationship. Although parents described normal aspects of raising a child,
excessive preoccupation and concern especially regarding food and feeding colored their description. In
addition unwillingness to entertain future problems was documented.
This research is partially supported by the PWS Association Israel.
73
QUALITY OF LIFE AND PSYCHOLOGICAL WELL-BEING IN GH-TREATED,
ADULT PWS PATIENTS: A LONGITUDINAL
I. Mori,1,4 L. Bertella,1,7 G. Grugni,2 R. Pignatti,1 F. Ceriani,1 E. Molinari,1,3 A. Ceccarelli,1,3 A. Sartorio,2
R. Vettor,6 & C. Semenza1,5
1
Psychological Research Laboratory, Italian Auxological Institute,Verbania, Italy; 2Division of Auxology,
Italian Auxological Institute,Verbania, Italy; 3Catholic University of Sacred Heart, Milan, Italy;
4
Department of Human Sciences, University of Bergamo, Bergamo, Italy; 5Department of Psychology,
University of Trieste,Trieste, Italy; 6Department of Medical Sciences, University of Padua, Padua, Italy;
7
Hildebrand Clinic, Brissago, Switzerland.
INTRODUCTION: The aim of this study was to assess the long-term effect (36 months follow-up) of
GH treatment on the psychological well-being and Quality of Life (QoL) in an adult PWS group.
METHODS: The inclusion criteria for participating in the study were a score over the cut-off value of 24
in the Mini-Mental State Examination (MMSE) and the presence of a minimum intellective level (IQ
score ≥ 45) allowing the administration of the Wechsler Adult Intelligence Scale-Revised (WAIS-R).
Thirteen PWS patients [(7 males and 6 females; aged 27.08 ± 4.55 years (range 20–33 years); body mass
index (BMI=kg/m²) 46.3 ± 5.7 (range 37.1–55.4)], their diagnosis confirmed by genetic tests, and their
parents were recruited for this study. Participants were administered the 36-Items Short Form Health
Survey (SF36) and the Psychological General Well-Being Index (PGWBI), for the assessment of QoL
and psychological well-being, at the beginning of GH treatment, and at following intervals of 6, 12, 24
and 36 months. Modified versions of the same questionnaires were given to the parents.
RESULTS: Significant, long lasting, improvement with respect to the baseline was found, on both scales,
in the evaluation of both physical and psychological well-being. While the parents’ evaluation was less
optimistic than that of the patients at the beginning, on the long term this difference appears to reduce.
CONCLUSION: Our findings suggest that the amelioration of QoL and psychological status is sustained
in patients who continue GH treatment as long as 36 months.
74
AUTISTIC SYMPTOMATOLOGY, PWS AND ITS DERIVATIONS FOR TREATMENT
L. Rosell- Raga 1, V. Venegas-Venegas 1 F. Mulas-Delgado 2, M. Peiro 3
1. Valencian Association Prader-Willi Syndrome. Valencia(Spain) 2. University Hospital “La Fe“ of
Valencia, Valencian Institute of Pediatric Neurology, INVANEP 3. Infantile Endocrinology Service of
the Universitary Hospital “La Fe” of Valencia.
INTRODUCTION: In recent years, PWS has been conceptualized as a widespread disorder of
development or as part of the autistic spectrum. There are many studies that relate chromosome 15 to
autism, but few have demonstrated that the genetic alteration in PWS is related to autism. If we relate
PWS with the autism spectrum or with general development disorders we have to base our foundations
on: 1) genetic foundations, studied by Demb and Papola, Rapin and Artigas, and 2) clinical foundations
(executive function and the Theory of the Mind)
METHODS: We studied PWS diagnostic approaches that are also found in autism in order to make a
therapeutic connection. From VAPWS we conducted a questionnaire study following the diagnostic
approaches for autistic disorder. We centre ourselves in the Diagnostic Manual of Mental Disorders (APA
1994). The questionnaire was carried out with 40 families whose children between 4 and 29 years had the
genetic diagnosis of PWS. We later selected 20 of the families (10 with an adult with PWS, 5 a child in
primary school and 5 an infant) to carry out the Autistic Spectrum Inventory (2002, Riviere. Fundec). We
called the test IDEA. The 10 families of PWS adults were also given the task of False Belief of first and
second order.
RESULTS: The tests demonstrated problems in PWS representing three nuclear features that define the
concept of autistic spectrum, that is to say, they present deteriorations in:
• Socialization (alteration of social development, especially interpersonal development). These
range from loneliness to excessive sociability with strangers.
• Verbal and non verbal communication (pragmatic aspects of the language).
• Restrictive and repetitive parameters of conduct (rigid aspects and limited interests).
DISCUSSION: In view of the results obtained in every dimension of the IDEA, we propose therapeutic
individualized treatment based on the following guidelines:
• A constructed environment. Try to establish a routine.
• Environmental changes. Recognize changes that take place in their environment that produce
changes in them.
• Anticipation of what we expect from them. In a concrete situation we have to tell them what we
expect from them.
• Training in social skills. Skills of communication and empathy.
• Sharing playful experiences. The activities have to be chosen by them.
• Learning without mistakes. We can not make mistakes because that increases the negative
aspects and causes problems of conduct in them. We learn from errors, but in them mistakes
produce negative results.
• Individualized aims and significant learning. Every person is unique and individual, so that we
have to adapt the programs to each person.
• Rules for comprehension. It is necessary to give them guidelines to help them to understand what
we have asked in a visual way or using clear language.
• Negotiation of inflexibility. People with PWS have mental inflexibility, so whenever a step of
inflexibility gives itself we’ll have to reinforce it. If we do not obtain it we’ll have to negotiate
with them.
75
MATH ABILITIES IN PRADER-WILLI SYNDROME
Carlo Semenza1,2, Ileana Mori2,4, Francesca Ceriani2, Riccardo Pignatti2, Laura Bertella2,3, Enrico
Molinari2,5, Daniela Giardino6, Francesca Malvestiti 6 and Graziano Grugni2.
1
Department of Psychology, University of Trieste, Italy; 2Istituto Auxologico Italiano, Ospedale S.
Giuseppe, Piancavallo di Verbania, Italy; 3Clinica Hildebrand, Brissago, TI, Switzerland; 4Dipartimento
di Scienze della Persona, University of Bergamo, Italy; 5Catholic University of Sacred Heart, Milano,
Italy; 6Istituto Auxologico Italiano, Laboratorio di Citogenetica Medica e Genetica Molecolare, Milano.
INTRODUCTION: Disproportionate difficulties with math have been systematically reported in the
literature concerning Prader-Willi syndrome (PWS) but little is known of the precise nature of this
deficit. The present investigation was aimed at assessing mathematical abilities by means of a
theoretically inspired battery of mathematical tasks. The difference between the deletion and the
disomy condition was explored.
METHODS: A group of people with PWS, whose diagnosis was confirmed via cytogenetic analysis
was administered a series of basic mathematical tasks for which normative data are available. Twenty
adult PWS patients (9 males and 11 females), aged 28.65 ± 5.14 (range 19-36), with a minimum of 8
years of education, 15 with Deletion and 5 with Disomy, participated in the study.
RESULTS: While a wide phenotypic variation was found, some basic findings emerge clearly. As
expected, deletion and disomy participants were found to differ in their degree of impairment, with
disomy being overall the most spared condition. The tasks selectively spared in the disomy condition
were not necessarily the easiest ones or those that discriminate less well between the PWS group and
controls. It rather seems that disomy patients are spared, with respect to deletion, in tasks entailing
transcoding and comparison of numbers in the Arabic code. Parity judgments proved to be a very
difficult task, in contrast with what is observed after acquired brain injury. In the Analog number scale
(a task requiring choosing among three alternatives the position corresponding to a given Arabic
numeral on an analog number scale), those with PWS seem, overall, to outperform controls.
CONCLUSION: The most interesting result is perhaps the performance in the Analog number scale.
This finding may help in understanding previously reported, surprising results about cognitive skills in
PWS. Elevated performances in PWS may result from life-long hyper-reliance on one visuo-spatial
system in the presence of underdevelopment of the other.
76
REPETITIVE BEHAVIOUR AND EXECUTIVE FUNCTIONS IN PRADER-WILLI
SYNDROME AND IN AUTISM SPECTRUM DISORDERS
Jeni Tregay1, Jane Gilmour, Tony Charman1
1
Institute of Child Health, University College London, UK
INTRODUCTION: Repetitive and ritualistic behaviours (RRBs) form part of the behavioural phenotype
of Prader-Willi syndrome (PWS). Research over recent years has found RRBs in PWS to be highly
comparable both in number and frequency to those seen in autism spectrum disorders (ASDs) in which
they are core diagnostic feature. Executive dysfunction has been implicated in the aetiology of these
behaviours in neurodevelopmental conditions, yet this relationship remains unclear in ASD and is
unexplored in PWS.
METHODS: Adolescents (mean 15 years) with a diagnosis of PWS (n=25) and ASD (n=25) completed a
comprehensive battery of tasks tapping aspects of the executive system (cognitive flexibility, inhibition,
generativity, planning). Parents completed the Childhood Routines Inventory (CRI) and the Repetitive
Behaviour Scale-Revised (RBS-R). Data were also collected from Controls with no diagnosis of PWS or
ASD. Groups were matched on age and IQ.
RESULTS: Results from the questionnaires showed that the PWS had a significantly higher mean total
score on the RBS-R than either controls or the ASD group. Parents of adolescents with PWS also
endorsed a greater number of RRBs on the CRI than parents of adolescents with ASD or Controls but
CRI frequency scores between the PWS and ASD groups were comparable. RRBs on both measures were
found to correlate highly with IQ in PWS and in Controls but not in ASD. Executive measures of
cognitive flexibility were found to correlate with IQ in all three groups. However, associations between
parent reports of RRBs and the executive measures revealed a significant correlation between RRBs on
both the RBS-R and CRI and a measure of cognitive flexibility in PWS and in Controls, but not in ASD.
An association between the same measure of cognitive flexibility and RRBs was also found in another
study of typically developing school-age children (n=78).
CONCLUSIONS: RRBs are correlated with cognitive flexibility in PWS (and Controls) but not in ASD.
This suggests that RRBs in the two disorders may arise through different mechanisms. Similar
associations between RRBs and cognitive flexibility in PWS and in typical development support the
hypotheses that these behaviours may be the result of developmental arrest in PWS (Holland et al., 2003).
77
HAS GUT-DERIVED HORMONE PYY 3-36 A CAUSATIVE ROLE IN HYPERPHAGIA
AND OBESITY IN PWS?
Alexander Viardot, MD1, Leonie Heilbronn, PhD1, Herbert Herzog, PhD1, Georgina Loughnan2, Kate S
Steinbeck, MD PhD2, Lesley V Campbell, MD PhD1
1
Garvan Institute of Medical Research, Sydney-Darlinghurst, Australia, 2Royal Prince Alfred Hospital,
Prader-Willi Syndrome Clinic, Sydney-Camperdown, Australia
BACKGROUND: Prader-Willi syndrome (PWS) is associated with hyperphagia and severe obesity,
which puts these subjects at high cardiovascular risk. Because the options for pharmacological support are
few, behavioural restraints are commonly used. While the cause of obesity is thought to be of
hypothalamic origin, the exact mechanism is not known. It has recently been postulated that gut derived
hormones involved in appetite regulation, such as PYY 3-36, GLP-1 and ghrelin, may play a role in PWS.
However, the method of measurement of these hormones, and especially PYY, are not standardised, and
therefore conflicting results are found in the literature regarding whether PYY may be involved as a cause
for obesity in PWS.
PYY 1-36 is secreted by the L-cells in the distal jejunum in response to meals, and is quickly cleaved into
its active form PYY 3-36 by depeptidyl peptidase IV. Whilst PYY 1-36 binds to all forms of NPYreceptors in the hypothalamus, only PYY 3-36 is specific to the Y2-receptor, which is believed to mediate
the central anorectic effect. Unfortunately, most studies investigating PWS report total PYY levels, which
may not reflect biological activity. Therefore, we aimed to measure active PYY 3-36 in subjects with
PWS as compared to weight matched and lean controls.
METHODS: 7 subjects diagnosed with PWS were recruited at the Prader-Willi Syndrome Clinic at
Royal Prince Alfred Hospital, Sydney Australia for a fasting blood sample (>8h). 5 weight matched obese
controls, 8 slightly overweight controls and 9 subjects with a high genetic risk for type 2 diabetes (strong
family history) were recruited at the Garvan Institute of Medical Research for fasting blood and a high
caloric high fat/low carbohydrate meal to validate our PYY assay. We used commercial RIA’s from
Linco™ detecting either specifically the cleaved PYY 3-36, with no cross-reactivity to PYY 1-36, or the
total PYY.
RESULTS: Our subjects with PWS (n=7, 28 y.o., BMI 39.5 kg/m2) had slightly higher PYY 3-36 levels
(79.5 pg/ml) as compared to weight matched controls (62.6 pg/ml, n.s.), and significantly higher levels
compared to leaner subjects (59.0 pg/ml, p<0.04). Subjects with high genetic risk for type 2 diabetes
showed a trend to lower PYY 3-36 fasting levels (52.5 pg/ml) as compared to age and weight matched
controls (59.0 pg/ml). The levels of PYY 3-36 and total PYY were congruent through the groups.
CONCLUSIONS: Our finding that PYY 3-36 (and total PYY) levels are elevated in PWS and similarly
in (nearly) weight matched controls as compared to leaner subjects is interesting, considering the
conflicting results in the literature of total PYY and its contribution to obesity. Our results suggest that
there is no primary deficiency of PYY 3-36 in PWS directly causing obesity. Certainly, this will not
predict whether pharmacological use of PYY 3-36 may not be useful in this disorder, considering the
supra-physiological doses which are needed and have been tested in clinical trials. Our future research
will investigate whether the response of PYY 3-36 and other related hormones are altered in PWS in
response to a meal stimulus.
78
RELATIONSHIP BETWEEN PRADER-WILLI SYNDROME (PWS) AND SIBLING
ABILITY (IQ)
Joyce Whittington1, Tony Holland1, Tessa Webb2
1
Department of Psychiatry, University of Cambridge; 2Institute of Biomedical Research, University of
Birmingham
INTRODUCTION: In a population sample of people with PWS, we reported a normal distribution of
IQ with a mean of 61.4 and standard deviation 13.0. The question then arose as to whether this
distribution was made up of random effects of PWS or a systematic effect in which IQ scores were
similarly depressed in each individual, either by a fixed amount or a proportional amount. We
investigated this by looking at the performances of people with PWS and their siblings
METHOD: We recruited 29 families with a PWS member and one or more siblings, through the PWSAUK. Each family was visited and the age-appropriate Wechsler IQ scales were administered to the person
with PWS and to one or more siblings.
RESULTS: The overall correlation between IQs of people with PWS and their siblings was .21, the
correlation between unaffected siblings in families with two or more PWS siblings was .54 (predicted
value for siblings is .5). However, when the PWS group was divided into genetic subtypes, there were
large unexplained differences in correlations.
Regression showed that the difference between PWS and sibling IQ was best explained by the PWS score
on the Arithmetic subtest with an R2 of .73.
DISCUSSION: Some of the variation in PWS-sibling differences is due to co-morbidity in some people
with PWS due to birth trauma. It was not possible to assess the extent of co-morbidity in the whole
sample. Genetic subtype differences will be discussed.
79
Presenters and Affiliations: In Alphabetical Order
Name:
Karina Abraldes
Dr. Fortu Benarroch
Neuropediatric Unit
Maria Bianco
Institution for Mental
Retardation Oasi Maria
SS (IRCCS)
Ulla M. Veltzé Bollerslev,
M.Ed.Psych.
Suzanne B. Cassidy, M.D.
Clinical Professor of
Pediatrics
Francesca Ceriani
Philippe J.L. Collin, M.D.
Department of Child
Psychiatry
Fanny Cortés M.D.
Antonino Crinò, M.D.
Paediatric and
Autoimmune Endocrine
Diseases Unit
Prof. Dr. Leopold M. G.
Curfs
Department Clinical
Genetics
Dr Gwenaëlle Diene
Centre de Référence du
Syndrome de PraderWilli
Daniel J. Driscoll, Ph.D.,
M.D.
Professor of Pediatrics
and Genetics
Oenone Dudley, Dip Clin
Psych
80
Address:
Shaare Zedek Medical Center
POB 3235
Jerusalem 91031, Israel
Via Conte Ruggero, 73
94018 Troina (En)- Italy
University of Oslo
Section of Endocrinology
National University Hospital
N-0027 Oslo, Norway
Division of Medical Genetics
University of California, San
Francisco
66 Toyon Lane
Sausalito, CA 94965
USA
Istituto Auxologico Italiano
IRCCS Ospedale San
Giuseppe Via Cadorna, 90
28824 Oggebbio-Verbania
ITALY
Gastenhof / Koraal Groep
Raadhuisstraat 13
6129 CA Urmond
The Netherlands
Macul 5540
Santiago, Chile
Bambino Gesù Hospital,
Research Institute
via Torre di Palidoro
00050 Palidoro (Roma) - Italy
University Maastricht /
Academic Hospital Maastricht
P.O. Box 1475
6201 BL Maastricht
Nederland
Equipe d’Endocrinologie
Hôpital des Enfants
330 av de Grande Bretagne
TSA 70034
31059 Toulouse Cedex 9
France
Hayward Professor of Genetics
Research
Box 100296
University of Florida College
of Medicine
Gainesville, FL
32610-0296 USA
IBDML
Campus de Luminy –
Case 907
13288 Marseille, France
E-mail:
kabraldes@hotmail.com
FORTUBEN@hadassah.org.il
mbianco@oasi.en.it
ullamvb@yahoo.no
cv.sc@sbcglobal.net
francesca.cer@gmail.com
pcollin@gastenhof.koraalgroep.nl or
collin-dewulf@skynet.be
fcortes@inta.cl
crino@opbg.net
Curfs@msm.nl
diene.g@chu-toulouse.fr
email: driscdj@peds.ufl.edu
web:
http://www.mgm.ufl.edu/faculty/Ddrisc
oll.htm
odudley@ibdml.univ-mrs.fr
Elisabeth M. Dykens,
Ph.D
Associate Director,
Vanderbilt Kennedy
Center for Research on
Human Development
Paolo Fanari M.D.
Department of
Pulmonary Rehabilitation
S. Giuseppe Hospital
Research Institute
Janice L. Forster, M.D.
and Linda M. Gourash,
M.D.
Dr. Tony Goldstone MA
MRCP Ph.D
Senior Clinical Research
Fellow,
Hon Consultant
Endocrinology &
Metabolic Medicine
Robert Steiner MRI Unit,
Imaging Sciences
Department
Donatella Greco, M.D.
Graziano Grugni, M.D.
Dr. Colin J. Hamilton
Division of Psychology
Tomoko Hasegawa
Rebecca Hawkins
Dr. Uros Hladnik, M.D.,
spec. gent.
Head Of Laboratories
Director, Vanderbilt Kennedy
University Center of
Excellence on Developmental
Disabilities
Professor, Psychology and
Human Development
230 Appleton Place
Peabody Box 40
Nashville, TN 37203
Istituto Auxologico Italiano
Foundation
PO Box 1
28921 Verbania
ITALY
Pittsburgh Partnership
615 Washington Road
Suite 107
Pittsburgh, PA 15228-2909
MRC Clinical Sciences Centre
Faculty of Medicine
Imperial College,
Hammersmith Hospital
Campus
Du Cane Road, London
W12 0NN
United Kingdom
elisabeth.dykens@vanderbilt.edu
Unit of Pediatrics Oasi
Institute for Research on
Mental Retardation and Brain
Aging
Via Conte Ruggero, 73
94018 Troina, EN - ITALY
Department of Auxology,
IRCCS S. Giuseppe Hospital,
Italian Auxological Institute
Foundation
PO Box 1
28921 Verbania, ITALY
School of Psychology and
Sport Sciences
Northumbria University
Newcastle upon Tyne
NE1 8ST
2-23-3 Hara-machi,
Meguro-ku, Tokyo,
152-0011 Japan
Learning Disabilities Research
Group Section of
Developmental Psychiatry
University of
Cambridge Second Floor,
Douglas House 18b
Trumpington Road
Cambridge CB2 8AH UK
B.I.R.D.
Europe Foundation Onlus
Via B.Bizio, 1
36023 Costozza di
Longare(Vicenza)
dgreco@oasi.en.it
rehab.med@auxologico.it
janiceforstermd@aol.com
tony.goldstone@imperial.ac.uk
g.grugni@auxologico.it
Colin.hamilton@unn.ac.uk
hasemoko@aol.com
rjh74@cam.ac.uk
uros.hladnik@birdfoundation.org
www.birdfoundation.org
81
Tony Holland
MBBS, MRCPsych,
M.Phil
Douglas House
18b Trumpington Road
Cambridge
CB2 2AH
UK
Ajh1008@cam.ac.uk
Engela M. Honey
Department of Genetics
Division Human Genetics
University of Pretoria
P.O. Box 2034
Pretoria, SOUTH AFRICA
Hufelandstrasse 55, D-45122
Essen, Germany
ehoney@medic.up.ac.za
Fritz-Pregl-Str. 3
6020 Innsbruck, Austria
alexander.huettenhofer@i-med.ac.at
Frambu, v/Marianne
Lindmark
Sandbakkeveien 18
1404 Siggerud, Norway
Royal Prince Alfred Hospital
L 6 West Missenden Rd
Camperdown NSW 2050
mal@frambu.no
Istituto Auxologico Italiano
IRCCS
Ospedale San Giuseppe
Via Cadorna 90
28824 Oggebbio-Verbania
ITALY
Koshigaya Hospital
2-1-50 Minami-Koshigaya
Koshigaya, Saitama 343-8555,
Japan
ileana.mori@libero.it
Parc Scientifique de Luminy
CNRS Case 907
13288 Marseille Cedex 9
France
muscatel@ibdml.univ-mrs.fr
http://ibdml.univ-mrs.fr
2-1-50 Minamikoshigaya
Koshigaya Saitama
343-0555, Japan
Str. Dambovitei nr.28 ap.35
Cluj-Napoca, ROMANIA
Jud. Cluj 400584
Istituto Auxologico Italiano
IRCCS
“San Giuseppe” Hospital,
Strada L. Cadorna 90
28824 Piancavallo – Oggebbio
(VB)(Italy)
t-nagai@dokkyomed.ac.jp
Bernhard Horsthemke,
PhD, Professor and Chair
Institut fuer
Humangenetik,
Universitaetsklinikum
Essen
Alexander Huttenhofer,
Ph.D.
Biocentre Innsbruck,
Division of Genomics &
RNomics
Marianne Lindmark,
Nutritionist
Georgina Loughnan
Metabolism & Obesity
Services
and The Prader-Willi
Syndrome Clinic
Ileana Mori
Nobuyuki Murakami
M.D., Ph.D
Department of Pediatrics,
Dokkyo Medical
University
Francoise Muscatelli,
Ph.D
Institut de Biologie du
Developpement de
Marseille-Luminy
Toshiro Nagai M.D.,
Ph.D
Lenuta Popa M.D., Ph.D
Lorenzo Priano M.D.
82
bernard.horsthemke@uni-due.de
georgie@email.cs.nsw.gov.au
nobuyuki@dokkyomed.ac.jp
lenapopa@yahoo.com
lorenzopriano@yahoo.it
Dinko Relkovic
Behavioural Genetics
Group
Psychological Medicine
Cardiff University
Laboratory of Cognitive
and Behavioural
Neuroscience
Laura Rosell-Raga
Astrid Schulze
Cristina Skrypnyk, M.D.
University of Oradea
Faculty of Medicine,
Genetics Department
Dr. Sarita Soni
Clinical Research
Associate
Mihaela Stefan, Ph.D
Domenica Taruscio
Takayoshi Tsuchiya M.D.
Department of Pediatrics,
Dokkyo Medical
University
Jeni Tregay
PhD Student
E. Vaiani
Tina Varlan G.N.
Dr. Alexander Viardot,
M.D.
Diabetes & Obesity
Research Program
Annick Vogels M.D.
Ph.D.
Department of Human
Genetics
Henry Wellcome Building
Heath Park Cardiff
CF14 4XN
UK
The Babraham Institute
Babraham Research Campus
Babraham Cambridge
CB2 4AT
UK
C/ Valle de Laguar
Nº 10 pta 43,
CP 46009
Valencia. España
Otte Ruds Vej 12
5220 Odense
Denmark
Clinical Children Hospital
"Dr. Gavril Curteanu"
Str. C. Coposu Nr. 12
Oradea, Romania
BH 410469
Section of Developmental
Psychiatry Top Floor
Douglas House
18b Trumpington Road
Cambridge
CB2 2AH
Department of Pediatrics,
Children's Hospital of
Pittsburgh,
3460 Fifth Avenue
Pittsburgh, PA
15213-2583 USA
Istituto Suoeriore di Sanità,
Viale Regina Elena, 299
Rome (Italy)
Koshigaya Hospital
2-1-50 Minami-Koshigaya
Koshigaya, Saitama 343-8555
Japan
Behavioural and Brain
Sciences Unit 4th Floor,
Institute of Child Health
30 Guilford Street
London WC1N 1EH
Department of Auxology,
IRCCS S. Giuseppe Hospital,
Italian Auxological Institute
Foundation
PO Box 1
28921 Verbania, ITALY
Garvan Institute of Medical
Research
384 Victoria Street
Darlinghurst NSW 2010
Australia
University Hospital of Leuven
Herestraat 46
3000 Leuven
Belgium
relkovicd@cardiff.ac.uk
laurarosell@ono.com
astridschulze@mail.dk
cristinaskrypnyk@yahoo.com
ss507@medschl.cam.ac.uk
mihaela.stefan@chp.edu
nephird@iss.it
t-tsuchi@dokkyomed.ac.jp
j.tregay@ich.ucl.ac.uk
elisvaiani@hotmail.com
tinavarlan@yahoo.it
g.grugni@auxologico.it
a.viardot@garvan.org.au
Annick.Vogels@uzleuven.ac.be
83
Dr. Tessa Webb
University of
Birmingham
Barbara Y. Whitman,
Ph.D.
Saint Louis University
Department of Pediatrics
Dr. Joyce E. Whittington
Kate Woodcock
Ph.D. Student
84
Department of Medical
Sciences, IBR, Medical School
University of Birmingham
Edgbaston, Birmingham B15
2TT, UK
Cardinal Glennon Children’s
Medical Center
1465 S. Grand
St. Louis, MO 63104
University of Cambridge
Department of Psychiatry
Douglas House, 18b
Trumpington Road
Cambridge CB2 8AH
t.webb@bham.ac.uk
School of Psychology
University of Birmingham
Edgbaston, B15 2TT, UK
kaw114@bham.ac.uk
Whitmanb@slu.edu
jew1000@medschl.cam.ac.uk
85
86
6th International Prader-Willi Syndrome Conference
Caretakers Program
Cluj-Napoca, Romania
June 21, 2007
Co-Organizers
Dr. Hubert Soyer- Chair (Germany)
N. Hödebeck-Stuntebeck- Chair (Germany)
Jackie Mallow- Chair (USA)
87
IPWSO Caretakers Program
Thursday- June 21, 2007
First Floor Auditorium One
9.00-9.15: Welcome and Opening- Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer, Jackie
Mallow
9.15-11.00: Presentation of What Different Countries Offer for People with PWS
9.15-10.00: USA- Barbara J. (“BJ”) Goff, Ed.D and Jackie Mallow
10.00-10.30: England (UK) - John Booth and Narinder Sharma
10.30-11.00: Germany- Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer
11.00-11.30: COFFEE BREAK (GENERAL LOBBY)
Pop Room 1
11.30-12.00: Sweden- Lisa Bowman
12.00-12.30: Denmark- Jytte Helgogaard
12.30-13.30: LUNCH (BUFFET IN GENERAL LOBBY)
Pop Room 1
13.30-14.00: Argentina- Jorgelina Stegmann
14.00-14.30: Israel- Larry Genstil
14.30-14.40: SMALL BREAK
14.40-17.15: Future Work for Future Conferences
Pop Room 1
14.40-14.55: Introduction- What kind of Standards and guidelines do we need in the future?
Moderators: Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer, Jackie Mallow
14.55-15.10: Working in a Large Group- Fields of work in PWS
Moderators: Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer, Jackie Mallow
15.10-15.40: COFFEE BREAK
Split Groups Pop Room 1 and Pop Room 2
15.40-16.15: Working in Small Groups- Assessing Resources and Needs in the field of PWS
Moderators: Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer, Jackie Mallow
Pop Room 1
16.15-16.45: Presenting Small Group Work
Moderators: Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer, Jackie Mallow
88
16.45-17.15: Conclusion and Perspectives on the Conference in Germany 2008
Moderators: Norbert Höedebeck-Stuntebeck, Dr. Hubert Soyer, Jackie Mallow
17.15: DINNER (GENERAL LOBBY)
14.40-17.15: Future Work for Future Conferences- Workshop Details
1. Introduction: Aims of the Workshop
• To have an overview about the working fields in PWS (Living, Working, School,
Physical Therapy, Psychological Treatments, etc…)
• To discuss what we know about practical work and people with PWS
• To discuss which of these things are helpful
• To discuss which kinds of things we need for the future
• What kind of main themes should be implicated in the Germany conference 2008?
2. Working in a large group
• Work out a list of the working fields in PWS with the whole group
• Fix the working fields, with which the small groups should working
3. Working in small groups
Every group should answer the same following questions:
a) Which themes or programs exist in this working field and which were helpful in
the past (List of themes or programs)?
b) Which questions have not been answered in the past and which must be answered
in the future (List of questions and themes)?
c) Fix, which themes of the two lists should be the main themes or the main
questions at the conference in Germany 2008?
4. Presentation of the results of the different small groups
5. Conclusions and Perspectives
89
6th International Prader-Willi Syndrome Conference
Associations Day Program
Cluj-Napoca, Romania
June 21, 2007
Co-Organizers
Joan Gardner- Chair (USA)
Jackie Waters- Chair (UK)
90
IPWSO Associations Day Program
Thursday- June 21, 2007
First Floor Auditorium One
9.00-11.00: Joint Sessions with Caretakers Day
11.00-11.30: COFFEE BREAK (GENERAL LOBBY)
First Floor Auditorium One
11.30-12.00: Growing Non-Governmental Organizations- Heinrich Schnatmann- Germany
Heinrich Schnatmann will describe strategies in working with foreign Governments and foreign
countries’ non-governmental organizations. He will highlight his successes for PWS
organizations in Germany and abroad.
12.00-12.30: Funding your Association- Narinder Sharma- UK and Tiina Silvast- Finland
In this session, Narinder Sharma and Tiina Silvast will explore creative and traditional ways in
which PWS associations from around the world have raised funds to support their work.
12.30-13.30: LUNCH (BUFFET IN GENERAL LOBBY)
13.30-13.40: The First Ten Years of IPWSO- Jean Phillips-Martinsson- Sweden
Jean Phillips-Martinsson will talk about the founding and first ten years of IPWSO history. She
will share the excitement and struggles that launched this international organization.
13.40-13.50: IPWSO and Developing Nations- Giorgio Fornasier- Italy
Giorgio Fornasier will talk about IPWSO’s work in developing countries, the explosive growth
of IPWSO membership and the International headquarters at BIRD in Italy.
13.50-14.15: Growing your Association- Dorica Dan- Romania
In this session, Dorica Dan will explore the innovative and successful ways in which her
organization has grown both in recognition and size. There will be time for discussion of
potential strategies.
14.15-14.20: Assembling of the Panel
14.20-15.10: Experiences of IPWSO’s Members- Ragnhild Overland Arnesen- Norway and
Dianne Rogers-Canada and additional participants. Representatives from different places in the
world will briefly describe their country’s situation including size, membership, national
awareness of PWS and available resources. They will highlight their country’s successes with
PWS. At the conclusion of these five minute presentations, the panel will respond to questions
from the audience.
15.10-15.40: COFFEE BREAK (GENERAL LOBBY)
15.40-16.00: Raising Awareness of Prader-Willi Syndrome- Urith Boger- Israel
Urith Boger will discuss practical experiences and successful strategies in raising the awareness
of both the general public and the professional community in her country.
91
16.00-16.45: Influencing Governments: The Growth Hormone Model- Linda ThorntonNew Zealand, Maria Libura- Poland, and audience participation
These presenters will share their country’s experience in obtaining growth hormone therapy for
their children or adults of their countries. Members of the audience will have time to share their
experiences and ask questions.
16.45-17.00: Associations Day Conclusion- Pamela Eisen- IPWSO President
Pam Eisen will end Associations’ Day with highlights of her visits to IPWSO member countries.
She will also talk of the vision and promises of the future for IPWSO and persons who have
PWS.
17.00: Conclude with the singing of “Flying High” and “Ich Auch”
17.15: DINNER (GENERAL LOBBY)
92
6th International Prader-Willi Syndrome Conference
Parents and Professionals Program
Cluj-Napoca, Romania
June 22-23, 2007
Co-Organizers
Susanne Blichfeldt, MD- Chair (Denmark)
Dorica Dan- Chair (Romania)
Pamela Eisen- IPWSO President, Chair (USA)
----------
IPWSO and the organizers would like to thank Pfizer Worldwide Endocrine
Care for their generous support of the Parents and Professionals Conference
for their generous sponsorship.
93
IPWSO Parents and Professionals Program
Friday- June 22, 2007
First Floor Auditorium One
9.00-10.30: Welcome and Announcements-PWS @ 50 years and IPWSO @ 16 years
Dorica Dan- Conference Host and Organizer and Pam Eisen- President IPWSO and
Organizer, Local Authorities Welcome
10.30-11.00: Positive Experiences and Successes
Keynote Speaker- Alexandru Tiberiu Dan- Growing Up with a Sister with PWS
11.00-11.30: COFFEE BREAK (GENERAL LOBBY)
11.30-12.30: Parent Groups-Daily Management - Sharing Experiences – Get to know each other
There will be two moderators with an introduction for each age group
Pop Room 1Birth to 5 years
Mariona Nadel- Spain
Janalee Heinemann,
MSW- USA
First Floor
Auditorium One6-10 years
Doris BaechliSwitzerland
Monika FuhrmannGermany
Workshop Room 111-18 Years
Elli Korth- Argentina
Dorica Dan- Romania
Pop Room 219 years through
Adulthood
Jackie Waters-UK
Rika Du Plooy- South
Africa
12:30-14:00: LUNCH (BUFFET IN GENERAL LOBBY)
First Floor Auditorium One
14.00-15.15: Chair- Susanne Blichfeldt
14.00-15.15: Overview of Prader-Willi Syndrome- Including genetic highlights from scientific
presentations- Suzanne Cassidy, MD USA
15.15-15.45: COFFEE BREAK (GENERAL LOBBY)
15.45-16.15: Split Sessions
First Floor Auditorium One- Children
Chair- Martin Ritzen
Growth and Physical Development
Growth hormone treatment in children
Laura Bosio, MD – Italy
Second Floor Auditorium Two- Adults
Chair- Tony Goldstone
Endocrinology
Hormonal Treatment in Adults
Kate Steinbeck, MD, PhD- Australia
16.15-17.00: Split Sessions
First Floor Auditorium One- Children
Chair- Martin Ritzen
Behavior & Psychiatry
Annick Vogels, MD, PhD. Child PsychiatristBelgium
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Second Floor Auditorium Two- Adults
Chair- Tony Goldstone
Behavior, Psychology, Psychiatry, Ethical
Aspects
Anthony Holland, MD, PhD.- UK
19.00: DINNER (GENERAL LOBBY)
Saturday- June 23, 2007
First Floor Auditorium One
9.00-10.30: Chair- Leopold Curfs
9.00-9.30: A Swiss comprehensive model-Urs Eiholzer, MD- Switzerland
9.30-9.45: PWS expert meeting held October 2007 in Toulouse- Highlights and Future
Expectations- Tony Goldstone, MD, MA, MRCP, PhD- UK
9.45-10.05: Sleep and skin picking- Leopold Curfs, PhD- The Netherlands
10.05-10.20: Scoliosis- Désirée Moharamzadeh, MD- Italy
10.20-10.30: Medical Alert Booklet Announcement- Janalee Heinemann, MSW- USA
10.30-11.00: COFFEE BREAK (GENERAL LOBBY)
11.00-11.30: Diet and Food
First Floor Auditorium OneChildren to Age 16
Chair- Annick Vogels
Diet management at home, school, and
everywhere- Peter Davies, B.Sc (Hons) M.Phil
PhD- Australia
Second Floor Auditorium TwoAge 16 to Adulthood
Chair- Janalee Heinemann, MSW
Management with focus on food, diet, and
weight- Linda Gourash, MD- USA and Janice
Forster, MD- USA
11.30-12.00: Physiotherapy and Motor activities
First Floor Auditorium OneChildren to Age 16
Chair- Annick Vogels
Kaja Giltvedt, Pediatric PhysiotherapistNorway
Second Floor Auditorium TwoAge 16 to Adulthood
Chair- Janalee Heinemann, MSW
Georgina Loughnan, Physiotherapist- Australia
12.00-12.30: Positive aspects forum- Kindergarten-School-Work Integration-Special Needs
First Floor Auditorium OneChildren to Age 16
Chair- Laura Bosio
Birth to age 6- Susanne Blichfeldt, MDDenmark
Age 6 to Age 16- B.J. Goff, EdD- USA
Second Floor Auditorium TwoAge 16 to Adulthood
Chair- Linda Gourash
Working and living at home- Jackie WatersUK
Working and living at home- Tiina SilvastFinland
Working and living in a group home- Jim
Gardner- USA
12.30-13.30: LUNCH (BUFFET IN GENERAL LOBBY)
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13.30-15.00: Special approaches around the world
First Floor Auditorium OneChildren
Chair- Shuan Pei Lin
Small Children- Tomoko Hasegawa, MDJapan
Children of Taiwan- Shuan-Pei Lin, MDTaiwan
The Frambu Model- Kai Rabben, MD- Norway
Eileen Greunke, Elke Neumann and René
Römling- Langenstein, Sachsen-Anhalt,
Germany
Second Floor Auditorium TwoAdults
Chair- Jim Gardner
PWS Center- Hendaye France (film)
Medical Intervention and Inpatient
Rehabilitation- Linda Gourash, MD- USA
B.I.R.D.- Anna and Giuseppe BaschirottoItaly
Sabine Bohnenpoll and Thomas PolomskyNaumburg/Hessen, Germany
15.00-15.30: Question and Answers Session in both Auditoriums- Written questions will be
submitted by the audience to the expertsFirst Floor Auditorium One
Moderator for Children (Birth through age 19): Suzanne Cassidy
Second Floor Auditorium 2
Moderator for Adult Children (age 19 through adulthood): Susanne Blichfeldt
15.30-15.50: COFFEE BREAK (GENERAL LOBBY)
15.50-16.50: Workshops
1. Weight Management- Workshop Room 2
Peter Davies, B.Sc (Hons) M.Phil PhD- Australia and Marianne Lindmark, Dietitian- Norway
2. Adults Health Issues & Aging- Workshop Room 1
Kate Steinbeck, MD, PhD- Australia and Jorgelina Stegmann, MD- Argentina
3. PWS Management- Second Floor Auditorium Two
Janice Forster, MD- USA and Linda Gourash, MD- USA
4. Group Homes- Parent- Caregiver-Dialogue- First Floor Auditorium One
Jim Gardner- USA and Jackie Mallow- USA and Grethe Ostergaard- Denmark
5. Psychology & How to Manage PWS Family Situations- Pop Room 2
Palma Bregani, PhD- Italy and Irune Achutegui, PhD- Italy
6. School Integration & Socialization- Workshop Room 3
B.J. Goff, EdD- USA
7. Physiotherapy- Pop Room 1
Kaja Giltvedt, Pediatric Physiotherapist- Norway and Georgina Loughnan, PhysiotherapistAustralia
17.00: IPWSO General Assembly- First Floor Auditorium One
19.00: Conference Close and DINNER (GENERAL LOBBY)
96
Parents and Professionals Presentations- In Order of Appearance:
Overview of Prader-Willi Syndrome
Including Genetic Highlights from the IPWSO Scientific Conference
Suzanne B. Cassidy, M.D., Clinical Professor of Pediatrics, University of California, San Francisco,
USA
Prader-Willi syndrome is a complex genetic condition affecting multiple systems. First described in 1956,
for many years its cause was unknown, and it was believed that affected individuals were destined to die
young of complications from inevitable obesity. Since that time, particularly since the genetic basis began
to be identified in 1981 and diagnosis was greatly improved, much has been learned about the
manifestations, clinical course, management, and cause. We now know that there is a wide range of
severity of all of the major manifestations—hypotonia, growth deficiency, hyperphagia (the drive to eat),
developmental disability, characteristic behavioral patterns, hypogonadism (sex developmental
insufficiency), and characteristic appearance. We also know that obesity is not inevitable, and can be
treated if it occurs. We have found several other effective ways to improve the lives of affected people,
including medications for growth and psychological disturbances. We have leaned a great deal about the
unique and complex alterations of chromosome 15q that can cause PWS, and are improving our
knowledge about which genes in the altered region are responsible for the manifestations. The more that
is known, the better the care of the affected people, the happier will be their families and caregivers, and
the more hopeful will be the future for those touched by PWS.
Hormonal Treatment in Adults
Kate Steinbeck
In adolescence and young adulthood in Prader-Willi Syndrome the management of hypogonadism is of
major importance. Central hypogonadism as a result of hypothalamic dysfunction is present in both
females and males, with males also experiencing primary hypogonadism with cryptorchidism and small
testicles. The gonadal hormones, estrogen and testosterone, are required for the development of secondary
sexual characteristics, for the prevention of osteoporosis and for cardiac wellbeing. The scientific studies
on hormone replacement (HRT) have all been performed on older populations (post-menopausal females
and aging males) and it is difficult to extrapolate findings from these studies to younger populations.
There is thus little evidence on which to base therapy regimens and in our experience there are often
barriers to the initiation of HRT. On review of the available literature HRT is used in less than 50% of
PWS clinic patients, although the prevalence of hypogonadism would be much higher. HRT would be
expected to improve bone density and reduce bone loss, is likely to be cardio-protective in the young
adult years and in males is likely to improve physical appearance and muscle strength. Physical changes
with HRT may be less apparent in females with PWS and many would prefer regimens without
menstruation. Some of the barriers to the use of HRT include concerns from carers and guardians about
behaviour change, adverse physical effects and drug interactions. There is no good evidence that initiation
of HRT worsens behaviour in PWS. This presentation will also discuss our Service’s experience with
HRT, particularly the need to slowly induce pubertal change and the advantages of certain types of
testosterone and estrogen preparations.
97
Behaviour and Psychiatric Problems in Children with Prader-Willi Syndrome
A.Vogels, V. Govers, M.J Descheemaeker, J.P. Frijns
Centre for Clinical Genetics, Leuven, Belgium
During the first years of life, infants and toddlers with PWS are usually easy going and affectionate.
Around the age of two and simultaneously with the change in eating pattern, children show significant
maladaptive behavioural and emotional characteristics including temper tantrums, stubbornness and
intolerance of frustration. Such episodes result in personalities that can be gentle and sweet at times, but
also persevering and obsessive compulsive at others (Whitmann and Accardo, 1987). By school age, the
compulsiveness and obsession of the behaviour significantly increase. Anxieties, obsessive compulsive
symptoms, poor peer interactions and inappropriate social behaviour become more evident. In addition,
the intellectual achievement in most children falls short of their intellectual abilities regardless of their IQ
(Holm, 1981).
Adolescents are described as extraordinarily stubborn, clever manipulative, moody and prone to temper
outbursts (Dykens et al., 1995). There are hardly any guidelines for the use of psychopharmacological
medication for non-food related behavioural problems in PWS. About 10% of the adolescents develop
major psychiatric problems ranging from severe and agitated depression to psychotic episodes (Vogels,
2004).
A special multidisciplinary program for prevention and guidance of behaviour problems was elaborated at
the Centre for Clinical Genetics of Leuven. The program is based on the interaction between the
behavioural problems, the diet and the physical problems. After discharge form the neonatal unit, parents
as well as the child are followed-up. Parents of young children are invited to group sessions. The child is
followed by the pediatrician and the dietician. Around the age of five, group sessions for the children are
organised during which a special diet program for PWS children is taught. The psychologist visits the
school to give information on the syndrome as well as to discuss the specific problems of the child. Four
basic rules are essential to prevent behaviour problems: schooling of the parents and the educators,
structure for the child, stress reduction and enough sleep for each child.
Follow-up of the physical problems is an essential part of the clinic: the child is seen by the psychiatrist,
the endocrinologist and the dietician. If necessary the child is also seen by the orthopedist, the dentist
and/or the ophthalmologist.
References:
Holm (1981) the diagnosis of Prader-Willi syndrome. In: The Prader-Willi Syndrome. Holm V,
Sulzbacher SJ, Pipes PL (eds). Baltimore, MD, University Park Press, pp 27-44
Vogels A. (2004) Psychosis in the Prader-Willi Syndrome: implications for psychiatric genetics. Doctoral
thesis, Catholic University of Leuven, Faculty of Medicine, Department of Human Genetics.
Dykens E., Cassidy SB (1995) Correlates of maladaptive behaviour in children and adults with PraderWilli Syndrome. Am J Med, 60, 546-549
Whitman BY, Accardo P (1987) Emotional symptoms in Prader-Willi syndrome adolescents. Am J Med
genet, 28, 897-905
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Behavioural, Psychological, Psychiatric and Ethical Aspects of PWS
Tony Holland
For families, and for people with PWS, it is often the consequences associated with over-eating and the
impact of other behavioural problems and of psychiatric illness that are the most problematic aspects of
the syndrome. The prevention and management of temper outburst, repetitive and ritualistic behaviour,
skin picking and the effects of additional psychiatric illness are likely to require different approaches
based upon a sound assessment. Whilst early diagnosis and advice means that access to food is often
managed from an early age and therefore severe obesity prevented, restricting access to food becomes
much more problematic as the person with PWS becomes more independent and insists on leading his/her
own life. Weight may increase dramatically at such times and how families and services should respond is
often far from clear. As weight increases so do the risks of physical illnesses such as diabetes mellitus,
and respiratory and sleep disorders. In adult life the risk of mental health problems also increase and, like
physical illness, these can go undetected.
This talk will focus on our understanding of the causes for the eating disorder and the other problematic
behaviours that are commonly associated with having PWS and how such problems might be managed.
Whilst in childhood families have a responsibility to act in the best interests of their child and to manage
the food environment, in adult life the issues are more complex. The ethical and legal principles that
might govern intervention at that time will be considered. Whilst there will be differences, depending on
the laws of any given country and the services that are available, the difficult balance is to manage the
wish for adults with PWS to self-determination versus the vulnerabilities and risks associated with such
independence.
Our understanding of the eating disorder and other behavioural and psychiatric problems associated with
PWS has advanced significantly and whilst there are no easy and straight forward solutions much can be
done to prevent some of these difficulties and to effectively manage and treat them when they arise,
thereby maintaining a better quality of life. The right social care environment and informed support are
keys to this.
Prader-Willi Syndrome:
Quality of life from the cradle to the grave
Urs Eiholzer, MD, Zurich, Switzerland
Life of children with Prader-Willi syndrome (PWS) has dramatically changed since the 90ies, when new
therapeutic options were developed. These therapeutic options can be summarized in the 5-finger-model:
• Restriction of the caloric intake
• Growth hormone treatment
• Daily training program
• Male sex hormone treatment
• Committed psychological support for families
Unfortunately, therapeutic milestones such as drugs modulating intrinsic control of appetite, activity and
behaviour most probably will not be available in the near future. However, quality of life for people with
PWS especially in their teen and adult years should be improved without waiting for breaking research
achievements.
Crucial for the well-being of adolescents and adults with PWS is a) finding an apprenticeship or a suitable
work place and b) finding homes specifically designed for people with PWS. Based on this the adolescent
will gain his/her independency and the parents will be able stepping back; the way it usually happens with
healthy children.
Yet another very important issue is protecting people with PWS from arbitrary and needless diagnostic
procedures. It is often easier for the modern doctor prescribing new and expensive examinations rather
than getting involved in the basic problems – for PWS these are difficult and do need personal
commitment and experience. Many parents of persons with PWS have folders full of endless
examinations illustrating the so called “qualified” care. But too often the care is not professional and
dedicated enough. We have to ask: What is the therapeutic consequence of any specific diagnostic
procedure? The most important therapeutic aim for people with PWS is to achieve normal weight and
body composition; in order to prevent the tremendous obesity related morbidity and mortality, which will
directly reflect quality of life for people with PWS.
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PWS Expert Meeting Held Oct. 2006 in Toulouse
Highlights & Future Expectations
Anthony P. Goldstone, MA MRCP PhD
Senior Clinician Scientist & Consultant Endocrinologist, MRC Clinical Sciences Centre, Imperial
College, Hammersmith Hospital, London, UK.
On behalf of the Scientific Committee: Maïthé Tauber, Toulouse, France; Berthold Hauffa, Essen,
Germany; Anita Hokken-Koelega, Rotterdam, The Netherlands; Anthony Holland, Cambridge, UK.
The Second Expert Meeting on PWS was held in Toulouse, France 26 to 27th October 2006 following on
from the success of the first meeting held in Zurich, Switzerland in 2002. Over 120 delegates, including
clinicians, scientists and health care professionals from over 20 countries, attended this meeting. Through
29 talks and round-table discussions the practical issues regarding the comprehensive care of this complex
genetic disorder were debated to clearly identify those approaches in which there is a general consensus
and those that are still debatable and need further research. Experts covered the varied features of this
disease from epidemiology to psychiatric and behavioural disorders, breathing and sleep abnormalities to
genetics and endocrinology, and management in infancy, childhood, transition and adulthood from the
point of view of both routine practice and research. Current evidence, outstanding questions as well as
future directions were discussed for each topic in order to stimulate research ideas and action.
Skin picking and sleep
Leopold M.G. Curfs
Prader-Willi syndrome is a genetically determined neurodevelopmental disorder associated with absence
of expression of the normally expressed paternally inherited alleles at the genetic locus 15q11-13. The
genetic mechanism involved are a deletion (75%), uniparental disomy (20-25%), imprinting center defect
(1%) or a balanced translocation (1%). The four genotypes share the core PWS phenotype, with
distinctive features like skin picking and sleep problems (excessive day time daytime sleepiness). These
problems which are stressful for both parents and children have been somewhat neglected in research and
clinical practice.
Literature findings will be reviewed and compared to own data. In our recent study in which 119
individuals with PWS (aged between 4 and 49 years) participated, we found that 86% showed skin
picking. This high prevalence is in agreement with results found by others. The paucity of studies
reporting effective treatments may be attributed to the fact that our knowledge about the cause(s) of skin
picking in individuals with PWS is limited. Several suggestions on possible effective approaches will be
presented.
References
Didden, R., Korzilius, H. & Curfs, L.M.G. (in press). Skin picking in individuals with Prader-Willi
syndrome: prevalence, comorbidity and functional assessment. Journal of Applied Research in
Intellectual Disabilities.
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Scoliosis in Prader-Willi Syndrome
M. De Pellegrin, D. Moharamzadeh*
Unità Operativa di Ortopedia e Traumatologia, Servizio di Ortopedia Infantile
Università Vita-Salute, IRCCS San Raffaele, Milano
*Scuola di Specializzazione Ortopedia e Traumatologia 1°
Università degli Studi, Milano
Prader-Willi syndrome (PWS) is a rare neurogenetic disorder. Its diagnosis is based on clinical criteria,
which include scoliosis, due to its increased incidence in PWS patients, and genetical analyses, to confirm
the diagnostic suspect. Although in literature scoliosis in PWS is reported to have an incidence of
approximately 50%, and, therefore, represents a relevant orthopaedic concern, studies regarding this
problem remain few and the patients enrolled in them are limited.
Aim of this study is to define the percentage of scoliosis in PWS patients, identify its characteristics and
evaluate its progression in time.
The data of our study was collected considering all PWS patients who arrived consecutively at our Centre
of Reference for PWS, during the period between the 1st of November 2004 and the 31st of May 2005.
The patients involved in our study were 72 (36 M, 36 F), with an age range between 6 months and 39
years (average age: 15.12 ± 10.77 years; median: 12.07 years), and scoliosis was documented in 38
patients. The patients had an average follow-up of 10.92 ± 9.43 years. The percentage of scoliosis in our
population was 53.5%; the majority of the scoliosis’ curves were right main thoracic curves with an
associated left lumbar curve (42.1%). The curve progression is defined as an increase ≥5° of the curves’
angles, highlighted in two subsequent (6 months – 12 months) x-ray examinations. The curve progression
was present in 31 patients (81.6%).
In conclusion, according to our study: scoliosis in PWS has a high incidence (53.5%), undeniably higher
than the normal population (2-4%); the male-female ratio in PWS is 1:1, which differs from the normal
population where the ratio is 1:5; there is a high tendency of progression of the scoliosis in PWS patients
(81.6%).
Medical Alert for Prader-Willi Syndrome
Janalee Heinemann, Executive Director, PWSA (USA)
Obesity related complications are the primary risk to a person with Prader-Willi Syndrome (PWS) but is
not the only risk. Due to the high pain threshold, the irregular temperatures, the lack of vomiting, the
gastro-intestinal problems, and the respiratory problems, the emergency room or hospital can be a very
dangerous place for children and adults with PWS. This is due to the lack of knowledge about the
syndrome and the masking of serious symptoms. This presentation will deal with the primary risk issues
that a need to be addressed when dealing with a medical crisis. PWSA (USA) has articles and a booklet
that are available for such situations at www.pwsausa.org.
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Weight Management in Prader-Willi Syndrome
A/Professor Peter SW Davies
Director, Children's Nutrition Research Centre, University of Queensland, Royal Children's
Hospital, Brisbane, QLD, Australia
Successful weight management in any individual is better achieved with an understanding of the basics of
energy balance. Chemical and physical laws that govern aspects of thermodynamics bound this concept.
In the biological condition the energy balance equation states that energy intake = energy expenditure
plus energy stored. Thus if more calories are consumed than expended we have no option but to store that
excess energy often as body fat. Equally, of course, if more calories are expended than consumed the
shortfall must be taken from energy stores, again often body fat, and the individual will lose weight.
There are no exceptions to this rule. A salient feature, however, of this equation in the human condition is
that it is relatively easy to consume excessive calories quite quickly, whereas the equivalent energy
expenditure obtained by increasing physical activity takes much longer to achieve. Understanding this
balance is important in weight loss management. Equally it is important to realise that all foods do not
have the same energy density. For example fat contains twice the energy of an equivalent weight of
carbohydrate, that is, it is also the quality of food consumption that matters as well as food quantity.
In children and adults with Prader-Willi syndrome the energy balance equation is confounded by the fact
that disturbances in body composition often found in the syndrome causes resting energy expenditure,
relative to body weight to be reduced in many cases. This does NOT, however, mean that children with
Prader-Willi syndrome have a “low” or “slow” metabolism as resting energy expenditure is quite normal
when the disturbances in body composition are taken into account.
Any attempt to achieve weight loss in children with Prader-Willi syndrome should bear in mind the need
to maintain a god supply of vital micronutrients and minerals essential for good health including iron and
calcium. Reduction in such nutrients may compromise short term and long term health.
Management of Food, Diet and Weight in PWS
Linda Gourash and Janice Forster
Management of PWS requires weight control, calorie control, food control and FOOD SECURITY.
Weight control is essential because obesity related health issues are the major cause of morbidity in
PWS. Syndromal obesity and hypotonia contribute to diurnal breathing problems that further
compromise exercise, but exercise and weight loss are restorative. Prevention of obesity requires calorie
control and regular exercise. The RED-YELLOW-GREEN diet plan is recommended because it provides
a generous amount of food that is pleasing to the eye, and it provides a lot of chewing which has been
linked to stress reduction. Other forms of calorie restriction can be effectively implemented. Exercise is
essential for weight regulation, breathing stimulation, sensory experience, stress reduction, and metabolic
benefits. Because individuals with PWS are not able to regulate food intake, food
control provides environmental restrictions to food access. Most of the time, this means locking the
refrigerator or pantry, or supervising the individual to make sure that they don't access food. Food
control is not synonymous with food security. FOOD SECURITY provides no doubt when meals will
occur and what will be served; no opportunity to get anything more than is planned; and no
disappointment related to false expectations. FOOD SECURITY is achieved by securing food access
across all settings, supervising food access in all environments, posting menus and meal times, and
training all team members. When an individual with PWS experiences FOOD SECURITY, a generalized
behavioral improvement typically occurs. For this reason, FOOD SECURITY is the mainstay of PWS
management.
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Follow up of motor skills and everyday function in young children with Prader-Willi syndrome
Kaja Giltvedt, Frambu National Centre for Rare Disorders, Siggerud, Norway
This presentation will illustrate different examples of how the physiotherapist can provide follow-up for
infants and children with PWS. Support for parents and caregivers forms an integral part of patient
centered care. It is important that structured treatment plans are in place at the time that infants with PWS
start day care. These infants need support from caregivers and their surroundings in order to develop their
skills through active play together with other children. Children with PWS also should have equal
opportunity as other children to participate in sports activities. Support that is given to them early in life
will help to establish good exercise routines so that they can live active and healthy lives. This kind of
support needs to be maintained all through life.
The Power of Exercise!
- Physical therapy in Adults with Prader-Willi Syndrome
Georgina Loughnan
Improved fitness, strength and posture are the aims of physical therapy for people with Prader-Willi
Syndrome (PWS). Based on the “Top 10” benefits of exercise, all clients attending the Royal Prince
Alfred Hospital (Sydney, Australia) PWS Clinic, are given both an aerobic and a strengthening exercise
programme. It is well known that exercise will increase energy expenditure, reduce stored fat, increase
muscle bulk, improve insulin sensitivity, improve blood circulation, decreased stress, protect against bone
loss and slow the decrease in general fitness that occurs with ageing. These benefits are essential to
people with PWS. Our clients are instructed to exercise daily for strength and toning, and 6 days per week
for fitness. As a result of a regular, effective exercise regimen, clients are often able to reduce their
medications, for example, for diabetes and hypertension, in association with weight loss and improved
cardio-respiratory fitness. Improvements in posture result from strengthening trunk muscles and improved
body awareness. Exercise is kept simple with a competitive aspect. Incentive awards are given for
achievement. Remembering that people with PWS rely on consistency and routine, exercise, once
introduced as a part of the client’s individual care plan, can play a vital role in their overall health and
well-being.
Positive Aspects
Children from Birth to age 6- Integration and Special Needs
Susanne Blichfeldt MD, Denmark
Small children with PWS are first of all family members, but also members of the society.
Socialisation and not isolation is important in life and therefore early integration of the child with PWS
will bring many advantages and create important contacts and friendships for the child and the family,
and important relationships that can last and be supported for many years. Successful integration depends
very much on correct information to all that are in contact with the child with PWS, and this brings
knowledge and understanding, and prevents misunderstandings, negative influences and wrong attitudes.
Experiences from Denmark show that early integration in nursery school and kindergarten can be of great
benefit for the child, the family and for the other children in contact with the child with PWS.
Physiotherapy and careful diet monitoring are important aspects during the early integration. Oral and
written information are key points. Examples will be given.
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School Integration and Socialization
B.J. Goff
The intent of the workshop is to discover common experience and identify best practices in educating
children with Prader-Willi syndrome. Toward that end, participants will address these essential
questions:
• Is there is an optimal educational environment: separate special services vs. integrated classes?
• Are different educational environments appropriate at different stages?
• What are the unique grade/age related educational and behavioral challenges for children with
Prader-Willi syndrome?
• What are the most effective classroom management strategies for children with Prader-Willi
syndrome?
• How do we facilitate relationships between students with and without PWS?
• How do we prepare students with PWS for the post-education adult world?
• How do we collaborate among parents, general and special educators, professionals, clinicians,
and the community to ensure an optimal educational experience?
Esther - an adult woman with PWS living at home in the UK
Jackie Waters
Esther, who has PWS, is 29 years old and lives at home with me, her mother, and my partner. This talk
will give an overview of Esther's varied lifestyle and the measure of independence she has, which allows
her to go out and about on her own.
How this independence has impacted on her health and quality of life, both positively and negatively, will
be discussed, as will the limitations which are put on her by having PWS.
The effect on her parent of having someone with PWS living at home will also be described, together
with the interventions which have been put in place by health and social services to help with this.
Tiina Silvast
President, Prader-Willi Association Finland
In my 10 minute talk at the 6th PWS conference I'm planning to talk about previous presentations I gave
to groups of families with Prader-Willi babies or small children.
It was a special talk where also my daughter and my husband were present. The subject of my talk was:
Getting on in life.
The talk took an hour and a half and since I have only 10 minutes this time I'm going to make it short.
I'm going to talk about what adults with Prader-Willi cannot do in their lives, what they CAN do and what
my daughter does and what she thinks about her life.
Finally, I'm going to tell what a father of a PWS baby told me and my family after the talk. What he said
to me, was something that made all the effort I had done over the years for PWS, worthwhile.
An Adult “Child” with PWS Working and Living in a Group Home
Jim Gardner
An adult “child’ in a group home is a never ending adventure. It can be extremely smooth or it can be
extremely stressful. Having had our 38 year old son in three separate group homes with various degrees
of success, has given a unique perspective on the subject of what makes group home experience and job
experience work and what does not.
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Approaches for small children with PWS in Japan
Tomoko Hasegawa, Genetic Support and Consultation Office
Generally speaking, characteristics of PWS are not yet recognized in Japan. Although diagnosis is made
mostly short after birth, the parents are given information only on future obesity without any help. The
condition of infants with PWS is treated only as a psycho-motor retardation. Of course physical,
occupational and speech therapies improve their function, but understanding of PWS should be
nevertheless essential to achieve positive effects. From 1996 to 2003 I held a PWS clinic for the small
children in Shizuoka Children’s Hospital (presented at the Conference in Italy in 1998 as a title of “PWS
clinic aimed at early intervention for children with PWS and their parents”). Through this experience I
have found out about the characteristics of PWS and that there are differences among individuals which
are met not only by genetics, but also by family and social environment. I present medical, dental,
nutritional and educational approaches and parent’s problems for the small children with PWS. Still there
is no systematic approach in our country. In Japan PWSA was organized in 2005, and since then it has
been working for providing useful information to the families and the professionals involved.
Prader-Willi Syndrome Children in Taiwan
Shuan-Pei Lin1, 2, 3, Hsiang-Yu Lin1, 2, and Taiwan PWSA. 1) Departments of Pediatrics and Medical
Research, Mackay Memorial Hospital, Taipei, Taiwan; 2) Department of Early Childhood Care and
Education, Mackay Medicine, Nursing and Management College, Taipei, Taiwan; 3) Department of
Infant and Child Care, National Taipei College of Nursing, Taipei, Taiwan.
The first Prader-Willi syndrome (PWS) patient in Taiwan was diagnosed in 1991. However, the need to
provide a comprehensive support for the PWS patients and their families was not fully recognized until
recent years. The launch of the National Health Insurance Program (NHI) in 1995, the establishment of
Taiwan Foundation for Rare Disorders in 1999 and the legislation of the Rare Diseases & Orphan Drugs
Act in 2000 give great impacts to the care for PWS children in our country. Totally 132 patients are
identified nowadays through the nation-wide reporting system. In 2002, the NHI approved human growth
hormone (HGH) therapy for the PWS patients who were proved to be GH deficient. Two years later, all
the young PWS patients up to the end of puberty were fully subsidized with HGH therapy.
We would like to present a retrospective analysis of 72 PWS cases (M:F=40:32; age from one month to
23 years) seen in 4 major medical centers in Taiwan from January, 1988 to June, 2006. All cases were
confirmed by methylation-specific PCR. Complete genetic study was performed in 56 patients. The
abnormalities found included deletions in 47 (84%), maternal UPD in 7 (13%), and probable imprinting
center deletion or imprinting defect in 2 (3%). The average weight at birth was 2588 gm. Bone age delay
> 2 years was detected in 12/42. GH deficiency was noted in 12/20. In 2000, Taiwan mandated a free
charge 3-phase screening protocol for PWS. Of the 41 diagnosed prior to 2000, only 4 (10%) were
diagnosed before age of 3 months; in the 31 patients diagnosed after 2000, 18 (58%) were diagnosed
before 3 months of age (p<0.001). Our finding is in contrast to most of the previous reports that indicated
a higher incidence of UPD. It is not clear whether this discrepancy in incidence of UPD arises from
under-diagnosis, or because of ethnic differences, or a younger maternal age in our group. This question
is worthy of further study. The 3-phase screening program has brought great impact to early diagnosis of
PWS in Taiwan. Our Bureau of NHI agreed to subsidize GH therapy, in May 2004, for all the PWS
children. Up to now, 44 patients have received the therapy for more than a year up to 4 years. They all
show a remarkable improvement in linear growth, weight control, and quality of life.
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Frambu – Centre for Rare Disorders
Kai Rabben
What is Frambu?
Frambu is a centre for rare disorders and disabilities and is a part of Norway’s answer to promoting
quality of life for persons and families affected by one of approximately 100 different rare diagnoses.
Frambu is a government-funded supplement to regularly available health and assistance programmes.
Frambu is a meeting place for families and professionals.
Frambu’s offerings span the entire life cycle from childhood to old age.
Vision
To be substantially knowledgeable in the field of rare disorders.
Objective
Frambu will gather, develop and disseminate knowledge about rare disabilities for persons who have been
diagnosed, their next of kin and professionals, so that children, adolescents and adults with impaired
abilities can live a life in harmony with their condition, aspirations and needs.
Working methods
Courses with duration from one to 12 days.
Health Camps from the ages between 10 and 30 years of age.
Networking at various level of society
Developmental work comprises surveying, gathering and systemizing knowledge and experience both
from the field of practical experience and from Frambu’s routine operation.
Communication and Documentation towards persons having a diagnosis and for their next of kin.
Everyday structure, respect creation and support for adult people with Prader-Willi Syndrome
Sabine Bohnenpoll, Thomas Polomsky
Internationales Bildungs-und Sozialwerk „Haus St.Martin“
Naumburg/Hessen, Germany
We would like to present the experiences we have made in our institution, in order to give assistance in
family everyday life, along with some ideas for professional work.
By the example of our institution we will have a look at how diet, everyday structure, and respect creation
will work together to support the learning of new behaviour.
We will describe which basic principles in creation of interpersonal relationships will lead to the fact that
the people living in our institution get themselves slowly acclimatized to their new situation. We will
follow the question of how people who would rather avoid movement, are to be motivated and get
interested in movement up to the point they decide by themselves to go out for a walk.
Medical Interventions and Inpatient Rehabilitation
Linda M. Gourash, MD
This lecture will be based on the extensive experience of the clinical team in Pittsburgh, PA (USA)
rehabilitating hundreds of persons with PWS who have become dangerously obese with respiratory
compromise. The focus will be on the medical management of obesity complications and the proven
successful strategy for rehabilitation. The speaker will describe common errors made by physicians caring
for persons with PWS including failure to recognize the early and even the later stages of obesity
hypoventilation in adults and children and typical errors in the management of hypoxia, hypertension,
hyperglycemia, and fluid retention.
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Mauro Baschirotto Institute for Rare Disease BIRD EUROPE
The Mauro Baschirotto Association for rare diseases founded the B.I.R.D Foundation Institute in
Costozza di Longare, Vicenza, and it operates within the National Health Service .The Institute aims to
give answers to patients suffering by rare diseases. The number of requests from Italy and abroad, proves
how appreciated and essential is a landmark structure like the B.I.R.D. Institute. It offers in particular:
1) Diagnostic activity, operating within the national health services, for the molecular genetics and the
cytogenetics. The Laboratory of Medical Genetics carries out many genetic analyses.
2) Daily Rehabilitation activity. Following the needs of each pathology, a multidisciplinary team of
doctors follows patients affected by the same disease stating a suitable rehabilitation protocol.
3) Specialists activity like psychiatry, neurology, medical genetics, medicine and others specialties.
4) Information to doctors and attendance to patients and their families.
5) Research activity for possible clinical applications of innovative therapies and basic research on
different diseases among these PWS has a high priority
Behavioural Disturbances of Children and Young Persons with PWS
Considering behaviour from a formative years perspective
Eileen Greunke, Elke Neumann, René Römling
Internationales Bildungs-und Sozialwerk e.V. „ Haus am Goldbach“,
Langenstein, Sachsen-Anhalt, Germany
Our work with children and young people with Prader-Willi Syndrome at the age of 10 to 17, we
recognize some behavioural disturbances going on, although the imperative security is caused by the daily
structuring of meals and dividing the quantity of kilocalories. Stereotypical inquiring, excessive curiosity
and rapid mood changes, as well as eruptions are observable. Limits of self-organized actions and
fulfilling own needs were exceeded without acquiring their own actions.
Based on the approach that every behaviour has a special significance and has one or more causes we
found that uncertainty, missing structure, self overestimating, and excessive demands are reasons for
observed behavioural disturbances.
One main constituent of our work is to give people with PWS more security, more structure, and demands
suitable to their stage of development. For this it is helpful to consider not only the life age but also a
formative years (stage of development) in people with PWS. A definite age of puberty provides special
abilities (and others even not yet) and requires solving special developmental tasks allowing a successful
transition to the following age of puberty. At the workshop we will have a look at this theoretical
approach and its resulting questions by practical examples. We will discuss the following questions:
1.
What help needs a human, who has no idea of time and space, to make sense of plans
and changes?
2.
How to create and implicate rules for someone, who cannot grasp the consequences to
his own acting-but discuss as if he could.
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Psychology and How to Manage PWS Family Situations
Palma Bregani, PhD Italy and Irune Achutegui, PhD Italy
Emotional vulnerability is the characteristic of PW syndrome which mostly affects the quality of life of
these subjects and their families. PWs’ emotional state is known to be due to the interaction of two
factors, genotype and environment. So far only the second factor is modifiable. It is therefore extremely
important to make the environmental influence as favourable as possible to prevent or limit the risk of
emotional disturbance.
PWs present typical behaviour characteristics such as mood swing, irritability, stubbornness, a tendency
towards repetition and rage attacks. The severity of these behaviours differs from patient to patient
according to the particular emotional state of each subject.
Parents are the most important affective relationships for these children, therefore the most influential. It
is often difficult for them to understand the underlying emotional states that cause PWs’ aberrant
reactions. Parents need to get rid of the stereotyped perceptions of their children as PWs and to
understand that each of them has a complex emotional life and an individual personality like all human
beings. It means that the various personality characteristics, including those more common in PWs,
combine in ways which differ from subject to subject making each PW as unique as all individuals.
In order to help parents to reach this goal, in the workshop, discussions will be focused on parents’
relationships with their children. Examples will be given related to the most important issues: conforming
to or disobeying rules, compulsion towards food, peer relationship, sibling relationships, sexuality,
difference between reality and imagination.
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6th International Prader-Willi Syndrome Conference
Children’s Program
Cluj-Napoca, Romania
June 22-23, 2007
Co-Organizers
Dorthe Pedersen- Chair (Denmark)
Fundatia Malteza- Chair (Romania)
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Children's Program
Friday- June 22, 2007
Meet at Hotel Capitolina
9.00-14.00: Visit to the Botanical Gardens
11.00-11.30: Snack
13.00-14.30: LUNCH (SACK LUNCH AT BOTANICAL GARDENS)
Hotel Capitolina
14.30-16.30: Movie
16.30-17.00: Snack
17.00-19.00: Puzzles and Games
19.00: DINNER (HOTEL CAPITOLINA)
Saturday- June 23, 2007
Hotel Capitolina
9.00-14.00: Arts and crafts
11.00-11.30: Snack
13.00-14.30: LUNCH (SACK LUNCH HOTEL CAPITOLINA)
14.30-16.30: Activities with Fundatia Malteza
16.30-17.00: Snack
17.00-19.00: Puzzles and Games
19.00: DINNER (HOTEL CAPITOLINA)
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6th International Prader-Willi Syndrome Conference
1st Romanian Prader-Willi Syndrome and Rare Diseases
Conference
Rare Diseases Awareness Programme
Cluj-Napoca, Romania
June 24, 2007
Co-Organizers
Dorica Dan- Chair (Romania)
Christel Nourissier - Chair (France)
Prof. Dr. Maria-Julieta Puiu- Scientific Chair (Romania)
Scientific Advisory Committee
Christel Nourissier - EURORDIS
Prof. Dr. Maria-Julieta Puiu – UMF Timisoara
Pr Rumen Stefanov-- Plovdiv, Bulgaria
Prof. Domenica Taruscio- Instituto Superiore di Sanita, Italy
Dr Cristina Skrypnyk- Children Hospital Oradea
Prof. Dr. Cristina Borzan – Comisia Nationala de Sanatate
Dr Min Chieh Tseng- Taiwan Foundation for Rare Disorders
(TFRD)
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Rare Diseases Awareness Programme
Sunday- June 24, 2007
First Floor Auditorium One
9.00-9.05: Introduction
Moderator: Prof. Dr. Maria-Julieta Puiu, Co-Chair of the Rare Diseases Conference (scientist)
9.05-9.30: Official Opening
Rare Diseases Must be placed at the Centre of Our Policy Making: Onorica Abrudan- ViceMayor Zalau, Romania
The Need to Address Rare Diseases at a European level: Antoni Montserrat- Health Directorate,
European Commission
9.30-9.45: Rare Diseases: Understanding this Public Health Priority and the Importance of
Patient Involvement to Improve Health Care: Christel Nourissier- Prader-Willi France,
EURORDIS
9.45-10.00: Rare Diseases as a Reality in Romania; Book presentation- Essentials in 101 rare
Diseases: Dorica Dan- Co-Chair of the Rare Diseases Conference (Patient Representative)
10.00-10.30: COFFEE BREAK (GENERAL LOBBY)
Session 1: 10.30-12.30: Accessing Appropriate Information about Rare Diseases
Moderator- Prof. Dr. Victor Pop- Romania, President of the Romanian Genetics Society
10.30-10.45: Information Tools: Ségolène Aymé- Director of Orphanet and Chair of the Rare
Diseases Task Force of the European Commission
10.45-11.00: Role of a Patient Organisation to Spread Information: Example of the International
Prader-Willi Organisation: Pam Eisen- President IPWSO
11.00-11.15: Role of National Information Centres: Pr Rumen Stefanov- Information Centre
for Rare Diseases and Orphan Drugs- Plovdiv, Bulgaria
11.15-11.30: Access to Information about Rare Genetic Diseases in Romania: Pr Dr Maria
Julieta Puiu- University Timisoara, Romania
11.30-11.45: Access to Information, Diagnosis, and Treatment for Romanian Patients with
Lysosomal Storage Diseases, 21 Hydroxylasis Deficiency and 11 ß Hydroxylasis Deficiency: P.
Grigorescu-Sido- Romania
11.45-12.00: The First Website Focused on the First Study in Romania; A.M. Neghina – UMF
Timisoara, Romania
12.00-12.15: The Experience of a Small Foundation: Dr. Anja Frankenberger and Dr. Anja
Frankenberger- Kindness for Kids, Germany
12.15-13.30: LUNCH (GENERAL LOBBY)
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Session 2: 13.30-15.30: Accessing Better Care
Moderator: Prof. Emilia Severin- “Carol Davila” Pharmaceutical Medical University Romania
13.30-13.45: The Different National Experiences of Organisation of Care in Europe: Examples
from Italy, France and Estonia: Prof. Domenica Taruscio- Instituto Superiore di Sanita, Italy
13.45-14.00: Approaching Rare Diseases in Romania: Prof.Dr. Mircea Covic- President
Orphanet Romania
14.00-14.15: Genetic Tests Across Borders: Dr Cristina Skrypnyk- Children Hospital Oradea,
Romania
14.15-14.30: Iasi Medical Genetics Center’s Experience in the Diagnoses and Management of
Rare Disorders: Cristina Rusu UMF Iasi, Romania
14.30-14.45: Orphan Drugs, 6 Years Experience in Europe: Pr Josep Torrent Farnell- President
of the Committee for Orphan Medicinal Product, EMEA (2000 to 2006)
14.45-15.00: Cooperation- Success of Rehabilitation: Dr. Ioana Rotaru- ACASA Foundation
Zalau, Romania
15.00-15.30: Questions and Answers
15.30-16.00: COFFEE BREAK (GENERAL LOBBY)
Conclusion: 16.00-17.00: Conclusion: Networking Activities, National, European, and
International
Moderator: Christel Nourissier- EURORDIS
16.00-16.15: Romanian National Alliance for Rare Diseases: Etelka Czondi- APWR
16.15-16.30: European Cooperation as a Way to Improve Care for Rare Diseases in Romania:
The Role of Eurordis: Jérôme Parisse-Brassens- Communication and Development Officer,
EURORDIS
16.30-16.45: Cooperation at a Global Level: Dr Min Chieh Tseng- Taiwan Foundation for Rare
Disorders (TFRD)
16.45-17.00: Questions and Answers
17.00-17.15: Close of Conference Remarks
18.00: Conference Close and DINNER (GENERAL LOBBY)
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Rare Diseases Awareness Program- Summaries in Order of Appearance:
Onorica Abrudan- Vice-Mayor Zalau, Romania
Rare Diseases have to be placed at the centre of our policy making
To address the important health challenges of the rare diseases patients, health must be placed at the
centre of Romanian policy making. Achieving a high level of health and well being for all citizens
throughout Romania can’t happen without a specific national approach of the Health Care System in the
field of the rare diseases.
Health in general is a very complex area, closely related to economic growth and sustainable
development. Rare Diseases are not known – both by general public and professionals –, they produce
disabilities, most often there are not known effective treatments and when they exist, they are very
expensive. This is why is necessary a comprehensive action to be taken in our country to counter the
health damage caused by rare diseases.
As a vice-mayor of Zalau, I am aware about the initiatives and activities developed by the Romanian
Prader Willi Association in Romania to improve available information about rare diseases, to disseminate
best practices and experiences of other countries from EU and the whole world and to integrate patients
with rare diseases into community. This is why the Local Council and the City Hall became partner in the
projects developed by this organization in the last years.
As partners, we have realized that there is a strong need to have a National Plan for Rare Diseases, a
coordinated approach for this major public health issue. The transparency of policy making and
stakeholders’ participation need strengthening. The involvement of NGOs working in rare diseases and
NGOs of professionals in health care is especially important in our country where health is not always
placed firmly on the political agenda.
I know that RPWA made important efforts to improve the information access for patients with rare
diseases, their families and professionals in Romania. An essential part of the health information and
knowledge system is to improve the dissemination of information. Their website and their Center for
Information about Rare Genetic Diseases became reference points for patients in Romania, but it has to
be also complemented by a public health report series for professionals, decision makers and authorities.
Christel Nourissier
Rare Diseases: Understanding this Public Health Priority
The Importance of Patient Involvement to Improve Health Care
I. It is essential to clarify what rare diseases are as a public health concept. Rare diseases are rare
(defined as less than one citizen in 2,000 in Europe), but rare disease patients are many. Indeed, it is not
unusual to have a rare disease. In order to be considered as rare, each specific disease cannot affect more
than a limited number of people out of the whole population, defined in Europe as less than one in 2.000
EU citizens (EC regulation on orphan medicinal products). About 30 million people have a rare
disease in the 25 EU countries. It can happen to anybody, at any stage of life.
In general people with a rare disease are not registered in databases. It is worth noticing that each and
every one of us is, statistically speaking, a carrier of 6 to 8 genetic abnormalities, which are, usually but
not always, recessive ones in their transmission. These abnormalities generally have no consequences, but
if two individuals carrying the same genetic abnormality have children, these may be affected.
Rare diseases are characterised by the large number (between 5000 and 7000) and broad diversity of
disorders and symptoms. They affect patients in their physical capabilities, their mental abilities, in their
behaviour and sensorial capacities. Many disabilities can coexist for a given person, and this is defined as
a polyhandicap.
80% of rare diseases have identified genetic origins, involving one or several genes or chromosomal
abnormalities. They can be inherited or derived from de novo gene mutation. They concern between 3%
and 4% of births. Other rare diseases are caused by infections (bacterial or viral), or allergies, or are due
to degenerative, proliferative or teratogenic (chemicals, radiations, etc) causes.
Relatively common conditions can hide underlying rare diseases, e.g. autism (in Rett syndrome, Usher
syndrome type II, Sotos cerebral gigantism, fragile X, Angelman, adult phenylketonuria, Sanfilippo,…) or
epilepsy (Shokeir syndrome, Feigenbaum Bergeron Richardson syndrome, Kohlschutter Tonz syndrome,
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Dravet syndrome…). For many conditions described in the past as clinical entities such as mental
deficiency, cerebral palsy, autism or psychosis, a genetic origin is now suspected or has already been
described.
Despite this great diversity, rare diseases have some major common traits:
• Severe to very severe, chronic, often degenerative and life-threatening;
• The onset of the disease occurs in childhood for 50 % of rare diseases
• Disabling: the quality of life of rare diseases patients is often compromised due to lack or loss of
autonomy;
• Highly painful in term of psychosocial burden: the suffering of rare disease patients and their
families is aggravated by psychological despair, the lack of therapeutic hope, and the absence of
practical support for everyday life
• Incurable diseases, mostly without effective treatment. In some cases, symptoms can be treated to
improve quality of life and life expectancy.
• Rare diseases are very difficult to manage: families encounter enormous difficulties in finding
adequate treatment.
The whole family of a patient is affected in a way or another. Rare disease patients and their families are
confronted with the same wide range of difficulties:
• Lack of access to correct diagnosis: the period between the emergence of the first symptoms
and the appropriate diagnosis involves unacceptable and highly risky delays, as well as wrong
diagnosis leading to inaccurate treatments.
• Lack of information: about both the disease itself and about where to obtain help, including lack
of referral to qualified professionals;
• Lack of scientific knowledge:, resulting in difficulty in defining the therapeutic strategy, and
shortages of therapeutic products, both medicinal products and appropriate medical devices;
• Social consequences: living with a rare disease has implications on all areas of life, whether
school, choice of future work. It may lead to stigmatisation, isolation, exclusion from social
community and often to reduced professional opportunities (when at all relevant);
• Lack of appropriate quality healthcare: combining the different spheres of expertise needed,
such as physiotherapist, nutritionist, psychologist, etc… Patients can live without competent
medical attention and remain excluded from the health care system even after the diagnosis has
been made;
• High cost of both care and the few existing drugs: the additional expense of coping with the
disease, in terms of both human and technical aids, combined with the lack of social benefits and
reimbursement, causes a global pauperisation of the family, and dramatically strengthens the
inequity of access to care for rare disease patients.
II. The importance of patient involvement to improve health care. Rare diseases patient and parent
organisations have been created as a result of the experience gained by patients and their families from
being so often excluded from health care systems and thus having to take charge themselves of their own
disease. Because they live 24 hours a day with the disease, patients and families become experts in their
own disease.
Rare disease patient associations aim at gathering, producing and disseminating the limited existing
information on their disease and making patients and parents voices’ heard.
How to be successful?
• Bring together people living with rare diseases and their families
• from different social, professional backgrounds: anyone can be stricken by a rare disease
• from different parts of each country
• from all member states at European level
• network with professionals
• create a community
How to improve access to diagnosis?
• by creating web-sites, web-forums, sending disease-specific information to health
professionals
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•
by raising awareness of MDs, carers and general public about rare diseases: information
campaigns, media contacts
• by helping people suffering with very rare diseases to get together at EU level.
How to encourage research?
• by creating databases: useful epidemiological data, and a way to learn about the natural
history of the diseases
• by giving DNA and tissues for research: cf Eurobiobank, a project run by Eurordis
• by bringing together scientists, discussing research protocols, informing our members
about research studies,
• by finding funds: successful funding stories: Telethon in France and Italy
• by disseminating outcomes
How to improve access to care?
• by providing clear, concise, information about existing knowledge
• by raising awareness about the necessity of early intervention and prevention
• “there is always something to do”
• by disseminating research outcomes
• by supporting the creation of networks of centres of competence, benchmarking best
practices in EU
• by improving access to orphan drugs
How to support patients and families?
• Reaching out isolated people: volunteer and professional help-lines, particularly
• after diagnosis
• in crisis situations
• when participating in clinical trials
• at the end of life
• regional, national and European meetings
Patient organisations fighting for better compensation and respite care
• PO explain their rights to people living with rare diseases and their families according to
the European Union disability strategy towards a society opened and accessible to all;
• advocate for financial, technical and human compensation policies at national level;
• support children integration in schools;
• and integration of adults throughout their life (at home, in group homes, in the working
environment);
• organise respite care: day care, holidays for children and adults with special needs, family
week ends with siblings…
Key points to start successful actions
Do not be afraid: most rare diseases patient groups are run by volunteers, on very small
budgets
• disseminate patient-friendly information
• use the internet to fight isolation
• organise the training of patient representatives
• establish links with other groups at a national and European level
• share best practices
We can achieve a lot by getting together...
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Dorica Dan- President Romanian Prader Willi Organization
Rare diseases as a reality in Romania
One of the most important things that we have to realize is that rare diseases can affect any family at
any time and in any country. Because of the big number and the large diversity of the rare diseases, they
are still unknown for both public and professionals. In the last years, mainly thanks to the work of patient
and parents’ organizations, things are slowly changing.
Romanian Public Health authorities and policy makers have largely ignored rare diseases until now.
There are some rare diseases for which a simple and effective preventive treatment is available are even
being screened for, as part of public health policy. But this is not enough, and it is time for public
authorities to consider rare diseases as a Public Health priority and take action to concretely support
patients and families affected by rare diseases.
Patient organizations have been usually established as a result of experience raised by patients and their
families from being so often excluded from health care systems and thus having to fight for their own
disease themselves.
Romanian Prader Willi Association represents patients with Prader Willi Syndrome and other rare
diseases in Romania, as well as their families and we wish to fight against the ongoing isolation that the
health system, mass media, and scientific researchers in our country foster. The Romanian Prader Willi
Association – RPWA was created in May 2003, in order to bring together the efforts of patients,
specialists and families to ensure a better life for all people with disabilities produced by rare diseases in
Romania. On October 16 2005 we opened the Information Center for Rare Genetic Diseases. It is the
first center of this type in Romania and we wish it to be a resource center for patients with rare diseases,
their families and specialists involved in the diagnosis and management of these diseases.
The access to information about diagnosis and management is essential and support groups of patients
who went through similar experiences may lead to a better acceptance of the situation and a more
efficient approach of the disease.
We are aware of the fact that, no matter how strong and motivated parents may be, they cannot succeed
by themselves to fight the disease. They need specialists and the understanding of the community they
are part of. The most important objective of our association is to provide support and understanding,
counseling and access to information, so that nobody feels alone anymore.
In order to provide better access to information about rare diseases, we have found a group of
professionals that decided to help us through writing the book: “Essential in 101 rare diseases” Also, in
order for this dream to become reality, we have been supported by a grant from the Trust for Civil Society
in Central and Eastern Europe. Thanks to all those who contributed their time and knowledge in order to
benefit the needs of people with rare diseases in Romania.
117
Ségolène Aymé
Orphanet – Inserm SC11 – Rare Diseases Platform, Paris - France
Information on rare diseases as a key issue for patients and physicians: the Orphanet
experience
Lack of information on rare diseases (RD), RD specialists, RD research, and RD clinical trials is a major
obstacle for all stakeholders in the field of RD. For patients and their relatives, as well as for nonspecialist health care professionals, it is very difficult to access appropriate information on RD and rare
disease specialists. For healthcare professionals it is often difficult to diagnose a rare disease and to know
how to treat it appropriately. For researchers, it is difficult to access enough data to conduct a research
project. For industry professionals it is difficult to identify the right experts, and to enroll enough patients
to conduct clinical research studies.
In an attempt to provide all these needs, Orphanet (www.orpha.net) was established in 1997 as a resource
centre for the rare disease community. The website is accessible to all members of the public and is
offered in six languages: English, French, German, Italian, Portuguese and Spanish.
The objective of Orphanet is to contribute to improved diagnosis, treatment and management of patients
suffering from RD, but also to accelerate the development of research and reinforce the participation of
concerned rare disease stakeholders.
Orphanet offers an encyclopedia of more than 2,200 RD. Entries for the encyclopedia are produced by
international experts in the field and validated by an editorial committee. The website also offers a
directory of services including information on specialised consultations, centres of reference, clinical
laboratories, research projects, clinical trials, patient registries, patient networks, and patient associations.
Orphanet is run by a consortium of European partners. The national teams are in charge of collecting
information about clinical services, research activity and support groups at the country level. All teams
adhere to a quality charter. The website allows users to search among approximately 2,300 syndromes by
clinical signs. The site also allows patients to register as volunteers to participate in research projects,
including clinical trials, with the goal of speeding up the enrolment of patients in clinical research.
Orphanet is responsible for the publication of the scientific journal, the Orphanet Journal of Rare
Diseases, which is freely accessible on the web.
Orphanet has recently established a new service, OrphanXchange, which is a database of molecules with
potential orphan indication and research projects with an identified potential of developing diagnostic
tests or treatments for RD. This service is intended to speed up the development of diagnostic and
therapeutic solutions for RD.
Orphanet also publishes a newsletter, OrphaNews Europe, which serves as monthly electronic newsletter
of the European Commision’s Rare Diseases Task Force and provides information on scientific and
political recent events on a global level.
Orphanet is accessed by over 20,000 distinct users every day. Half of the users are health professionals.
Patients and their families account for one third of the users, while the remaining portion of users includes
teachers, students, journalists, industry managers or interested people.
Professionals in Romania are invited to register their activities in the field of RD by completing the
questionnaires accessible on the Orphanet website and to register to receive OrphaNews.
118
The International Prader-Willi Syndrome Organisation
Pam Eisen
President IPWSO
In 1991, the first International Prader-Willi Syndrome Conference was held in the Netherlands and a few
days later the International PWS Organisation, representing 22 national associations, officially formed
and registered in Sweden. Our founders, parents and professionals, established this organization to
represent all persons with PWS, their families, and all those who work and care for them throughout the
world. Having just passed our 15th anniversary, following the “footsteps of the great souls that walked
before us,” IPWSO is now the established global PWS ambassador, spreading education and following
our mission “to raise the quality of life for all people with Prader-Willi Syndrome and their
families.
During this time, IPWSO has grown in size and in dimension of services, representing 76 member
associations. Financed by subscriptions from member associations, by donations, and grants, IPWSO is a
non-profit organization, run by volunteers, with one part time paid Director of Program Development and
one part time Business and Technical Advisor, IPWSO operates with very little cash and an abundance of
help from compassionate global friends.
IPWSO fosters the formation of new associations throughout the world. To qualify as a member of
IPWSO, a nation needs only one parent delegate and one professional delegate. Although this requirement
sounds simple, in some countries, this is not a reality. One desperate mom wrote that she was going to kill
herself because she could not find a single doctor in her country who knew anything about the syndrome.
She had no hope for her newly diagnosed child, until we helped her find an interested physician. In one
country, where the government does not allow Parent Associations, we have two professional delegates.
Another association has a parent delegate who lives in another country. Our flexibility, to include all
nations, also extends to the annual fee, based on membership, with a minimum fee of $ 50. Given the
actuality of our emerging associations, this fee is often not attainable, so we also offer an associate
membership, with no fee. IPWSO’s heart extends to all people with PWS without discrimination.
Education is the key to our objective of early diagnosis and early management of the syndrome. We
strive to meet this goal by providing printed and electronic educational material in a multitude of
languages to families and professionals. Global distribution of three educational packages (General
Awareness, Medical, and Crisis) in a multitude of languages has been a significant accomplishment for
IPWSO. Since less than half of our associations have publications, these precious packets represent the
gateway to a better life for their children. In the past few years, we distributed over 6,000 Educational
packets in English and other languages. We dispersed an additional 5,000 IPWSO Educational Packages
in Spanish throughout Spain, Latin America, and the United States. Thanks to cooperative efforts with
PWSA (USA), in 2004 we produced a DVD Food, Behavior, and Beyond,” (Pittsburgh Partnership). With
collaboration and sponsorship from our USA association, we have distributed medical management books
and hundreds of additional articles and publications. We are presently printing small Medical Alert
booklets for emergency medical situations. IPWSO will distribute these to our associations and to
physicians at major medical conferences. Many of our publications are also available by PDF, readily
available for translation and printing globally
IPWSO encourages initial national and continual regional conferences, providing support in programming
and supplying speakers. Education extends also into lectures at medical schools and hospitals and for the
past three years has included PWS Awareness Booths at major medical conferences, including regional
Endocrinology meetings in Europe, Latin America, and Australasia. In 2005, IPWSO sponsored the first
Prader-Will Syndrome training meeting for physicians at the Peking Union Medical College Hospital in
China. Our website (www.ipwso.org) opens the doors to multilingual websites throughout the world.
IPWSO has also offered a course on PWS group work for psychologists and we are now developing
courses for scientists learning diagnostic techniques.
One of the most important goals of IPWSO is to provide an international forum for scientists and
multidisciplinary professionals. In addition to encouraging and facilitating a global network of research
and services, IPWSO holds an international conference every three years. This conference in Cluj
represents our “sixth international forum.” Using our loud voice as one of the largest educational
networks among rare disease organizations, we have formed cooperative projects and alliances with
similar groups. Our final day of the International Conference 2007, with a day conference on Rare
Disease, is an example.
119
IPWSO responds to the needs of our members. We are very proud to provide free diagnosis, and
sometimes an initial medical evaluation, for families living in countries where the facilities and training
does not exist. Based on statistics of this three-year-old program, we anticipate offering sixty free
diagnoses during 2007. In countries where GHT and other medical services are not covered by the
government (more than half of our membership), IPWSO assists member associations in lobbying for this
right. Even in the most remote places in the world, IPWSO has provided legal and medical services for
people with PWS in crisis.
Now faced with a recently diagnosed older population, many of our nations are requesting help in
developing respite services, rehabilitation programs, multidisciplinary clinics, group homes, and
supportive living options. IPWSO is assisting these countries in gathering information on the existing
services provided in our older established nations. There are many positive approaches to the same
challenges. Working with PWS caretakers (from countries where programs exist) we are planning an
international conference 2008 for establishing PWS standards of care and informational publication on
initiating programs. By exchanging information among countries, we can present many options for
associations to choose and adapt to the financial and cultural realities of their country.
On behalf of people with PWS all over the world, I wish to thank our “IPWSO Angels” … the volunteer
International Board of Directors, our Scientific Advisory Board, our legal advisors, and other consultants,
our IPWSO Director of Program Development, our Business and Technology Consultant, our Parent and
Professional Delegates, engaged parents and interested friends, and our sponsors. Volunteers with
determination and big hearts move many mountains on a shoestring budget and continue to open new
doors and possibilities to improve the quality of life for all people with Prader Willi Syndrome and their
families.
On the welcoming page of our website www.ipwso.org you will find our IPWSO song, Ich Auch, Me
Too, composed and sung by Giorgio Fornasier, IPWSO past president and present Director of Program
Development with lyrics by Pam Eisen, President IPWSO.
For more information on the history of our international organization, you can read “From the Beginning”
by Founder and Past President, Jean Phillips-Martinsson. You will find this publication on our website by
looking on our welcoming page and clicking on PWS, and then publications.
Rumen Stefanov
Information Centre for Rare Diseases and Orphan Drugs – Bulgaria
ROLE OF NATIONAL INFORMATION CENTRES FOR RARE DISEASES
The presentation demonstrates the significant role of information centres for rare diseases and orphan
drugs as promoters of awareness, research and policy at national level. Examples are given with the
Information Centre for Rare Diseases and Orphan Drugs (ICRDOD) in Bulgaria, which is the first Eastern
European free educational and information service, providing personalized replies to requests from
patients, families and medical professionals. ICRDOD aims at facilitating the access of patients with rare
diseases to information about the disease affected them; providing medical professionals with quality
information about rare diseases; encouraging people with rare disease to establish patient associations,
which is the way to protect their human rights and to participate in regulatory actions; bridging between
patients with rare diseases, researchers and industry; lobbying and advocating for adopting of adequate
rare disease and orphan drug legislation and networking and integrating with the other similar national
and international organizations.
120
Maria Puiu
Access to Information in Rare Genetic Diseases in Romania
Rare diseases represent a major public health problem for at least two reasons: 1. although the diseases
are rare, there are many patients considering that there are listed a lot of rare diseases; 2. rare diseases
contribute to premature mortality and frequently determine disabilities.
European Commission for Health, patients’ organizations and other medical forums identified numerous
problems raised by these diseases: insufficient knowledge concerning rare diseases in all levels: patient,
his family, primary care, non-specialists and specialists. Insufficient knowledge involves and is increased
by lack of information at different levels of understanding and interest.
In Romania the information concerning rare diseases is insufficient and hardly accessible especially for
patients and their families. The medical personnel have easy access to the European information sources
(Orphanet, Eurordis, etc), but these are hardly accessible for the general population.
The information concerning rare diseases is incomplete also at the educational level (training of the
medical staff, doctors, kinetotherapists and paramedical professional groups such as psychologists,
logopeds and social workers). Until these problems are solved the improvement perspectives regarding
the access to information don’t register quick and consistent progress.
The information is also poor at the authority level which explains the lack of interest for rare diseases and
for the problems of the patients and their families.
Romanian Patients’ Associations and I recall the brilliant example of Romanian Prader Willi Association,
but also the professional Associations (Romanian Society of Medical Genetics), make all efforts to
change these aspects and to improve the access to information in rare genetic diseases.
121
Access to Information, Diagnosis, and Treatment for Romanian Patients with Lysosomal
Storage Diseases, 21 Hydroxylasis Deficiency and 11 ß Hydroxylasis Deficiency
P. Grigorescu-Sido1), C. Drugan2), A. Zimmermann3), V. Creţ4), C. Al-Khzouz1), S. Bucerzan1), C. Denes4),
M. Crişan4)
1)
“Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj Romania,
Children’s Emergency Clinic Hospital - Cluj, Romania,
2)
Department of Biochemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj, Romania,
3)
Johannes Gutenberg University Mainz, Germany
4)
Children’s Emergency Clinic Hospital - Cluj, Romania
Keywords: lysosomal storage diseases, 21-hydroxylasis deficiency, 11 ß hydroxylasis deficiency
Lysosomal storage diseases, caused by acid hydrolasis deficits, have as clinical presentation
organomegaly, hematological, bone and often neurological disturbances, with possible disability
evolution and life threatening risk. 21-hydroxylasis deficiency (1/15.000 newborns) has two clinical
forms: simple virilising (SV) with ambiguous genitalia, heterosexual pseudo-precocious puberty (PPP)
and infertility in females, isosexual PPP in males and salt wasting form (SW) which associates severe
metabolic disorders: dehydration, colaps, metabolic acidosis and diselectrolytemia, with fatal evolution
without treatment. 11 ß - hydroxylasis deficiency has the same clinical presentation as SV form of 21hydroxylasis deficiency and a severe arterial hypertension.
Romanian patients with these diseases have access to information, specific diagnosis and treatment in
Cluj at Genetic Diseases Center from First Pediatric Department of Emergency Children’s Hospital.
Enzyme specific diagnosis for 17 lysosomal storage diseases and molecular diagnosis for Gaucher disease
are established at Medical Biochemistry Department - “Iuliu Haţieganu” Medicine and Pharmacy
University, Cluj and by cooperation with other laboratories from Germany, Sweden and Netherlands in
other cases.
85 patients were diagnosed with lysosomal storage diseases: 65 sfingolipidosis (Gaucher disease; GM1
gangliosidosis; Fabry disease; GM2 gangliosidosis - Sandhof disease; Niemann Pick type A disease and
metachromatic leucodistrophy: 50; 5; 4; 3; 2 and 1 patient); 13 mucopolysaccharidosis (MPS III B; MPS
I; MPS II; MPS IV B and MPS VII in 6; 3; 2; 1 and 1 patient) and Pompe disease (2 patients). 34 patients
with Gaucher disease and 2 patients with MPS type I are specific treated. Romanian Foundation for
Lysosomal Storage Diseases is constituted.
44 patients are diagnosed with 21-hydroxylasis deficiency (SV – 25, SW – 19) and 5 patients with 11 ß
hydroxylasis deficiency, all treated and rhythmically evaluated. The molecular diagnosis showed in
Romanian patients with these two diseases different incidences of known mutations and also still
unknown mutations: triple mutation P30L+I2G+del8bp in 21-hydroxylasis deficiency and P94L
substitution in 11 ß hydroxylasis deficiency.
122
Hereditary Hemochromatosis Type I- The first Website Focused on the First Study in
Romania
A.M. NEGHINA1, C. SAMOILA1, M. PUIU2 and A. ANGHEL1
1
Biochemistry Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara, Romania
Medical Genetics Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara,
Romania
2
Corresponding author: Adriana-Maria Neghina, M.D. Assistant Professor “Victor Babes” University of
Medicine and Pharmacy, Biochemistry Department
Keywords: hereditary hemochromatosis, website, HFE gene, screening
Background: Hereditary hemochromatosis is an iron-storage disease characterized by massive iron
deposits in parenchymal cells leading to multiorgan dysfunction: liver, pancreas, heart, skin, joints, testes.
With an estimated prevalence of 0.5% in European population for C282Y homozygotes (HFE gene),
hereditary hemochromatosis type 1 (HH1) is more common than cystic fibrosis, muscular dystrophy and
phenylketonuria combined. Early detection of iron overload using the genetic test allows a correct
diagnosis of HH1 and facilitates the treatment-by means of therapeutic phlebotomy-slowing down the
course of the disease.
Objectives: The present study is first motivated by the lack of data regarding the incidence and
prevalence of hereditary hemochromatosis type 1 in Romania. Our purposes are: 1. to develop of a
website on hereditary hemochromatosis in Romania, addressed to both physicians and people not
involved in health-care services, as an interactive educational and laboratory service which creates an
efficient communication framework for physicians and people who are at risk or have been diagnosed
with HH1; 2. to confirm the diagnosis in early stages using the genetic test for the C282Y mutation; 3. to
outline the genetic profile of HH1 in Romania.
Materials and Methods: We have developed the first website about HH1 in Romania:
http://www.umft.ro/hemocromatoza/. An efficient large-scale screening method for the C282Y mutation
based on AS-PCR (allele specific-polymerase chain reaction) has been applied in order to establish the
diagnosis in suspected cases.
Results: Since 2004, our website has been accessed by more than 20000 people, which proves its utility
as an information and communication resource. We have reports on 11 suspected cases of HH1 based on
clinical and laboratory features. After HFE genotyping, 2 patients were found to be homozygous
(C282Y/C282Y), 2 patients were heterozygous (C282Y/wild-type) and 7 subjects had a normal genotype
(wild-type/wild-type).
Conclusions: HH1 information database has been greatly improved for the Romanian patients, and not
only, who can now access the website: http://www.umft.ro/hemocromatoza/. The genetic test’s results
allowed, in the above cases, the proper guidance of their therapy.
Kindness for Kids
Kindness for Kids is a foundation for children with rare diseases. It is a family foundation located in
Munich and was established in July 2003. Administrative expenses are financed separately by the family.
The European Commission on Public Health defines rare diseases as "life-threatening or chronically
debilitating diseases which are of such low prevalence that special combined efforts are needed to address
them. Rare diseases are those affecting a limited number of people out of the whole population, defined as
less than one in 2,000. Rare diseases affect in many cases children, because these severe pathologies often
put the lives of patients at risk.
Kindness for Kids supports in two ways:
In the fight against rare diseases the greatest successes can be achieved by medical progress. Therefore
Kindness for Kids finances research projects of institutions like hospitals or laboratories, which are
engaged in the topic of rare diseases.
On the other hand we support children and their families. Kindness for Kids organises for example
summer & winter camps for affected children. The children find others they can talk to, exchange about
their problems and the most important thing is, that the camps are a lot of fun.
123
The different national experiences of the organisations of care in Europe, examples from
Italy, France, and Estonia
Taruscio Domenicaational Centre Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
taruscio@iss.it
Introduction Developing European collaboration for the delivery of health care and medical services in
the field of rare diseases (RDs) has major potential in bringing benefits to European citizens. There are
difficulties in establishing such cooperation, as policies and practises are not homogeneous at European
level. Here we report the status in 3 EU countries: Italy, France and Estonia. This information was
collected thanks to a questionnaire developed and administered by the Rare Disease Task Force Chair and
from a survey performed by the Network of Public Health Institute of Rare Diseases (NEPHIRD) project.
The latter was supported by the Public Health Programme of DG Health and Consumer Protection.
Italy: In 1998, the National Health Plan indicated RDs as a priority for public health. In 2001 a specific
national low (Legislative Decree 279) established the Italian National Network for RDs to tackle the
problem of prevention, surveillance, diagnosis and treatment of RDs. The Decree identify approximately
500 RDs for which patients are diagnosed and treated completely free of charge. In addition, the Decree
identifies the criteria for the establishment of the centre designated to manage RDs patients (centre of
reference). Each region identifies the centres for RDs and free treatment for RDs is ensured only at
centres designated specifically for RDs within each Region. France launched its National Plan for Rare
Disease in 2004 which will be in affect from 2005-2008. The plan includes a specific provision for care
management of RDs. Criteria for national centres of reference (CR) are focused on their provision of
expertise. CR receive a specific budget to run their coordination activities Decrees are currently in
preparation to designate other expert clinics accepting to work in a network coordinated by the CR with
the intention of increasing the geographical coverage of the CR and preventing unnecessary travelling of
patients.
Estonia Due to Estonia’s small population, there is no outpatient clinic purely dedicated to RDs.
Two clinical genetics centres (Tallinn, Tartu), are responsible for the final diagnosis of RDs.
On the basis of appropriate applications, Estonian Science Foundation supports at national level research
on rare diseases.
There is no concrete list of orphan medicines for reimbursement; however reimbursement of the price of
medicines to patients is made from joint medical-insurance funds on the basis of Estonian Health
Insurance Fund’s (medicine reimbursement budget in accordance with the diagnosis). There are also rare
diseases in the catalogue of described diagnoses.
Measures for the prevention, early detection or treatment of rare diseases are constituted in particular by
DNA diagnostics and screening programmes for newborn infants. Support for patients' associations
comes from a national budget for Estonian Patients’ Association. In addition there are plans to use funds
arising from the gambling tax for project-based financing of patients’ associations.
In summary:
Italy
3 National Health Plans ‘98-00; 2003-05; 2006-08
Regional Health Plans
National Network for Rare Diseases (2001- )
Agreement between the Ministry of Health and Regions (2002)
National Committee on RD
National Research Projects for RD
Research funds for Orphan Drugs (Italian drug Agency - AIFA)
Estonia
National grant for research on RD
Neonatal DNA diagnostics, newborn screening
Annual Government support Patient’s Association of Estonia
Orphanet member
124
France
French national Plan for RDs with ten strategic priorities
Data base on RDs (ORPHANET)
Two specific telephone information services, Maladies Rare Info Service and the Federation des Maladies
Orphelines
There is a national neonatal screening programme Phenilketonuria, Congenital Hypothyroidism and
Congenital Adrenal Hyperplasia
National Plan
National Networks/National registries
Public funded structures on RDs (specific
RDs or groups):
Steering Committee on RDs:
Steering Committee on orphan drugs
Database on RDs:
Databases on orphan drugs
Research: specific schemes
Research: RD as priority topic
Public support to patients organisation
Italy
X
X
X
France
X
X
X
X
X
X
(X)
X
X
X
X
X
X
X
X
X
Estonia
X
X
X
X
X
X
X
Approaching Rare Diseases in Romania
M. Covic
University of Medicine and Pharmacy “Gr. T. POPA” Iasi, Romania
A “rare disease” affects a small number of people compared to the general population, about 1 person per
2000. There are six to seven thousand rare diseases and so the global number of patients is important
(about 1 million in Romania). Most of the rare disease are caused by genetics defects, have a serious
chronic evolution (sensory, motor or mental deficits) and are life/threatening.
In Romania the diagnosis and the management of the genetics diseases is made by five regional Center of
Medical Genetics and many other cytogenetics and molecular laboratories. The specialists offer also
genetic counseling and prenatal diagnosis.
Romania is also connected to ORPHANET – database dedicated to information on rare diseases and
orphan drugs which aims is to improve management, care and treatment of rare diseases. Orphanet
includes a rare diseases encyclopedia, which is expert-authored and peer-reviewed, and a directory of
services. This directory includes information on specialized outpatient clinics, clinical laboratories,
research activities and support groups. The national team- represented by Center of medical genetics from
Iasi – is in charge of collecting information about clinical services, research activity and support groups at
the country level. All of these data and many others about rare diseases are accessible by
www.orphan.net
125
C. Skrypnyk
Clinical Children Hospital, Genetics Unit, Oradea, Romania
Genetics Tests across Borders
Key words: patients, tests, geneticists, benefits
Introduction: Gene testing already has dramatically improved lives all over the world. Some tests are
used to clarify a diagnosis and direct a clinical geneticist toward appropriate management, while others
allow families to avoid having children with devastating diseases or identify people at high risk for
conditions that may be preventable. Available types of testing include: newborn screening, diagnostic
testing, carrier testing, prenatal testing, predictive and pre-symptomatic testing. Cost of testing can range
from hundreds to thousands of euros or dollars, depending on the nature and complexity of the test.
Objective: This paper tries to present the results of the Romanian geneticists’ efforts in order to improve
the rare genetics disorders patient’s diagnosis and care. Results: Genetics services continued to develop
and to improve in Romania in the last 17 years but, complex biochemical and molecular tests are still not
available and the state health insurance plans do not cover the costs when these tests are recommended by
a geneticist. Instead of all these impediments, during these years, some hundreds of Romanian patients
with various rare genetics disorders benefited by complex genetics tests in order to elucidate their
diagnosis. The tests were performed by certified genetics laboratories of well known universities or
genetics institutes from Europe and USA, free of charge or at the lowest cost and were possible through
the collegial relationships between Romanian geneticists and geneticists from abroad. These helpful
connection were established over the years by Romanian geneticists from all over the country, on their
own efforts, at international congresses, conferences and courses and during the scientifically exchanges
between Romanian Genetics Centers and others centers from Europe and USA.
Conclusions: Genetic testing had enormous benefits for the Romanian patients and their families,
allowing to make informed decisions and to reduce the recurrence risk, offering a correct case
management also. All this efforts established a strong relationship between geneticists and their patients,
increased the confidence and offered a better medical care and support in an international perspective.
Cristina Rusu
Iasi Medical Genetics Center’s Experience in the Diagnosis and Management of Rare
Disorders
We are presenting our experience in Iasi Medical Genetics Center in the diagnosis of rare genetic
disorders (1985-2007). Our center is based in “Sf Maria” Children’s Hospital and covers the Eastern part
of Romania (Moldova, 6 counties). The number of patients examined and diagnosed increased in time due
to the improvement of the referral and diagnostic system. We are diagnosing the entire spectrum of
genetic disorders: chromosomal abnormalities, monogenic disorders, birth defects and fetopathies,
mitochondrial disorders and cancer. We have to mention our experience in the diagnosis of X-linked
mental retardation and lisosomal storage disorders. Statistics with the disorders diagnosed will be
provided for every category. In our daily activities we are using diagnostic databases (Possum and OMD)
that help us in making a diagnosis. In the detection of chromosomal disorders we are using an automatic
karyotyping system, cytogenetic technique for Fragile X syndrome, bone marrow karyotyping, FISH
(prenatally on interphase cells and postnatally for Velo- cardio- facial and Williams syndrome) and
MLPA for subtelomeric rearrangements. For the diagnosis of monogenic disorders, we extract DNA and
send the samples abroad to different labs. The immunological anti-FMRP test on hair root is used for
Fragile X screening. We have to mention the work relationship we have with other Genetics Centers in
Romania, as well as with international organizations (Orphanet, Eurocat).
126
The Collaboration-The Rehabilitation’s Success
The integral concept of caring for clients with multiple deficiencies aplied in Rehabilitation,
Treatment and Care Centre “ACASA” Zalau
Ioana Rotaru,Monika Varga, Andrea Codre
Keywords: maximum functional ability, multidisciplinary team
INTRODUCTION: Often, genetics diseases lead to complex pathological situations related with
important disfunctional consequences. Medical rehabilitation, developed therapeutical programs for
recovering affected functions and/or developing compensatory mechanisms, with a view to reach
maximum individual performance and maximum economic and social independence.
PRESENTATION: “Acasa” Foundation is a Romanian-Dutch Foundation, created for offering care,
treatment and rehabilitation for children and adults. In order to reach this goal, foundation offer medical
and social services at peoples home and in one Rehabilitation Centre.This Centre include medical offices,
phisiotherapy rooms, ocupational therapy rooms and bedrooms for 120 clients.
The services granted in our Centre subscribe the two aspects of rehabilitation process: functional
rehabilitation and socio-profesional readaptation. The quality and the period of time for functional
rehabilitation depend on earlier intervention. Is obvious that functional rehabilitation will be as easy and
favorable as early the treatment is started, especially for little children who do not have motor experience,
so neither abnormal reflexes or vicious dinamic stereotype. The limits of functional rehabilitation are
dictated by lesion type, associated pathology, by involving or not of central nervous system, and the
severity of this involving. Pursuing reachable goals, we must admit also the fact that in some diseases,
rarely do we obtain a full rehabilitation; in this case, socio-familial reinsertion will provide autonomy to
the client, and this is not negligible.
Rehabilitation programs - especialy in genetic diseases, with complex polymorphous clinical aspects – are
creative programs requiring collective effort of a large specialist team: rehabilitation specialist,
phisiotherapyst, ergotherapyst, logopedist, psychologist, social worker and other professionals involved in
client assistance. Rehabilitation requires also the client family involving which can provide support and
motivation. Therapeutical program is personalized after all specific needs are revealed. Therapeutical
approach will be differential depending on disfunction type and severity: biomechanical approach-for
clients with peripheral neurological and orthopedical lesions; sensorio-motor approach- for clients with
central nervous system disfuncions; rehabilitating approach- for clients with residual disfunctions.
Romanian National Alliance for Rare Diseases – RONARD
Etelka Czondi- Romanian Prader Willi Association (RPWA)
The Romanian Prader Willi Association, created in 2003, opened the first Information Center for Rare
Genetic Diseases from Romania in 2005.
In the same year, 2005, the idea to create a national network was born – involving different stakeholders
from the field of rare diseases – in order for the voice of patients and patient organizations to be better
heard at national level. In 2006 we submitted a project proposal to the Trust for Civil Society for CEE and
in March 2007 our project was approved. Our goal through this project is to increase the awareness of
the community on rare diseases through consensus building between different stakeholders involved in
this field (patients, professionals, social workers, etc).
Each of our project objectives represents one stage towards the achievement of our broader goal:
1. To develop a national network of key representatives of patient organizations, communities, and
public institutions - RONARD;
2. To establish a common strategy for tackling the issues related to rare diseases;
3. To organize an Information Campaign on rare diseases as part of the National Conference for
Rare Diseases;
4. To create a national training program targeting all stakeholders involved in rare diseases.
We are convinced that creating a national alliance represents the solution to advocate for rare disease
patients. It is impossible to develop a public health policy specific to each rare disease. But a global
approach would enable the individual disease to escape anonymity and promote real, public health
policies to be established in the areas of scientific and biomedical research, drug research and
development, industry policy, information and training, social benefits, hospitalization and outpatient
treatment.
127
European cooperation as a way to improve care for rare diseases in Romania: the role of
Eurordis
Jerome Parisse-Brassens, Communications and Development Officer, Eurordis
EURORDIS is a non-governmental patient-driven alliance of patient organisations and individuals active
in the field of rare diseases, dedicated to improving the quality of life of all people living with rare
diseases in Europe. It was founded in 1997. EURORDIS represents more than 280 rare disease
organisations in over 33 different countries, covering more than 1,000 rare diseases. It is therefore the
voice of the 30 million patients affected by rare diseases throughout Europe. Work priority areas are to
build the rare disease community in Europe; to advocate for patients and raise awareness on rare diseases;
to improve access to care for patients and help develop public health policies; and to foster therapeutic
development and research; and funding and organisation.
Building the community: with over 280 members today and an additional 300 allied members through its
national rare disease alliances, Eurordis builds patient group capacity all over Europe and empowers them
through information, information exchange and networking. Eurordis coordinates a council of 11 national
rare disease alliances. The organisation of annual membership meetings and of the biennial European
Conference on Rare Diseases are key cornerstones of the building of the European rare disease
community. To liaise with the community at large, Eurordis works in 6 languages (website, newsletter,
reference documents).
Advocacy and policy development: Eurordis is present in many Europeans institutions and platforms. It
leads proactive advocacy work both at European and national levels in coordination with national rare
disease patient organisations. Some of the successes in advocacy work include the adoption of the EU
Regulation on Orphan Medicinal Products in 1999, the adoption of the EU Regulation on Medicinal
Products for Paediatric Use in 2006 and the promotion and maintenance of rare diseases as an EU public
health policy priority and EU Research Framework Programmes priority. Current priorities include the
future EU Regulation on Advanced Therapies and the future EU Legislation on Health services (including
the critical issue of patient mobility).
Public health and access to care: Eurordis leads scientific surveys, organises training sessions for patient
representatives, and develops a range of services for patients (European networks of help lines, of respite
care services, of therapeutic recreational programmes for rare diseases; online patient communities).
Work on centres of reference for rare diseases is a key element of Eurordis’ work in the public health
area.
Therapeutic development and research: Eurordis has contributed to the designation of over 450 orphan
drugs by participating in the Committee on Orphan Medicinal Products (COMP) of the European
Medicines Agency (EMEA) since 2000. It works closely with the EMEA and leads surveys on patient
access to the 37 orphan drugs authorised in the EU and potentially benefiting 1.6 million patients. It also
contributes to transparent and quality information on medicines for patients and improvement of
pharmacovigilance. Eurordis has created the European network of rare disease Biological Resource
Centres (EuroBioBank) for DNA, cells and tissue. Eurordis is also a partner in many European research
projects such as OrphanPlatform, E-Rare, ECRIN, CliniGene, and Treat-NMD.
Contact:
Jerome.parisse-brassens@eurordis.org
www.eurordis.org
128
The Development of Policies on Rare Diseases in East Asia: The Cases of Japan, Korea,
and Taiwan
Min-Chieh Tseng
Vice President, Taiwan Foundation for Rare Disorders, Taiwan
Associate Prof., Dep’t of Social Work, National Taipei University
1. Introduction
The major purposes of this presentation are to review the development of policies on rare diseases in
terms of orphan drug regulation, newborn screening program, government-sponsored program, and
medical welfare of rare disorders among Japan, Korea, and Taiwan.
2. The Case of Japan
Japanese government has implemented newborn screening program that screens for 6 congenital
metabolic disorders since 1984. Japanese government also provides those children with metabolic
disorders with free special formula. In 1993, Orphan drug regulation was proclaimed in order to
guarantee medical rights of rare disease patients, whose diseases prevails less than 50, 000 people in
Japan. The Orphan Drug Regulation not only support patients’ medication and the medical equipment,
but also encourages rare disease research through the establishment of the Organization for
Pharmaceutical Safety and Research. To further encourage the pharmaceutical industry to invest orphan
drug research and designation, Japanese government even provides incentives such as research funds, free
tariff (for imported orphan drugs) and 7-year market monopoly.
Furthermore, since 1973, Japanese government has been providing medical subsidies specifically for
intractable rare diseases. By 2006, 45 diseases were listed as intractable rare diseases. Various
organizations have been established for rare diseases. Japan Intractable Diseases Research Foundation
was established in 1973 to provide medical assistance, employment counseling and life-support
counseling. Later in 1997, Japanese local government carried out home nursing project which provide
various subsidies including 17 kinds of life subsidies, and physical therapy subsidies. Home nursing
project also include services such as bathing assistance, cooking service, cleaning service and shopping
service.
3. The Case of Korea
In Korea, severe rare diseases patients have national health insurance and medical support from the
government since 2001. The number of diseases subsidized increased from 4 diseases in 2001 to 89
diseases in 2006, while the number of patients increased from 8,693 in 2001 to 16,756 in 2005. The
amount of money subsidizing rare disease patients was 16.4 billion Korean Yen in 2001 and 33.8 billion
Korean Yen in 2005, which was used on subsidizing the cost of diagnosis and treatment, medical
equipments such as respiratory machines, nurses, assistive equipments and special foods. Korean Orphan
Drug Center was established in 2001 in order to provide orphan drug that were not imported because of
lack of incentives and recommend and subsidize special medication that were not officially approved yet.
Korean Center for Rare Diseases was established in Korean National Institute of Health (KNIH) to
encourage research and services for rare diseases, such as setting up Helpline network to collect and
disseminate rare disease information.
4. The Case of Taiwan
Taiwan’s newborn screening program was implemented in 1982, screening 5 congenital metabolic
disorders and since 2006, and Tandem Mass Spectrometry has been applied in expanded newborn
screening to detect around 26 metabolic disorders. Children with metabolic disorders will be provided
with free special formula. Rare Diseases and Orphan Drug Act was implemented in 2000, and that
provides the funds for rare diseases research, 10-years market monopoly, and medical subsidies outside
national health insurance. By April, 2007, there have been 161 rare diseases and 86 orphan drugs
reimbursed by a global budget within the national health insurance system. In 2001, the "Physical and
Mental Disabled Citizens Protection Act" covered people with rare diseases and thus unveiled a new era
in the rights of rare disease patients, which further guarantees rare disease patients’ medical rights as well
as the fundamental right to be an integral part of our society. In 2001, Orphan Drug Service Project and
International Diagnostic Testing Project were carried out in order to supply orphan drug for emergent use
and sending specimen to laboratories abroad to confirm the diagnosis. Around 60 pieces of specimen are
sent abroad per year.
129
Rare Diseases Poster Platform (In Alphabetical Order):
Poster Session – (1ST FLOOR CORRIDOR)
1.
Borzan Cristina et al: COMMUNITY NEEDS IN SUPPORTING CHILDREN
WITH PRADER WILLI SYNDROME
2.
Crenguta Albu et al: CONGENITAL GLAUCOMA IN SIBLINGS
3.
L.I.Butnariu et al: DIFFICULTIES IN GENETIC COUNSELLING IN FOUR CASES OF
DOWN SYNDROME
4.
K. Csep et al: INNOVATIVE STRATEGIES FOR GENETIC DISEASE MANAGEMENT
5.
Dana Liana David, CONTROVERSIES IN GENETIC COUNSELING, ETHICAL
MANAGEMENT OF PATIENTS WITH GENITAL AMBIGUITY
6.
Gafencu Mihai et al: INFORMATION AND TRAINING FOR SKILL DEVELOPING IN
DOWN SYNDROME CHILDREN
7.
Glavan F. et al: THE ROLE OF ORTHODONTIC THERAPY IN CORRECTION OF DENTOMAXILLARY ANOMALIES FROM DOWN SYNDROME
8.
Glavan F. et al: THE PSYCHO-SOCIABLE IMPROVEMENTS AFTER COMPLEX ONSET
IN TREACHER COLLINS SYNDROME
9.
Gorduza et al: DIFFICULTIES IN DIAGNOSIS AND GENETIC COUNSELLING IN WOLFHIRSCHHORN SYNDROME – CONSIDERATIONS ON TWO CASES
10.
Ioana Ispas et al: THE HUMAN EMBRYONIC STEM CELL: AN ENTITY WITH OR
WITHOUT IDENTITY?
11.
S. Marchian et al: GENETIC COUNSELLING IN CEREBELLAR ATAXIA
12.
T. Marcovici et al: MENTAL RETARDATION IN CHILD-A REAL CHALLENGE FOR A
BETTER QUALITY OF LIFE
13.
O Marginean et al: CONSIDERATION UPON A CASE OF FACIAL DYSMORPHYSM AND
PSYCHO-MOTOR DELAY IN AN INFANT
14.
Mihailov Delia et al: LIVING WITH HAEMOPHILIA IN ROMANIA
15.
M. Pop et al: GENETIC COUNSELING IN CANCEROLOGY
16.
Prof. Dr. Maria Puiu et al: COLLABORATIVE EXPERIENCES OF THE ROMANIAN
PRADER-WILLI ASSOCIATION WITH MEDICAL SPECIALISTS
17.
Prof. Dr. M. Puiuet al: THE ROLE OF GENETIC COUNSELING IN DIAGNOSIS OF
DISMORPHISM IN CHILDREN
18.
L. Tamas et al: INTEGRATION OF PRENATAL DIAGNOSIS IN
GENETIC COUNSELING FOR CYSTIC FIBROSIS
130
19.
Alina Tărniceru et al: THE ROLE OF THE PRIMARY CARE PHYSICIAN IN MANAGING
RARE GENETIC DISEASES
20.
D. Vasilie et al: LONG-TERM PSYCHOLOGICAL OUTCOMES OF HYPOSPADIAS
131
COMMUNITY NEEDS IN SUPPORTING CHILDREN
WITH PRADER WILLI SYNDROME
Borzan Cristina, UMF “Iuliu Hatieganu” Cluj Napoca
A problem of Social Paediatrics, with genetic determination, it fits into the category of avoidable
morbidity causes. The current developments in genetics, makes the pre-natal diagnosis possible, which is
extremely important for planning health and social services for this category of the population. Reduced
as incidence, the pathology has implications which go beyond the sphere of specialized medical
interventions and it expands in the social field, the field of pedagogy and community. It is a typical
example of community intervention need for an individual case, applying the conclusions of the Almaty
Conference, according to which the responsibility for the individual and community health equally
belongs to the individual, the family, the community, the health system but also decision makers, who
must respect the right to health for all citizens, with no discrimination.
The responsibility of care in a case cannot only belong to the family, but there is need for solidarity in
providing care, by dividing responsibilities between many community sectors, as well as by developing
training programmes.
Borzan Cristina, MD Public Health and Management, University Professor, Head of Public Health and
Management Department, UMF “Iuliu Hatieganu” Cluj Napoca, President of the Consultative
Commission of Public Health from the Ministry of Public Health
132
CONGENITAL GLAUCOMA IN SIBLINGS
Crenguta Albu, Dinu Florin Albu, Emilia Severin
Genetics Department, “Carol Davila” University of Medicine and Pharmacy – Bucharest
Romania
Background: congenital glaucoma (CG) is an autsomal recessive inherited disorder and occurs in the
first month of life. Mutations in CYP1B1 gene were found in 20-30% of patients with congenital
glaucoma.
Objective: to describe the clinical manifestation of CG in this family and to examine the prenatal genetic
findings associated with GC.
Patients and Methods: One family of Romany ethnic group was investigated: unaffected parents and
their two affected sons. The mother being pregnant again asked for genetic counseling. Ophthalmic
examination included: ophthalmoscopy, tonometry, perimetry and gonioscopy. Prenatal diagnosis for CG
was performed and included cytogenetic and DNA analysis (consisted of PCR amplification and direct
sequencing of all 3 coding exons of the CYP1B1 gene with corresponding intron - exon boundaries).
Results: The family medical history for CG was negative; parents were unrelated and all affected family
members were male. The mother is affected by severe myopia (more than 6.00 diopters). The two sons
(aged 9 and 17 years, respectively) are affected by congenital glaucoma. Age of onset was in the first
two month of life for both brothers. The sibs shared similar CG phenotype (Fig.1). Ultrasound
examination of the pregnant woman revealed a singleton pregnancy with enlargement of the eye (Fig.2).
Karyotype of the fetus indicated a normal male (46, XY) but DNA analysis confirmed the CYP1B1
mutation. A missense mutation E229K was identified in homozygous form in exon 2 from the CYP1B1
gene. The E229K mutation is a known disease-causing mutation in the CYP1B1 gene responsible for
autosomal dominant congenital glaucoma. This mutation replaces a glutamic acid for a lysine at amino
acid position 229 of the CYP1B1 gene (GENDIA, 2006).
The parents decided to terminate the pregnancy.
Conclusion: Our results support previous studies reporting that the mutations in CYP1B1 gene represent
the molecular basis for congenital glaucoma in families of Romany ethnic group.
133
DIFFICULTIES IN GENETIC COUNSELLING IN FOUR CASES OF DOWN
SYNDROME
L.I.Butnariu, E.V.Gorduza, M. Gramescu
Disciplina de Genetica Medicala, Universitatea de Medicina si Farmacie “Gr.T.Popa”, Iasi, Romania
Keywords: DS, karyotype, unbalanced chromosomal anomaly.
Down Syndrome (DS) is determined by total or partial trisomy of chromosome 21 and his incidency is
1/650 live births. Critical region (Down Syndrome Critical Region) is 21q22. A major problem is genetic
counselling in families who have a child with DS. There are many factors involved: maternal age, type of
anomaly, the sex of the parents who carry the anomaly.
We present four particular cases of DS in order to present the problems of what can appear in genetic
counseling.
Case 1: T.D., female, 5 mounths old. The parents had one misscarige. Clinical evaluation revealed:
dysmorphism (characteristic facies), short stature, microcephaly, ASD and VSD. Familial anamnesis was
negative. The karyotype confirmed the diagnosis: 46,XX,dup21q. Most probably is a de novo anomaly,
so, the risk of recurrency is unsignificant.
Case 2: U.M., male, 1 mounth, with observation of DS and congenital lues, present of clinical evaluation
the distinctive phenotype of DS, microcephaly, and cardiac anomalies. The karyotype confirmed the
diagnosis: 47,XY,t(1;2)(p32→pter;q37→qter),-3,-21,+der(3)rcp(3;21)
(p11.1;q22.2),+der(21)rcp(3;21)(p11.1 ;q22.2),+21. The karyotypes of the parents were normal, so, the
risk is unsignificant, except a germinal mosaicism.
Case 3: T.M., female, 16 years old, present short stature, characteristic facies, moderat mental
retardation. The karyotype confirmed the diagnosis of DS: 46, XX, dic21. Dicentric chromosomes appear
from postzygotic errors, so, the risk is unsignificant.
Case 4: R.M., male, 15 years old, present distinctive phenotype of DS, microcephaly, extrasystolic
cardiac arrhythmia, ASD, moderate mental retardation.
The karyotype confirmed the diagnosis of DS: 47, XY, ins (21; 18) (p11.2 ; p11.3→pter), +21. If one
parents has the insertion (21; 18), the risk of recurrency is between 15-20%, because both chromosomes
involved in this anomaly, present partial viable trisomy and monosomy. In this case is necessary to do the
the karyotype of both parents.
Conclusions: genetic counseling may be difficult and depend by the mechanism of the unbalanced
chromosomal anomaly.
134
INNOVATIVE STRATEGIES FOR GENETIC DISEASE MANAGEMENT
K. Csep
University of Medicine and Pharmacy Tg. Mures, Romania
Keywords: lysosomal storage disorders, treatment, diagnosis, information, research
There is always hope for incurable diseases. What was life-threatening and debilitating twenty years ago,
allows a normal life-span and good quality of life today. Though the sequence of the representative
human genome was announced a couple of years ago and recombinant DNA technology is decades’ old
already, we are only at the beginning of offering true treatment in genetic disorders instead of palliative or
symptomatic care. Gene therapy will ultimately target the etiology of these disorders; however, today
efficient pathogenetic treatment is already part of everyday care. The best example world-wide and in
Romania is the management of some lysosomal storage disorders (LSDs). The standard care in Gaucher,
Fabry, Pompe disease and some MPS forms is enzyme replacement therapy (ERT). Though ERT in
Gaucher disease appeared in 1991 and treatment was first administered intermittently in 1997 in our
country, Aldurazyme became available in 2003 and was already administered to Romanian patients in
2005. In 1997, specific diagnosis became available at the Biochemistry Department of the University of
Medicine and Pharmacy and the National Center for LSDs was established at the 1st Pediatric Clinic in
Cluj. Diagnosis, treatment and monitoring are coordinated by the Center in collaboration with different
local specialists, treating physicians all over the country and specialised centers abroad. By meetings and
contacts with organizations all over the world, the Foundation for LSDs in Romania facilitates the
patients’ access to information and support. Physicians may register on-line their patients to international
databases; contribute to gather a large collection of confidential data that helps understanding the natural
course of such rare disorders and founding optimal care. Treatment efficiency is confirmed by regular
monitoring of clinical data and different tests. However, for patients and families results translate in the
disappearance of fractures after initiating infusions in a patient who had more than 50 fractures by her
mid-thirties or the progressive amelioration of facial traits in a child whose parents described how she
became uglier every day due to the subcutaneous infiltration prior to ERT. The structure, the possibilities,
results and difficulties of LSD management in Romania will be presented.
135
CONTROVERSIES IN GENETIC COUNSELING, ETHICAL MANAGEMENT OF
PATIENTS WITH GENITAL AMBIGUITY
Dana Liana David, Maria Puiu, Manuela Deutsch, N.Hrubaru, Brigitte Hrubaru, S. David, A. Anghel
University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania
Keywords: congenital adrenal hyperplasia, genetic counseling, psychological, ethical management
Introduction: Intersex cases are rare and even medical personnel may not fully understand the nuances,
implications and complexities of these cases. Management of patients with congenital adrenal hyperplasia
(CAH) is controversial. Modern treatment of infants with ambiguous genitalia involves a team-oriented
approach. This gender-assignment team usually involves neonatologists, geneticists, endocrinologists,
surgeons- gynecologist, counselors, and ethicists.
Material and Methods: We did a study of a clinical based sample of women with CAH, all were
genetically female. We recruited 10 sequential female patients (aged 18 – 44) from the Endocrinology
Clinic of Timişoara, in 2005 – 2006. They were evaluated by an endocrinologist, gynecologist, geneticist
and a psychologist. All were raised as female. There were interviewed with questionnaires about eating
disorders, mental disorders, the knowledge of their medical/surgical history and karyotype, their
satisfaction with their gender assignment and sexual function and their need for consultative
psychological assistance.
Results: The study has its limits, the small number of patients, and the lack of the control group. The
comparison was made with the general population. Two of them had the criteria for mood disorders, six
of them had anxiety disorders, two had alcohol disease, no depression, and no eating disorders were
present. Eight women were sexually active, heterosexual, one was homosexual, one was sexual inactive.
Two of them are mothers, each one with one child. All patients were smokers.
Conclusions: The action of genes, their products, the hormones and their receptors are not completely
known. There are still a great number of questions regarding gender assignment, gender identity, gender
role and sexual preference. We are not able to give reasonable answers to the questions posed by parents
of children with intersex and by those of the patients themselves.
136
INFORMATION AND TRAINING FOR SKILL DEVELOPING
IN DOWN SYNDROME CHILDREN
Gafencu Mihai, Maria Puiu, Doros Gabriela, Violeta Stan, Carina Dragu, Sandu M., student Per Silvia
University of Medicine and Pharmacy “Victor Babes”, Children’s Hospital “Louis Turcanu” Timisoara
Keywords: Down syndrome, volunteer, “Soul-Friends”.
Introduction: Down syndrome or trisomy 21 is a genetic disorder caused by the presence of all or part
of an extra 21st chromosome. It is named after John Langdon Down, the British doctor who described it
in 1866.
Materials and Methods: 32 children with Down syndrome were part of an ongoing project called
“Soul-Friends”. A group of 14 volunteers of the Timis County “Save the Children” Organization have
had weekly meetings with children with Down syndrome and their caretakers. The main goal of this
project is to provide education to the children with Down syndrome, their siblings and their caretakers.
Description and Results: Each volunteer is responsible for one child and becomes his “Soul-Friend”.
The children get involved in different educational activities like games, artistic performances, trips and
sport at summer camps. All of these activities create a comfortable environment for the children and a
special bond between the “Soul-Friends”, and at the end point a better knowledge about there disease.
The caretakers and the siblings are given information about the Down syndrome and support but there are
also open discussions among them to help them cope to day-to-day challenges. The sportive and artistic
performances presented to the public on different occasions have made the community more perceptive
and aware of the problems of the children with Down syndrome. The acceptance and the involvement of
the community in supporting these children have risen together with a good understanding of Down
syndrome characteristics.
137
THE ROLE OF ORTHODONTIC THERAPY IN CORRECTION OF DENTOMAXILLARY ANOMALIES FROM DOWN SYNDROME
Glavan F., Puiu M., Moise M., Dinu S.
University of Medicine and Pharmacy Victor Babes Timisoara
Patients diagnosed with Down syndrome were presented by their parents at the Department of Pediatric
Dentistry and Orthodontics for dental, ocluzal and functional problems. Many well-known disorders such
as hearing loss, congenital heart diseases, and ophthalmic disorders are found with increased prevalence
among. The dental disorders like: caries, gingivitis, light class III malocclusion, canine impaction, severe
maxillary deficiency, moderate to severe dental crowding are a characteristic for a patient with Down
syndrome.
Knowledge of many medical disorders found in individuals with Down syndrome enables clinicians to
provide rational medical monitoring.
Regarding the psycho-emotional aspect, they were raised in a normal social environment (normal kinder
garden and general school, not a special institution). They had a normal behavior, are sociable but they
have a pronounced sensibility.
Key words: Down syndrome, light class III malocclusion, maxillary deficiency.
138
THE PSYCHO-SOCIABLE IMPROVEMENTS AFTER COMPLEX ONSET IN
TREACHER COLLINS SYNDROME
Glavan F., Puiu M., Moise M., Dinu S.
University of Medicine and Pharmacy Victor Babes Timisoara
Treacher Collins Syndrome or TCS is a genetic disorder caused by a mutation on chromosome 5. The
main characteristic features of Treacher Collins syndrome are: eyes that slang down at the outer corners;
notched lower eyelids (coloboma), small lower jaw, which may slant with cleft palate unusually large
mouth, underdeveloped, malformed or missing ears, underdeveloped or missing cheekbones and side
wall/ floor of the eye socket.
Many need help such as specialized hearing aids or speech therapy to develop speech and language, facial
aesthetics.
Most of them have normal intelligence but because of the physical aspect they are very shy, very difficult
to communicate, and they avoid eye contact constantly. That why this patients need a complex onset:
genetic consult and adequate counseling, orthodontic and orthopedic treatment, cosmetic surgery, oral
surgery all completed by physiological counseling for the patient and his family.
After the complex rehabilitation we observed a significant amelioration: he started to communicate, to
socialize and smile.
Key words: Treacher Collins Syndrome, genetic disease, orthodontic and orthopedic treatment, cosmetic
surgery.
139
DIFFICULTIES IN DIAGNOSIS AND GENETIC COUNSELLING IN WOLFHIRSCHHORN SYNDROME – CONSIDERATIONS ON TWO CASES
Eusebiu Vlad Gorduza1, Mihail Voloşciuc1, Elena Braha1, Mihaela Grămescu2, Lăcrămioara Butnariu1,
Mircea Covic1
1
2
Universitatea de Medicină şi Farmacie „Gr. T. Popa” Iaşi, Disciplina de Genetică Medicală,
Universitatea de Medicină şi Farmacie „Gr. T. Popa” Iaşi, Laboratorul de Citogenetică, România
Key words: genetic counselling, Wolf-Hirschhorn syndrome, 4p deletion
Wolf-Hirschhorn syndrome is a rare chromosomal disease (1/50.000 new-borns) generated by a 4p
deletion. In our work we present the difficulties of genetic counselling in two cases of Wolf-Hirschhorn
syndrome with different chromosomal abnormalities. The first case was a girl, diagnosticated at age of 2
months. The clinical motivations of genetic examinations were: low height and weight, microcephaly,
bilateral coloboma of iris and cleft palate. The reproductive history of mother indicated a spontaneus
abortion at age of 4 months and another malformated child with cleft palate (dead soon after birth), but
that was not investigate. In our patient classical karyotype was normal, but FISH analysis indicated the
presence of a 4p16.3 microdeletion. Because of abnormal reproductive history of mother, the FISH
analysis was made at mother and indicated a t(4;20)(p16;p13) translocation. In this situation our patient
presented a asociation between a 4p partial monosomy and a small 20p partial trisomy. In this case the
genetic risk was about 10%. The second case was another girl with Wolf-Hirschhorn syndrome,
diagnosticated at birth for IUGR, microcephaly, facial dysmorphy and cardiac congenital abnormalities.
The karyotype of child indicated a 4p deletion, while the parent’s karyotypes were normal. In these
conditions, the genetic risk of parents is very small (<0,1%). Our data certify the cytogenetic and genetic
counselling difficulties in a rare chromosomal disease with some specific clinical particularities.
140
THE HUMAN EMBRYONIC STEM CELL: AN ENTITY WITH
OR WITHOUT IDENTITY?
Ioana Ispas
Advisor for Bioethics, Genomics and Health
Ministry of Education and Research
National Authority for Scientific Research
European Integration and International Cooperation Division, Bucharest,
Motto: Human responses are the core of the humanity which contracts within humanity they are widely
distributed. But to identify them with humanity is only partial an empirical claim. It remains also partly
and aspiration.
Johnathan Glover: “Humanity: A Moral History of the 20th Century””
The embryo is not defined in most of the countries or the definitions are very diverse. Embryonic stem
cells poses a moral problem which doesn’t appear in the general case of human subject research: whose
life has to be protected first: the donor or the tool for experiment (embryo)? In most of the cases this kind
of experiment will consume the embryo. Are embryos destructive experiments morally permissible and
why? A lot of debates already started since a couple of years about morality of this kind of research. But
the science has to progress even is still a disagreement on the extent of the protection to which the human
life is entitled during early embryonic development. In case of rare diseases this issue is even more
debated, taking into account the frequency of these diseases.
Besides of Aristotle hylomorphic view of the human being, now days the church plays an important role
in this debate. In Declarato de Abortu Procurato (1974) the church argues for zygotic personhood by
identifying a person with a genome. In most of the cases the tendency is to transfer to the human embryo
moral values like: respect for personal dignity, autonomy, welfare, justice, quality of life. But does this
approach correspond with scientific realities of embryos functions? The article is investigating the
consequences of transferring the human values to the embryos and the status of embryonic stem cells,
taking into considerations the situations in which one value is realized with the compromises of other
values .The double standard principle is analyzed in case of embryonic stem cell research and IVF. The
ethical alternatives to embryonic stem cells are discussed (stem cells from amniotic fluid, stem cells
derived from embryos without it destruction etc).
141
GENETIC COUNSELLING IN CEREBELLAR ATAXIA
S. Marchian, L. Moga
Facultatea de Medicina “Victor Papilian”, Universitatea “Lucian Blaga” din Sibiu
Genetic counseling is a complex medical act which aims both at evaluating a persons risk to get a genetic
disease or transmitting it to their offspring and providing information about its consequences and how
they can be prevented or treated. One ought to consider the particular family background against which
such counseling is achieved. The act is based on clinical and molecular (if possible) diagnosis for the
identification of the way and risk of passing on the disease to descendants. The couple F.M. asked for
genetic counseling before conceiving a baby as the already have a child diagnosed with Friedreich ataxia
(the proband F.S, aged 10).The diagnosing was base on clinical signs and laboratory tests. Friedreich's
disease, the most frequent form of ataxia, is clinically and genetically heterogeneous. It is characterized
by progressive evolution, ataxic gait, dysarthria, areflexia of the lower limbs, cardiomyopathy, slow and
diffluent speech, dysmetria associated with hypermetria, and sudden, ample, awkward movements. The
genetic heterogeneity of Friedreich’s disease is caused by the marked genetic polymorphism of the gene
X25, produced by the variable expansion of the GAA triplet repeat in the genotype of the members of the
same family, as well as by the various point mutations in the gene X25. This variable expansion of the
GAA triplet repeat also determines the clinical heterogeneity, the severity of Friedreich’s ataxia
symptoms varying in the same family. In our case the mutation could not be identified with the help of
molecular diagnosis. Nevertheless considering this monogenic disease a recessive autosomal model of
transmission has been identified on account of the family s pedigree. Genetic counseling was possible, the
couple were informed that the risk for the disease to become manifest in the baby amounted to 25% for
each pregnancy, because both parents were carriers of the mutant gene inducing this disease. The couple
were given the freedom to decide whether they would conceive another baby or not, since they were
provided with all the information about the complications evaluation and severity of the disease. The
genetic counseling session had its limitations and turned into partial failure as a result of the inexistence
of a molecular diagnosis. This was the reason why it was not possible to identify the mutation in relatives,
in order to prevent giving birth to other affected children from couples related to couple F.M. Also, it has
not been possible to evaluate the prognosis of the disease in the proband. Even under such circumstances
genetic counseling remains an important prophylactic method.
142
MENTAL RETARDATION IN CHILD – A REAL CHALLENGE FOR A BETTER
QUALITY OF LIFE
T. Marcovici1, M.Puiu1, I. Sabau1, I. Simedrea1, R. Tudorache2, E. Gamaniuc2
1 University of Medicine and Pharmacy „Victor Babes” Timisoara, Romania
2 „Louis Turcanu” Children’s Emergency Hospital, Timisoara, Romania
Key words: mental retardation, child
Background: Mental retardation and neurological delay are often associated with atypical physical
features. The cause may be: chromosomal abnormalities, genetic anomalies or non-genetic (infections,
trauma, and hypoxic insult). The children and their families are vulnerable and they need help and support
to improve life quality.
Materials and Methods: We present four cases, one male and three females, aged 14-24 months
admitted for psychomotor retardation and craniofacial dysmorphism.
Results: A comprehensive medical evaluation was made: complete prenatal and birth history, clinical,
neurological and ophthalmologic examinations, skull X-ray, brain MRI and blood tests. Cortical and optic
atrophy were present in one case. Microcephaly was present in all cases. Tests for TORCH syndrome and
karyotype analysis were normal. Life-consequences for the families of these patients were evaluated.
Conclusions: The quality of life is compromised due to the child’s psychomotor delay, high parental
stress, lack of information and physician’s limited ability to formulate a specific prognoses in the
preschool years.A better collaboration is necessary between medical staff, families and patient support
groups to improve the children’s lives, to provide help to the families and to increase the social tolerance.
143
CONSIDERATION UPON A CASE OF FACIAL DYSMORPHYSM AND PSYCHOMOTOR DELAY IN AN INFANT
O Marginean *, I Micle,* O Belei *, M Marazan *, R Giurescu *, C Bochean **
University of Medicine and Pharmacology “Victor Babes” Timisoara, Romania
* I Pediatric Clinic Pediatrie, UMF Timisoara
** Children Emergency Hospital “Louis Turcanu” Timisoara
Keywords: Stickler syndrome, particular facial phenotype, infant
Aim: The authors present a case that associates particular facial phenotype, plurimalformativ syndrome
and psycho-motor delay in a 7 month infant, diagnosed with Stickler syndrome. An important objective
was to establish the diagnosis criteria. Material and methods: A 7 month old infant was admitted in our
clinic in 2005 for respiratory pathology and hypotonia. Clinical examination revealed facial, ocular,
cardiac malformations. The familial history showed the presence of malformations in 2 other paternal
family members (2 uncles). Clinical and complex biological investigations were performed including
ocular, auditorial, cardiac tests and assessment of biochemical and metabolic parameters. The karyotype
investigation shown anomalies of chromosome 1: 46 XY, 1qh+, 21s+, yq+. Oftalmological exam revealed
ocular modification: congenital cataract with fetal vitreous body persistence. Conclusions: Stickler
syndrome is under diagnosed. Corroborating anamnestic data, clinical exam and karyotype investigation
are very important for diagnosis of rare genetic diseases. Genetic counseling was performed to the family
due to the dominant autosomal inheritance.
144
LIVING WITH HAEMOPHILIA IN ROMANIA
Mihailov Delia, Serban Margit, Bataneant Mihaela, Maria Puiu
University of Medicine and Pharmacy “Victor Babes” Timisoara
Haemophilia is an acquired X-linked coagulopathy which can be consider an example of the
socioeconomic impact of biotechnology in rare diseases. The cost of the treatment requires a large amount
of economic and human resources. In developed countries, adequate substitutive therapy is associated
with a low complication rate and a normal life span. In our country, because of poor financial resources
allocated, haemophilia treatment is inadequate, with serious short and long-term consequences. Because it
is a chronic disease which can not be cured, it has a strong influence on patients and their families. In the
absence of home therapy programs, patients have to travel long home-hospital distances in order to
receive an adequate care. In these conditions, any bleeding episode means important travel costs,
numerous absences from school and work place, long hospitalizations, and an important delay in
substitution administration. Joints and muscles bleedings and their long-term complications lead often to
pain and disability and to dramatic impairment in the overall quality of life. Haemophilia complications
and especially joint complications affect the possibility to perform a paid job, have a negative influence
on social integration and affect the quality of life. Joint deformations which affect bodily appearance,
financial difficulties caused by the poor social integration and also risk of blood-transmitted infections
can cause psychological disturbances. Starting from these realities, we can conclude that it is necessary to
offer a better care to these patients, in order to allow them to have a better social integration, a normal life
and a better quality of life.
145
GENETIC COUNSELING IN CANCEROLOGY
M. Pop (1), M. Puiu (2), A. Tarniceru (3)
1. University of Medicine and Pharmacy V. Babes, Timisoara Pediatric Clinic III
2. University of Medicine and Pharmacy V. Babes, Medical Genetics
3. Bucovat Medical Practice, Timis
Cancer represents a sequence of changes of the genes and of their expression and most forms of cancer
are placed in the rare disease category.
More and more forms of cancer are associated with a genetic cause or are determined by a genetic
predisposition. Knowing this predisposition can be a profitable intervention for patients and their
families:
People who have a genetic predisposition for cancer constitute a high risk population and it can benefit of
prevention efforts and of systematical detection.
The existence of a genetic predisposition constitutes a resource to study the genetic modifications
succeeded in development of a cancer. The familial forms are less frequent but usual forms, non-familial
looks from the genes point of view like the familial forms. The study of the familial forms represents an
important phase in understanding the other forms.
Numerous cases of genetic predisposition for cancer are associated with other development anomalies of
other tissues allowing a better understanding of the physiological role of perturbated genes.
Genetic counseling constitutes a new and useful approach in cancerology because of its role in
prevention, to avoid recurrence risk, but also for research purpose. Considering the seriousness and the
dramatic character of the disease in question, the consultation and the genetic counseling need extra care
and understanding to reduce the psychological effect determined by the announcement of a negative
result.
Respecting rigorously the bioethical norms is a positive practice of the genetic counseling in cancerology.
146
COLLABORATIVE EXPERIENCES OF THE ROMANIAN PRADER-WILLI
ASSOCIATION WITH MEDICAL SPECIALISTS
Prof. Dr. Maria Puiu, Dorica Dan- President RPWA
Topic: Genetic counseling, education, genetic services, NGO collaboration, and public policy
Keyword: Rare Diseases, genetic counseling, NGO collaboration
Material: In our NGO partnership (a branch of an international NGO from Romania and a local one)
Introduction: In the absence of a national governmental strategy for Rare Diseases, an EU priority for
Romania, the collaboration of local and national NGOs and medical specialists is essential.
The aim of our paper is to focus on the encouragement of a collaborative effort between Higher Education
Medical Universities, medical specialists, and NGOs serving beneficiaries in the rare diseases sector
through a multidisciplinary approach including, understanding the role of geneticians/specialists in NGOs
working with patients with rare diseases, providing adequate medical support and consultation to
understanding and correctly diagnosing various rare genetic diseases, continuing to provide support and
care through the duration of patient’s lives including evaluation through multidisciplinary approaches,
opening doors to discoveries in best practices and research engines in this field, collaborating and
instructing a created team of medical professionals and families, improving life visions and applying
these methods in special care circumstances, and encouraging the participation of parents in the
advocating of medical and social politics.
Results: Families of children with Rare Diseases have interacted with medical specialists and benefited
by becoming more assertive and by achieving more developmental milestones.
APWR has established contacts with a Genetic Lab in Bucharest, Romania and renewed the contact with
Mauro Baschirotto Institute for Rare Diseases (Italy) and established new relationships with genetics
specialist which helped us to diagnosed the patients in important genetics Institute and laboratories:
Institute of Medical Genetics from Zurich (Switzerland), Institute of Human Genetics- Wuerzburg
(Germany), Institute of Clinical Genetics, Olgahopsital-Stuttgart (Germany), Genetic Lab- Bucharest.
Families of children with Rare Diseases have interacted with medical specialists and benefited by
becoming more assertive and by achieving more developmental milestones.
Together we have organized a training course for parents, genetic evaluating for children with mental
handicaps, psychological problems, and social and genetic counseling with the help of professional
volunteers from Timisoara and Oradea;
• Organized a training course in genetics for family doctors at the request of Doctors Collegium
and RPWA under the auspices of the Medicine University from Timisoara;
• Organized and attended common activities with professional organizations: OAMMR, Doctors’
Collegium;
Conclusions: The health of people with disabilities and the social integration of these people can be
improved if they have every opportunity to enjoy family life, education, friendship, access to public
facilities and freedom of movement. Action should be aimed at collaboration among medical specialists,
families,
and
NGOs.
Developing awareness about the needs of children with Rare Diseases and engaging the public in a shared
strategies for the development of genetic services, will ensure a collaborative international approach in
sharing of expertise and experience.
147
THE ROLE OF GENETIC COUNSELING IN DIAGNOSIS OF
DISMORPHISM IN CHILDREN
M. Puiu (1), A. Tarniceru (2), D. Mihailov(1), T. Marcovici(1), M. Pop(1)
1. University of Medicine and Pharmacy, Timisoara
2. Bucovat Medical Practice, Timis
The study was made between 2000 and 2005, in Department of Genetics of „Louis Turcanu” Emergency
Children Hospital Timisoara. This study included an extremely varied pathology and it followed to
establish many aspects: the etiological diagnosis, the incidence of different dimorphic syndromes, age at
diagnosis, the necessary time for a correct and complete diagnosis, the correlation between a suspicion
diagnosis and a certain one. The subjects requested genetic counseling and investigations at the
recommendation of the neonatologist, the pediatrician, the dermatologist, the cardiologist and rarely at the
recommendation of the family doctor. The detection of a morphological anomaly represented the
beginning of a familial research (supporting diagnosis and identifying the individuals with risk). As much
as it was possible and necessary were investigated all family members who received an adequate genetic
counseling. In some cases it was demonstrated that the family comes from a community in which the
matrimonial traditions have a consanguinity level that can be in correlation with the prevalence and type
of the most frequent anomalies from the endogamy populations. Sometimes were involved more
pediatricians in the diagnosis of the malformative syndromes, of some specific or nonspecific
dimorphisms, isolated or in very bizarre associations. It is proved that most dimorphisms have a genetic
cause and that’s why it is important to know them and to recognize them. It is possible to establish the
risk of recurrence and to give an adequate genetic advice.
The conclusions of the study revealed that the number of dimorphisms in children is big and this
pathology is frequently compromised because of the insufficient training in medical practice. It is
necessary to apply some investigation scheme for a quick and correct diagnosis which can provide a
better prevention of these diseases (consultation and genetic advice). The study also revealed that the
diagnosis of dimorphisms is frequently difficult because of many reasons: lack of some complex methods
of molecular investigations, the training level of the medical personnel (nurse, pediatrician, family doctor
and other specialists), the low level of addressability to the doctor, the rarity of cases, the genetic
heterogeneity, which makes, in many cases, impossible to establish the exact diagnosis. Because of the
clinician’s rising level of interest over the genetic pathology and because the interdisciplinary
consultation becomes a usually practice the number of unelucidated cases will decrease providing a better
prevention of genetic diseases.
148
THE ROLE OF THE PRIMARY CARE PHYSICIAN
IN MANAGING RARE GENETIC DISEASES
Alina Tărniceru (1), Lucreţia Tărniceru (2), Maria Puiu (3)
1. Medic rezident Medicină de Familie - Spitalul Clinic Municipal Timişoara
2. Medic de Familie - Cabinet Medical de Medicină Generală Dr. Tărniceru Lucreţia – Bucovăţ, jud.
Timiş
3. Departamentul de Genetică Medicală, Universitatea de Medicină şi Farmacie “Victor Babeş”,
Timişoara
Family physicians assume responsibility for the management of undifferentiated problems in un-selected
patients. They are specialists in the care of common problems. Yet common patients sometimes have rare
diseases, and primary care includes the responsibility for recognizing such problems and managing such
patients.
Many approaches to facilitate the involvement of primary care in genetics have been proposed
i)
ii)
iii)
iv)
Improved communication between primary care and specialist services;
The development of accessible data resources
The development of genetics specific skills;
The use of ‘primary care geneticists’
Primary care practitioners should be able to: understand cytogenetic, biochemical and molecular
laboratory reports, provide patients with acces to diagnostic and predictive test that are appropriate for the
condition in their family and advise patients of the benefits, limitations, and risk of such tests. Primary
care practitioner has to communicate genetic information in a manner that is suitable for each particular
patient and family, tolerate and encourage reiteration of information because of patient anxiety or
unfamiliarity with the concept being presented.
The involvement of primary care in genetic medicine presents substantial challenges to both the primary
care and the clinical genetics communities. If we are able to resolve these difficult challenges
successfully, the care of all patients with genetic disorders should improve dramatically, with obvious
positive implications for patients with rare, severe, multisystem disorders.
149
INTEGRATION OF PRENATAL DIAGNOSIS IN
GENETIC COUNSELING FOR CYSTIC FIBROSIS
L. TAMAS1, I. POPA2, L. POP2, A. ANGHEL1, Z. POPA3, C. SAMOILA1, M. MOTOC1, C. GUG4, I. M.
POPA2
1 – Biochemistry Department, “Victor Babes” University of Medicine and Pharmacy, Timisoara,
Romania
2 – Pediatric Clinic Nr. 2 - „Victor Babes” University of Medicine and Pharmacy, Romania
3 – National Center of Cystic Fibrosis Timisoara, Romania
4 – Department of Medical Genetics, “Victor Babes” University of Medicine and Pharmacy, Timisoara,
Romania
Corresponding author: Tămaş Liviu Athos, M.D. Assistant Professor “Victor Babes” University of
Medicine and Pharmacy, Biochemistry Department
Keywords: cystic fibrosis, genetic counseling, CFTR gene, prenatal diagnosis
Introduction: Cystic fibrosis is the most common autosomal recessive disease in Caucasian populations,
potentially lethal, having a frequency of 1 in 2200 live birth and a carrier frequency of 1 in 25. The aim of
this study was to use the results from prenatal diagnosis for a better genetic counseling for couples which
are carriers for CFTR mutations detected by genetic testing.
Materials and Methods: Three couples of CFTR mutations carriers were selected (CFTR mutations
were detected by previous genetic testing) which had sick children with cystic fibrosis confirmed by
genetic testing and were in evidence at the National Center of Cystic Fibrosis from Timisoara or had
deceased children with positive diagnostic of cystic fibrosis in family history and wanted a new child. The
couples were informed by genetic counseling about the steps they must follow and about the risks
involved in each step. The biologic material used for prenatal diagnosis was amniotic fluid collected by
amniocentesis during the 16th week of pregnancy. Genetic testing was performed using an ElucigeneTM
CF29 kit which can detect 29 different CFTR mutations and the normal allele for ∆F508. ElucigeneTM
CF29 can detect point mutations or small deletions in deoxyribonucleic acid (DNA) using a method based
on ARMS allele specific amplification technology. Genomic DNA was extracted from amniotic fluid
samples and was amplified by ARMS-PCR. The PCR products were visualized on a UV transiluminator
after electrophoresis on agarose gel and staining with ethidium bromide.
Results: for each fetus the mutant alleles were detected and the genotype was identified - ∆F508/N, N/N
and ∆F508/621 + 1 G>T. The results were consistent with the results obtained by genetic testing of the
parents. The first two genotypes indicated a fetus who was only a carrier for ∆F508 and the second one
who was healthy, and the genetic advice in this situations was to continue the pregnancy, but the last
genotype indicated a fetus with cystic fibrosis and in this case were provided all the information the
couple need, in order to know and understand all the possibilities and to make a responsible decision.
Conclusion: By performing prenatal diagnosis to couples which are carriers for CFTR mutations we can
achieve a complete genetic counseling, but a thorough information of the couple is need it because cystic
fibrosis is potentially lethal and has a different symptomatology depending on the mutations which affect
the patient (there are over 1400 mutations of the CFTR gene described until now).
This study was supported by CNCSIS Research Grant type A Nr. 1188/2004-2006.
150
LONG-TERM PSYCHOLOGICAL OUTCOMES OF HYPOSPADIAS
D. Vasilie1, A. Gyurian3, M. Puiu1, A RadulescuV4. L. David2
1 University of Medicine and Pharmacy “Victor Babes” Timisoara
2 Children’s Hospital “Louis Turcanu” Timisoara
3 West University Timisoara
4 Children's Hospital Columbus, Department of Pediatric Surgery, Columbus, Ohio, U.S.A
Correspondence to:
Doru V. Vasilie – Children’s Hospital “Louis Turcanu” Timisoara – Pediatrics Surgery and Orthopedics
Department
Hypospadias is a congenital anomaly affecting approximately one boy in 300. The defect consists in the
abnormal location of the urethral orifice on the ventral aspect of the penis. The etiology remains unknown
and only in a small number of case the genetic factor can be incriminated. Hypospadias can occur isolated
or associated to other malformations in various genetic syndromes. Obtaining a functionally and
cosmetically normal penis can be achieved by numerous surgical procedures: Duplay-Fevre, DenisBrowne, Mathieu, Leveuf-Godard, Ombredanne, MAGPI, Duckett. The precise moment when the
corrective surgery should be performed is still a subject of debate. The disease has serious and potentially
life-long psychosocial and psychosexual consequences for affected individuals. Therapeutic methods vs.
psychological implications have been studied previously but mostly in prepubescent children. We
interview an 18 years old patient that suffered 14 successive surgical interventions for hypospadias from
early childhood till adulthood. The presence of the disease at this age and the high number of surgical
intervention determine overall a more profound psychological implication with a more obvious sexual
mark. For these reasons we consider that choosing the appropriate surgical procedure and the best
moment to perform it is a complex process in which the psychological aspect should play a leading part.
Also associated with the medical treatment we advise psychological counseling for the child and his
family. Hypospadias management should be a team work with equal contribution from the surgeon,
geneticist, paediatrician and psychologist.
Keywords: hypospadias, psychology, penis, malformation, surgery.
151
Short Biographies and Contact Information from Speakers (In
Alphabetical Order):
Ornorica-Mariana Abrudan
Vice-Mayor Zalau, Romania
Ornorica has been the Vice-Mayor of Zalau in Romania since 2004. The main activities she is
responsible for are the community and social assistance issues, local public transportation, and
administrative duties within the City Hall. Before becoming the Vice-mayor, she taught English for eight
years. She graduated from Babes Bolyai in Cluj-Napoca in the Management of International Relations
and European Affairs. She received her Masters degree from the University of Vasile Goldis in Arad,
Romania in Local Public Administration in the context of actual legislation. Having the responsibilties of
working with community and social assistance issues, she has always been supportive, helpful, and
trustworthy in helping the Romanian Prader-Willi Association work toward their goals.
Ornorica-Mariana Abrudan
Str. Corniliu Coposu
Zalau, Romania
Tel: 0744-130-741 Fax: 0260-661-869
aonorica@zalausj.ro
Irune Achutegui
Irune Achutegui is a Psychologist and a member of the Balint Association.
Since 1995, she has been a Psychologist in the Psychological Unit of the Pediatric Endocrine Department,
H.San Raffaele Milan, and dealing with Prader-Willi patients, their parents and teachers.
She is specifically involved in psychological and educational treatment for Prader-Willi children and in a
yearly group program for children and parents.
Since 1998 she has been a Psychologist in the Center "Paolo Pini" for disabled children in Milan, as
supervisor for volunteers (aiming at improving the quality of life for PW children in the leisure time).
She has participated in PWS International workshops and conferences: in Jesolo- Italy 1998, St. Paul
Minnesota USA 2001, and in South America (Santiago 2002, Mexicali 2003) and Spanish National
Conferences (2002; 2005) presenting studies about Psychological aspects of PWS and family
management.
She participated in 1995 in Italian National Conferences on PWS.
She was a teacher in a course for Italian Psychologists focusing on young PWS and their families 2001
(40h) and in courses in Spanish for Psychologists to increase their ability to deal with PWS, in 2003 and
2005, sponsored by IPWSO and the Hospital San Raffaele Milan (each course was 45 hrs.).
Irune Achutegui
Via Delle Regioni 28, Segrate
20090 Milan, Italy
irune@fastwebnet.it
152
Ragnhild Overland Arnesen
Ragnhild lives in Bergen, Norway. She is a member of the board of The Norwegian PWS Association,
delegate to IPWSO, and responsible for the Norwegian PWS-newsletter. She has daughter with PWS,
who is 28 years old.
This is her third international PWS Conference. Ragnhild participated New Zealand three years ago, and
again in Oslo in 1995.
Besides this, she is an information adviser in the Municipality of Bergen, working in the Department for
health and welfare.
Ragnhild Øverland Arnesen, Information Officer, Departement of Health and Welfare, City of
Bergen
Kollbulia 22
N-5124 Morvik, Norway
Tel: +47 5556 7441 or +47 480 96 709
ragnhoa@online.no
Ségolène Aymé
Ségolène is a medical geneticist, the director of Research INSERM, and the director of Orphanet since
1997. She researches the impact of new technologies in human genetics on the public and their ethical
implications. Since 1996, Ségolène has been an expert to the European Commission and, since 1998, she
has been the president of the "Public and Professional Policy Committee" of the European Society of
Human Genetics.
She is also a board member of the European Platform of Patients Organizations, Science and Industry
(EPPOSI0, a committee member for Marketing Authorization of Drugs at AFSSAPS, and a member of
the COMP-WGIP at the EMEA.
Also, in the recent past, Ségolène was a member of the INSERM ethics committee, of the scientific
advisory board of the French Agency for the Evaluation and Accreditation in Health (ANAES), the
French Clinical Research Committee at the Ministry of Health and the president of the International
Federation of Human Genetics Societies. Ségolène is also married and has two children.
Ségolène Aymé, Director of Orphanet and chair of the Rare Diseases Task Force of the European
Commission
102 rue Didot
75014 Paris, France
Tel: 33 1 56 53 81 37 Fax: 33 1 56 53 81 38
Doris Baechli
Doris Baechli is the Mother of Pascal (14), Carla (9) and Samuel (5) and lives in Trübbach, Switzerland.
Shortly after Pascal was diagnosed, the Baechli family moved to the US and had the chance to interact
with many families and PWS experts through PWSA and its California chapter. Based on their experience
and how much a family benefits from such a support, Doris got involved in the Swiss PWS association
and became an international representative. Together with her husband she now leads the association.
They believe in a comprehensive management approach to support our children as promoted e.g. by Urs
Eiholzer ... and know that active parent networking is an essential part of it.
www.prader-willi.ch
153
Anna and Giuseppe Baschirotto
Anna and Giuseppe Baschirotto founded the Association for Rare Disease in 1988 in memory of their
son, Mauro Baschirotto, who died from a rare auto-immunitary syndrome at the age of 16 years. It was
founded in order to carry out studies and research about those diseases, which usually present diagnostic
and therapeutic difficulties, sometimes without solutions. Moreover, it is very difficult to find suitable
pharmacological treatments for these diseases, because research costs are often too expensive and not
very profitable for the pharmaceutical industry. The Association is fully committed to fighting these
diseases (over 5,000 are known) with strategic initiatives aimed at:
Epidemiologic studies, a consultation and information service for patients and their families, and for
medical and paramedical staff they offer international competitive examinations, scientific workshops and
meetings, task forces for each specific disease biological bank, and data base.
Associazione Malattie Rare
"Mauro Baschirotto"
Costozza Vicenza - Italy
Tel/Fax: +390444555557
http://www.birdfoundation.org/
Susanne Blichfeldt M.D.
Susanne Blichfeldt is a Pediatric consultant, specializing in neuropediatrics, including diagnostic
investigations and treatments of children with various syndromes including Prader-Willi Syndrome
(PWS).
She has done PWS research on growth hormone and on sex steroids in adults. She has distributed
questionnaires on PWS in Denmark and in Scandinavia. She Co- founded the Danish PWS Association
in 1986, and now is a medical advisor and leader of the advisory board. She is a medical advisor for the
International PWS Organization (IPWSO), and a former board member. Since 1986, she has had
presentations and educational sessions on PWS nationally and internationally for both parents and
professionals involved in PWS. She has co-chaired programs for Parents and Professionals at the
International Congresses on PWS in 1991, 1995, 2001 and now in 2007.
Susanne Blichfeldt M.D.
Kildehusvej 12
4000 Roskilde, Denmark
Tel: (+45)46373204
s.blichfeldt@dadlnet.dk
John Booth
John Booth is the chairman of the Prader-Willi Syndrome Association (UK, formed in 1981)
He is 72 yrs old, married with 3 children of whom the second, Rachel, is a 43 year old woman with PWS.
John’s working career was spent in the Oil Industry around the world. Rosemary, his wife, will be with
him at the conference.
John has been a Trustee of the Association since 1992 (he thinks), Chairman from 1996 to 2001, and then
again from last year.
John Booth
Prader-Willi Syndrome Association UK
125A London Road
Derby DE1 2QQ
England/UK
Tel: 0044 (0) 1332 365676 Fax: 360401
admin@pwsa.co.uk
www.pwsa.co.uk
JohnLBooth@aol.com
154
Urith Boger
Urith was born in 1946 in Tel Aviv, Israel. For many years, she was a stage actress and playwright and in
recent years Urith has been practicing painting. At the age of 19 she married an Air force pilot, so they
have been a service family until 11 years ago when her husband retired. Doron, who is her child with
PWS is 3rd out of 4 children, and was born when Urith was 35 years old. Doron and is now 26. She has 6
grandchildren, and the oldest grandson has PDD, which caused her a lot of pain in the beginning. But he
is doing very well so they have come to terms with that.
In 1992, Urith established a PWS association with a gathering of 8 families. Since than they grew to be a
group of 80 families, out of which 25 are registered members and with all the others they have more or
less tight connections.
Unfortunately, and very much like in other countries it seems that the activity of their group lies mainly
on her shoulders. Urith gave lots of thought to that problem in the past and came to the conclusion that a
group of 25 couples is too small to grow more than 7 active persons that are in the board forever.
In the panel Urith will give a short presentation of the process of growing awareness of PWS in her
country.
Urith Boger
31 Aya st.
Ramat Hasharon 47226
Israel
Tel: 972-3-5409882 or 972-50-5322542 Fax: 972-3-5405271
Koshi1@017.net.il
www.pwsil.org.il
Sabine Bohnenpoll
Sabine Bohnenpoll was born on 28.04.1958. She is working as a certificate psychologist in Naumburg,
Germany in education as an integrative therapist. She has counseled adult people with PWS and their
caretakers since November 2004 in Naumburg.
Jerome Parisse-Brassens
Jerome Parisse-Brassens joined Eurordis, the European Organisation for Rare Diseases, in 2005 to be in
charge of communication and development. Jerome is a communication and organisational development
specialist who has been advocating for patient rights for many years, initially for the Deaf and the hearing
impaired, and more recently for people living with rare diseases. Prior to joining Eurordis, Jerome taught
project management at the University of New South Wales, Sydney, Australia, and worked as a
management and organisation consultant. He has been involved in a wide range of projects in Europe,
Australia and America. Jerome is a French and Australian national, with wide experience in multicultural
environments.
155
Palma Bregani
Palma is a psychologist and psychotherapist, a member of the Balint Association.
Since 1977, she has been head of the Psychological Unit of Pediatric Endocrine Department, H.San
Raffaele Milan, dealing with, in particular, Prader-Willi patients. This involves follow-up evaluations,
individual interventions, as well as a specific yearly program including pedagogic groups with children
and adolescents and Balint groups with parents.
She has had participation in PWS International workshops and conferences presenting studies on PW’s
emotional vulnerability and family management in Noordwiijkerhout -The Netherlands 1991, SormarkaOslo 1995, Jesolo- Italy 1998, St. Paul Minnesota USA 2001, in South America (Asunciòn 2000,
Santiago 2002, Mexicali 2003), in a Spanish National Conference in 2005 and in all yearly Italian
National Conferences on PWS.
She was a teacher in a course for Italian Psychologists focusing on young PWS and their families 2001
(40hrs.) and on courses in Spanish for Psychologists to increase their ability to deal with PWS, in 2003
and 2005, sponsored by IPWSO and Hospital San Raffaele Milan(each course was 45 hrs.).
Palma Bregani
Via Solferino 22,
20121 Milan, Italy
bregani.palma@hsr.it
Suzanne B Cassidy, M.D.
Dr. Cassidy is currently a Clinical Professor of Pediatrics at the University of California, San Francisco.
She is a board certified Clinical Geneticist and Pediatrician whose career includes doing patient care,
teaching for medical students, residents and advanced trainees, and clinical research mainly focused on
Prader-Willi syndrome. She has also been the director of clinical genetics divisions at two institutions in
the past. She has conducted multi-disciplinary specialty clinics for PWS since 1981 and has published
widely on her clinical observations and research on PWS. She has been the Chair of the Scientific
Advisory Board of Prader-Willi Syndrome Association (USA) and has been the professional delegate to
IPWSO from the USA since IPWSO was established. She has helped to organize several IPWSO and
PWSA(USA) Scientific Conferences, and is a frequent speaker about PWS at local, regional, national and
international educational and medical conferences related to PWS.
Suzanne B. Cassidy, M.D.
Clinical Professor of Pediatrics, Division of Medical Genetics
University of California, San Francisco
66 Toyon Lane
Sausalito, CA 94965 USA
cv.sc@sbcglobal.net
Mircea Covic
Mircea is a medical geneticist, the professor of human genetics in University of Medicine and Pharmacy
"Gr. T. Popa" – Iasi and the director of Center of medical genetics Iasi, since 1980. Principals study and
research fields are: human chromosomes and chromosomal diseases; clinical genetics (genetic
consultation and counseling); reproduction and sexualization disorders; epidemiology and diagnosis
of congenital anomalies; renal genetic diseases; medical- legal genetics and bioethics. He is author or
joint author to 7 genetic text-book (e.g.: “Autosomal dominant polycystic kidney disease (adpkd)”, 1999;
"Medical Genetics”, 2004) and 68 publications. Mircea is the past-president of the "Romanian Society of
Medical Genetics". Mircea is also married and has two children.
Mircea Covic
Str. Universităţii 16
Iasi, Romania
Tel/Fax: 0040-232-272754
covicmircea@astralnet.ro
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Katalin Csép
Katalin is an internal medicine specialist and medical geneticist. She works as Assistant Professor at the
Department of Genetics from the University of Medicine and Pharmacy Tg. Mures. Her main area of
research is the heredity of common diseases like type 2 diabetes, hypertension, obesity, and the metabolic
syndromes. As a collaborator of Genzyme, she is involved in the organisation and coordination of the
identification and treatment of patients with lysosomal storage disorders in Romania.
Katalin Csép
Str. Gh. Marinescu nr. 38
UMF Tg. Mureş, Romania
Tel: +40265215551/182
kcsep@rdslink.ro
Professor Leopold M.G. Curfs, PhD
Professor Leopold M.G. Curfs, PhD, heads the Governor Kremers Centre at the University Maastricht
and Academic Hospital Maastricht. Research in his group is aimed at understanding mechanisms by
which specific genes affect morphological structure and information processing at different levels of
biological organization and thereby contribute to the cognitive abilities of the person.
He was rewarded with the ‘Gouverneur Kremers’ professorship at the University Maastricht, a research
chair in learning disabilities.
He has been published on different aspects of PWS, most specifically behavioral and psychiatric
disorders, and comparisons between genetic subtypes. Leopold Curfs has been a member and the
chairman of various university and professional committees and boards. He is a board member of PWS
the Netherlands and chairman of their scientific committee. He is the scientific representative for the
Netherlands to the International PWS Organization.
Prof. Leopold M.G. Curfs
Director Governor Kremers Centre
University Maastricht / Academic Hospital Maastricht
Department of Clinical Genetics
University Hospital Maastricht
P.O. Box 5800
6202 AZ
Maastricht, The Netherlands
Tel: + 31-43-3877850
curfs@msm.nl
Etelka Czondi
Etelka was born in 1978, in Zalau, Romania, and she has been involved in the social field since 1998,
working with different non-governmental organizations in child welfare and in promoting the rights of
people with disabilities.
In 2004 she began her collaboration with The Romanian Prader Willi Association, as Public Relations
Officer, representing the organization at different levels – local, national, European and international.
She is currently representing the Romanian Prader Willi Association and her country in the Drug
Information, Transparency and Access Task Force (DITA-TF). The mandate is for three years, and the
task force has the general objective to provide recommendations to PCWP (Patients’ and Consumers’
Organisations Working Party) regarding all matters of direct or indirect interest in medical products.
Etelka Czondi
Information Center for Rare Genetic Diseases
Str. Avram Iancu nr. 29
Zalau, Romania
Jud. Salaj 450143
Tel/Fax: 0040 260 611 214
office@apwromania.ro
www.apwromania.ro
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Dorica Dan
Dorica has been involved in the founding of the Romanian Prader Willi Association in 2003, serving as
its president from the beginning. They would never do this without the permanent encouragement of the
PWS international family.
Since 2005, she has been also responsible for coordinating the activities of the first Centre for Information
about Rare Genetic Diseases in Romania, a centre that is considered of great importance to their
organization. Currently, they are working to establish the National Alliance for Rare Diseases.
Dorica is both a patient and a mother of a child with PWS. She had poliomyelitis as child and was always
surrounded by people with disabilities. Her daughter Oana, 22, has Prader-Willi Syndrome and for many
years Dorica believed that she was diagnosed incorrectly, but didn’t know where to look for help. Oana is
well integrated into the community and her parents are very proud that she finished an ordinary high
school and now she is helping in the centre as a secretary. Dorica has been involved in working with
disabled people since 1993 as a board member of the Association for Disability People in Salaj, Zalau
(Romania).
Recently, Dorica was elected as a board member of EURORDIS. She really hopes to be able to continue
working for the benefit of people affected by PWS and other rare diseases, to acknowledge and help in
the evolution of the realities of the Eastern European countries in this field.
Dorica Dan- President
Romanian Prader-Willi Association
Str. Avram Iancu, nr. 29
Zalau, Romania
Jud. Salaj 450143
Tel/Fax: 0040 260 611 214
www.apwromania.ro
doricad@yahoo.com
Peter SW Davies
Associate Professor Peter SW Davies has a long track record of research in the area of nutrition, growth
and body composition in both health and disease. PSW Davies is a recognized international expert in
children’s growth and development. He has served on a number of expert panels and committees relating
to growth and development, energy and body composition. He was awarded the Nutrition Society medal
for the UK in 1991, and was nominated for the Australian Commonwealth Health Minister’s Award for
Excellence in Health and Medical Research 2002. He has over 50 peer reviewed publications in
nutritional science since 2000. He has written a number of book chapters and co-edited books in the field
of nutritional science. PSW Davies is a founding editor of the International Journal of Body Composition
Research and also an editor of the International Journal of Obesity and Acta Paediatrica. A/Professor
Davies has published a number of papers relating to Prader-Willi syndrome over the years, notably in
relation to growth hormone treatment and body composition assessment. He is Chair of the Australasian
Prader-Willi Syndrome Advisory Committee and also Scientific Adviser to the PWS Association in New
Zealand. He is the Director of the Children’s Nutrition Research Centre (CNRC), at the University of
Queensland, Royal Children’s Hospital in Brisbane Australia. PSW Davies also oversees the Ozgrow
research project which is a national data depository relating to growth of all children in Australia who are
receiving growth hormone therapy. He is also Director of Research in the School of Medicine at the
University of Queensland and Chair of Nutrition Australia.
Associate Professor Peter SW Davies
Director Children's Nutrition Research Centre
Discipline of Pediatrics and Child Health
University of Queensland
Royal Children's Hospital
Herston Brisbane QLD, Australia
Tel: + 61 7 3636 3765 Fax: + 61 7 3346 4684
www.som.uq.edu.au/cnrc.htm
158
Urs Eiholzer
MD PhD. Urs Eiholzer studied medicine at the University of Basle (1971-1978) and became specialized
in pediatrics while he was at the University hospitals of Lausanne and Zurich as well at the Cantonal
Hospital of Lucerne (1978-1983). Between 1983 and 1985 he received training in pediatric endocrinology
at the University of Zurich. He was a fellow of Prof. Andrea Prader and Prof. Milo Zachmann and parttime head of the division of pediatric endocrinology at the University of Lausanne (1985-1992). Since
1992 he has been the head of the 'Center for Pediatric Endocrinology Zurich' (www.pezz.ch, former
'Institute Growth Puberty Adolescence') and holds private practices in Zurich and Lausanne. His clinical
research deals with growth and puberty related questions, with the regulation of appetite, activity and
body composition and with the Prader-Willi syndrome. He is author of numerous scientific publications
and several books, some which contain valuable information for patients and their families.
PD Dr. med. Urs Eiholzer
Center for Pediatric Endocrinology Zurich (PEZZ)
Moehrlistrasse 69
CH-8006 Zurich
Switzerland
Tel.: +41 44 364 37 00 Fax: +41 44 364 37 01
http://www.pezz.ch
Pam Eisen
President of the International Prader Willi Syndrome Organization (IPWSO)
Pam Eisen, President of the International Prader Willi Syndrome Organization (IPWSO), has been
internationally involved since 2001, first as Parent Delegate (PWS-USA), and as a board member.
Immediately immersed in the organization, she helped with the development of the IPWSO educational
packets and the Twining Project, learning more about the realities of our associations. Working with
many cultures and associations at different levels of development to further education and awareness of
early diagnosis and treatment, Pam’s heart opened to the children and she has been devoted to helping
families around the world find opportunities for raising the quality of life for their family members with
PWS. Responsible for developing PWS Educational booths at regional pediatric endocrinology
conferences, Pam is committed to spreading education and awareness to the global medical community.
With dedication to emerging countries, Pam helped “Open PWS Doors” in Asia and in Eastern Europe,
expanding IPWSO’s membership to 76 countries. With the IPWSO Board, the Director of Program
Development, and the assistance of members worldwide, she has worked diligently to increase services
and meet the growing needs of members, with such programs as the development and free distribution of
educational material, the encouragement of respite programs, rehabilitation services and PWS supportive
living homes. She has participated in and presented at PWS conferences throughout the world, meeting
many of our families and bringing optimism and hope for the future. As an ambassador for IPWSO,
promoting education and research, Pam visited schools, hospitals, diagnostic laboratories, dental clinics,
therapeutic programs, and a myriad of other relevant community programs. In her travels as President of
IPWSO she has lectured to medical students, teachers, and other related professionals, encouraging a
global network of experts and collaborative efforts. Working to help families obtain the indication for
growth hormone treatment, Pam has lobbied governments for reimbursement and better medical
coverage. What impresses Pam most from these experiences is, “that there is still so much to learn!”
A widow, Pam, is most proud of her role as parent to three beautiful children, Gabriella (27 years old with
PWS), Benjy, and Jeremy. After her Gabriella was born, Pam retired from her career in child psychology,
but always remained involved in community work for disabled and underprivileged children. Her
inspiration as president comes from the beautiful children that she has met around the world and the
courageous families who use their love to move the “mountains beyond the mountains!”
Pam Eisen, President International Prader Willi Syndrome Organisation
14 West Lawn Circle
Wormleysburg, PA 17043 USA
pame.1@comcast.net
Tel: +1.717.737.5555 Fax: +1.717.265.6527
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Giorgio Fornasier
Giorgio Fornasier was born in Belluno (Italy) on 29 September 1947. He has been married since 1972
and has two children.
He has a son with Prader-Willi Syndrome, Daniele, born in 1976, and is member of the Italian PWS
Association. They asked him to be their representative abroad and Parent Delegate at IPWSO
conferences. In Oslo in 1995 he was elected as member of IPWSO Board with the charge of international
promotion and later as IPWSO Treasurer. During the 3rd International PWS Conference in Italy in 1998
he was elected as IPWSO President. Giorgio served as IPWSO President for two mandates until 2004,
and today he works for the same international Organization represented in 76 countries, as Director of
Program Development.
Giorgio Fornasier
IPWSO D.O.P.D.
via Villa, 45
32020 Limana, Italy
Tel: +39 0437 97973 Mob: +39 335 369252
g.fornas@alice.it
Janice L. Forster, M.D.
Current Position: Child, adolescent and adult psychiatrist in solo private practice specializing in
developmental neuropsychiatry; founding partner of the Pittsburgh Partnership, specialists in PraderWilli Syndrome. Professional activities: career educator; senior examiner in general psychiatry and child
and adolescent psychiatry for the American Board of Psychiatry and Neurology (ABPN); chair of the
audio-visual subcommittee of the American Board of Psychiatry and Neurology; member of the Clinical
Advisory Board of the Prader-Willi Syndrome Association of the United States; and consultant for the
International Prader-Willi Syndrome Organization. Clinical and research interests: translational
neuroscience; phenomenology of neuropsychiatric conditions; diagnosis and treatment of the psychiatric
co-morbidity associated with autistic spectrum, Asperser’s and Tourette’s disorder; verbal and nonverbal
learning disabilities; brain injury (dysphasia and dyspraxia); mental retardation, cerebral palsy and
epilepsy; and management of genetic syndromes (Prader-Willi, William, Fragile X and Down).
Janice L. Forster, MD
Developmental Neuropsychiatrist
Pittsburgh Partnership, specialists in Prader-Willi Syndrome
615 Washington Road, Suite 107
Pittsburgh, PA 15228-1909 USA
Tel: 412-247-5822 Fax: 412-344-7717
janiceforstermd@aol.com
Monika Fuhrmann
Monika Fuhrmann is from Germany and has a ten year old son with PWS. Her son was diagnosed at the
age of 2 months. After contact with the German PWS association, she attended the International PWS
Conference in Italy 1998 as parent delegate and became a member of the IPWSO Board from 2004.
Presently, she is an active member and on the Board of the German PWS association. Her son Johannes
attends a regular school. Two teachers, one from the regular school and the other from a special
education school, teach all students in cooperation, sharing the teaching load.
Monika Fuhrmann
Weiherstr.23
D-68259 Mannheim
Tel: +49 6217992193
monikafuhrmann@prader-willi.de
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Mihai Gafencu
He has been a medical pediatrician, the former director of Emergency Children Hospital Louis Turcanu
Timisoara, and the president of Save the Children Timis branch since 1999 (vice president for Romania
since 2001). He researches the impact of new technologies in children dialysis and work together with
volunteers on the NGO project for Down syndrome group. Since 2002, he has been the speaker for
Romanian NGO to the UN Commission for children rights and, since 2006; he has been the vice president
of the Romanian Society of Pediatric nephrology and urology.
He is also member in European Society of Human Genetics – ESHG, European Society of Cardiology,
European Dialysis and Transplantation Association –EDTA, European Academy of Children Dissabilities
EACD, International Society of Nephrology – ISN, International Pediatric Nephrology AssociationIPNA, European Society Pediatric Infectious Disease – ESPID.
He has been married since 2006.
Jim Gardner
Jim Gardner is a parent of a 38 year old son who has PWS. He has participated in the founding of group
homes for his son in 1992, 1997, and 2001. He has served on the PWSA USA board of directors,
including several years as treasurer. He has also served on the PWS of Minnesota board for 16 years
including the positions of president, treasurer, and currently vice president. He co-chaired the 2001
International and PWSA USA conference in Minnesota. He has presented at several national and
international conferences. He is a graduate of Yale University and retired from banking and commercial
real estate management.
Jim Gardner
4710 Bouleau Road
White Bear Lake, MN 55110 USA
Tel: 651-429-6441 Fax: 651-429-6601
JPGMN@earthlink.net
Joan Gardner
Joan Gardner is a parent of a 38 year old son who was diagnosed with Prader-Willi Syndrome when he
was three months old. She co-chaired the 2001 IPWSO Scientific Workshop and Conference in the USA
and served on the organizing committee of the 2004 New Zealand Conference. She was a program chair
for PWSA USA conferences from 2001 to 2005. She is a past president of PWSA of Minnesota. Her
career has been in community service including Children’s Hospitals and Clinics, Hamline University,
F.R.Bigelow Foundation and Lifecore Biomedical Inc. boards of directors in recent years.
Joan Gardner
4710 Bouleau Road
White Bear Lake, MN 55110 USA
Tel: 651-429-6441 Fax: 651-429-6601
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Larry Genstil
Larry is a psychologist. He received a Ph.D. in Educational Psychology and Special Education from the
University of Southern California in 1981, and an M.S. in Rehabilitation Counseling also from USC in
1976. He also has a BA in Psychology from Grinnell College, Grinnell, Iowa, from 1971.
Larry was born and raised in Los Angeles. During his junior year of college, Larry attended Hebrew
University, in Jerusalem, Israel. There he met his future wife, Sara. They married at the end of that
academic year. Upon graduation from Grinnell, in 1971, they returned to Israel. Larry and his wife lived
there for two years, during which their two sons were born, in 1972 and 1973. They then returned to the
US, also to Los Angeles, in 1973, when Larry began attending USC. He worked in various paraprofessional positions both to gain experience and to support his family during his schooling. Beginning
in 1976, Larry worked with people with developmental disabilities. In 1979, he worked with two people
with PWS, and from then on, I almost always had a PWS person or two on his caseload.
In 1984 Larry became a Licensed Psychologist in the State of California. He opened a private office for
the treatment of people with developmental disabilities in 1978, and became a vendor for the Regional
Centers for the Developmentally Disabled in California. He also consulted in various group homes and
actually ran two of them during these years. As his office grew, Larry hired additional people. By 1986,
when Larry left, there were 22 people working in his office.
He moved back to Israel with his family in 1986. There, he worked in two large institutions for the
retarded, and also worked as a psychologist for the Rehabilitation Center of the Union of Kibbutz
Movements. Through this center, Larry worked in over 100 kibbutzim in Israel, primarily with people
with developmental disabilities.
He had a daughter born in 1988 in Israel. His sons are now married, one living in Israel and the other
living in the US. His daughter is just now finishing high school.
On June 1, 1991, Larry opened his own group home in Israel, through his own organization, the Genstil
Institute of Human Behavior, called the Genstil Institute Hostel. On May 1, 1993, Larry accepted the first
resident with PWS. As word got out that he was familiar with the syndrome and would accept people
with the syndrome, additional referrals began filtering in. The hostel was recognized by the Department
of Rehabilitation of the Ministry of Social Affairs in 1993. The Department of Rehabilitation suggested
separating the two groups of residents, making the PWS residents a separate program on Dec. 1, 1998.
Since then, this program has grown such that currently there are 17 residents with PWS, housed in two
houses, males in one and females in the other.
In 1996, Larry was asked by Prof. Varda Gross, a Pediatric Neurologist at Sha'are Zedek Hospital in
Jerusalem to be the psychologist for a Prader-Willi Syndrome Multi-Disciplinary Clinic that she wanted
to open. He agreed, and they began seeing people with PWS. Since this is the only PWS clinic in Israel,
they see almost all people in the country who have been diagnosed with PWS. The clinic consists of Prof.
Gross; Dr. Fortu Ben-Harouch, a Pediatric Psychiatrist; Dr. Harry Hirsch, a Pediatric Endocrinologist;
Yael Landau, a developmental psychologist; and Ronit Dadoush, a Dietitian. When needed, medical
specialists, in additional areas of expertise are called in. The clinic continues to see patients about once
every two months.
Larry currently directs the hostel and also serves as its psychologist. He also has a small private practice.
He works at Sha'are Zedek Hospital in Jerusalem eight hours a week as a psychologist in the Children's
Units. And he teaches Special Education in a teachers' college in Jerusalem.
Larry Genstil
12 Haruvit St.
Mevasseret Zion, Israel 90805
Home: 972-2-5343388 Work: 972-2-5704277 Cell: 972-50-4600480
lgenstil@bezeqint.net
162
Kaja Giltvedt
Kaja Giltvedt has her physiotherapy education from Oslo, Norway 1981, and a Bachelor of Physical
Therapy Degree from the University of Manitoba, Canada 1984. She has a Masters in Health Sciences
from the University of Oslo 2001, and is a certified Pediatric Physiotherapist. Since 1990, she has worked
with children from 0-18 years both in community care, at the Ullevål University Hospital in Oslo and at
Frambu centre for rare disorders where she has met many of the children with PWS in Norway.
Kaja Giltvedt
Pediatric physiotherapist
FRAMBU Centre for Rare Disorders
Sandbakkveien 18
1404 Siggerud
NORWAY
Tel: +47 64 85 60 00
kgi@frambu.no
Florica Glavan
Florica Glavan is a professor doctor at Faculty of Dentistry from Timisoara, the Department of
Pedriatrical Dentistry and Orthodontics, possessor of two patents of invention and one of innovation
based on odontal therapy for children, useful in dental dimorphisms in rare genetic diseases. She is the
author of 10 books and over 120 scientific publications. She is a fellow member of World Society of
Orthodontics, Romanian Society of Medical Genetics.
Barbara J. (“BJ”) Goff, Ed.D
Barbara J. (“BJ”) Goff, Ed.D is an Associate Professor of Education at Westfield State College in
Massachusetts, USA. She has 35 years of experience working with individuals with developmental
disabilities in residential, educational, vocational, and home settings. She is as a consultant and trainer for
schools and providers serving individuals with Prader-Willi syndrome throughout the US. Her work
includes the development of residential, vocational, and crisis intervention programs; advocacy; providing
expert testimony; program evaluations; training and consultation with educators and other professionals.
She co-authored a handbook on PWS for Educators, entitled The Student with Prader-Willi Syndrome:
Information for Educators with Barbara Dorn, RN, BSN. She authored two chapters on educational
issues and co-authored one chapter on sexuality in the third edition of Management of Prader-Willi
Syndrome (2006). She is currently writing a training manual for residential providers. Dr. Goff serves as
an educational crisis consultant for PWSA/USA; assisting families and schools to successfully collaborate
on behalf of students with PWS. She is a frequent presenter at national, state, and local conferences. She
also served as a conference planner for the Provider/Careers Day for the 2004 International PWS
Conference in New Zealand. BJ is excited and honored to be part of the international conference in
Romania and hopes to connect with colleagues from around the world.
Barbara J. Goff, Ed.D, Associate Professor
Westfield State College, MA
33 Benz St.
Springfield, MA, USA 01118
Tel: 413-783-8192 or 413-572-5319
galagof@msn.com or bgoff@wsc.ma.edu
Eileen Greunke
Eileen Greunke was born on 11.02.1972. She has been actively working as a certificate psychologist in
Langenstein, Germany since March 2006.
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Dr. Anthony P. Goldstone MA, MRCP, PhD
Tony Goldstone attended medical school at both Cambridge and Oxford University in the United
Kingdom, and trained in general medicine, adult endocrinology and diabetes at the Hammersmith, St.
Bartholomew’s and Royal London Hospitals in London. He obtained his Ph.D. from Imperial College
London, researching the hypothalamic control of feeding and metabolism.
He is currently a Senior Clinician Scientist and Consultant Endocrinologist at the MRC Clinical Sciences
Centre, Hammersmith Hospital, and Imperial College in London.
He has researched and published widely on neuroendocrine and metabolic abnormalities in Prader-Willi
syndrome, particularly investigating the causes of hyperphagia and obesity, through clinical, postmortem, animal model, interventional, fat and brain imaging studies.
Dr. Tony Goldstone MA MRCP PhD
Senior Clinician Scientist in Metabolic Imaging, Hon Consultant Endocrinologist
Robert Steiner MRI Unit, Imaging Sciences Department
MRC Clinical Sciences Centre, Faculty of Medicine
Imperial College, Hammersmith Hospital Campus
Du Cane Road, London W12 0NN
United Kingdom
Work Tel: + 44 (0)20 8383 1510 Mobile Tel: + 44 (0)7958 612893 Work Fax: + 44 (0)20 8743 5409
tony.goldstone@imperial.ac.uk
Linda M. Gourash, MD
Affiliation: PWSA-USA Board of Directors; Pittsburgh Partnership, Specialists in Prader-Willi
Syndrome
Dr. Gourash is a Developmental Pediatrician. She has worked with behavioral disorders and medical
problems in the developmentally handicapped for nearly 30 years beginning as full time faculty in the
departments of Pediatrics and Psychiatry of the University of Pittsburgh School of Medicine.. She began
her focus on Prader-Willi Syndrome upon becoming the program medical director of the Prader-Willi
Syndrome and Behavioral Disorders Unit of The Children’s Institute in 1999. Dr. Gourash led a team of
clinicians managing hundreds of children and adults with PWS in medical crisis from extreme obesity,
diabetes, obesity hypoventilation, right heart failure and respiratory failure and those who presented with
severe behavioral dyscontrol, psychosis and other mental disorders.
Dr. Gourash is co-founder of the Pittsburgh Partnership (2004). Together with Dr. Janice Forster she
teaches and writes about the practical management of persons with PWS and provides consultation for
physicians managing complex cases of PWS. Their “Psychiatrists’ Primer for PWS” is widely used by
clinicians in the USA and is available as a PDF file from the PWSA-USA website. Their DVD, “Food,
Behavior and Beyond” is widely used for training caretakers and is very popular with parents.
Dr. Gourash serves on the Board of Directors of the PWSA-USA.
Linda M. Gourash, MD
6919 Rosewood Street
Pittsburgh PA, 15208
Tel: 412 831-0355 ext 534
wfgourash@aol.com
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Tomoko Hasegawa M.D.
Dr. Hasegawa is a Clinical Geneticist and Pediatrician. She was born and brought up in Japan. She
graduated from Keio University School of Medicine in Tokyo. She studied clinical genetics and
cytogenetics studies at the Human Genetic Institute, the University of Muenster in Germany as an
assistant doctor from 1973-1975. Since 1985, she has been the Chief of the Clinical Genetics and
Cytogenetics, Division of Shizuoka Children’s Hospital in Japan, and from 1996-2005 PWS Clinic. In
2005 she resigned and set up a Genetic Support and Consultation Office. Her first encounter with PWS
was in 1979, when a friend who edited an American magazine “Family Circle - Japanese Version”
showed her an article about PWS. She was asked to write an explanation about the characteristics of PWS
for the magazine, but how? At that time she did not know anything about PWS. Later as a cytogeneticist,
Tomoko have analyzed chromosomes from many individuals with PWS. She has attended International
PWS Conferences since the first in 1991. She is a professional delegate for IPWSO, and has cooperated
with the parents for organizing the PWSA in Japan.
Hasegawa, Tomoko, M.D.
Genetic Support & Consultation Office, Professional Delegate to IPWSO
2-23-3 Hara-machi, Meguro- ku
Tokyo, 152-0011 Japan
hasemoko@aol.com
Janalee Heinemann, MSW
Prader-Willi Syndrome Association (USA) Executive Director
Janalee Heinemann, MSW – parent of an adult son with PWS; masters in social work from Washington
University in St Louis, MO; volunteer for PWSA (USA) for 16 years prior to becoming Executive
Director in 1997.
Past Professional Experience: Oncology Pediatric Medical Social Worker at St Louis Children’s Hospital
– 10 yr.; Hospice Social Worker-3 yr.; Child Abuse & Neglect Social Worker – 6 yr.
Achievements: Co-founder of the MO State Chapter of PWS; Wrote chapters for all three editions of
Management of PWS; Wrote numerous articles and two booklets on PWS; Presented at twelve national
PWS conferences, the international PWSA conferences in Italy and New Zealand, and in several nations
including Israel, Taiwan, China, Japan, Mexico, Chile, Monaco, and Brazil. Also presented at various
state meetings and conferences; Developed and ran multiple support programs and groups for children
with cancer and their families; Developed and lead several bereavement programs.
Honors: “Volunteer of the Year” award, Victim Assistance Program, Sarasota County Sheriff’s Office,
2001; President of PWSA (USA), 1991-1994; National PWSA Board Member, 1986-1991; “Service and
Rehabilitation Award” from American Cancer Society, 1988; John Krey III award for “Outstanding
Humanitarian of the Year”, 1991; Dean’s Fellowship at Washington University, 1981-1983; Summa Cum
Laude, IVCC, 1975; “Volunteer of the Year” award, Illinois Dept of Children and Family Services, 1975;
Janalee Heinemann
Executive Director
PWSA (USA)
5700 Midnight Pass Rd. Suite 6
Sarasota, FL 34242
Tel: 941-312-0400
execdir@pwsausa.org
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Jytte Helgogaard
The Danish Association of Prader-Willi Syndrome
The Danish Association of Prader-Willi Syndrome was founded in 1986 by a group of parents of children
with PWS.
Today the association counts about 500 members. Besides the board, an advisory board is attached the
association consisting of professionals within medical, social and pedagogical areas.
Jytte has been a member of the board since 1993 and is the editor of the Danish newsletter, PWS NYT.
She has three children of whom the eldest, Cecilie, is an 18 year old woman with PWS. She was
diagnosed 8 months after her birth. In her professional life she is a teacher – and has classes with both
normal children and children who need special education.
The Danish Association of Prader-Willi Syndrome
Agervej 23
DK 8320 Maarslet
Tel: +45 86 29 21 41
www.prader-willi.dk
Jytte Helgogaard
Heibergs Have 67
DK 4300 Holbaek
Tel: +45 59 44 48 43 Mob: +45 21 67 12 99
jyttehelgogaard@tdcadsl.dk
Autumn Henderson
Autumn is a special education teacher and she has taught mild disabilities, learning disabilities, emotional
disabilities, and has had some experience working with autistic children of all ages. She graduated from
Ball State University in Muncie, Indiana in 2000. She has a BA in Special Education (Mild Disabilites k12), a coaching endorsement and multiculturalism minor. She is currently a Peace Corps Volunteer
serving in Zalau, Romania working with the Romanian Prader Willi Association in Institutional
Development. She has lived in Romania for two years with her husband, also from Indiana. Before
joining Peace Corps, she worked with children doing reading, writing, math and behavioral interventions
and spent a lot of time volunteering at many school activities and has worked within her community to
develop programs between the local University and local schools.This is her first time on the organizing
committee of and International PWS Conference.
Autumn Henderson
Romanian Prader-Willi Association/Center for Information about Rare Genetic Diseases
Str. Avram Iancu, nr. 29
Zalau, Romania
Jud. Salaj 450143
Tel/Fax: 0040 260 611 214
www.apwromania.ro
autumnhenderson@hotmail.com
Psych. Norbert Hödebeck – Stuntebeck
Norbert is a liscensed psychologist and is affiliated with Diakonische Stiftung Wittekindshof. He
currently works for an organization that works with people with PWS.
Norbert Hödebeck – Stuntebeck
Neinstedterweg 5
32549 Bad Oeynhausen
Tel/Fax: 0049 (0)5734-611288
norbert.hoedebeck-stuntebeck@wittekindshof.de
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Tony Holland
Tony Holland is a psychiatrist specializing in intellectual disability. He holds a Chair in the Department
of Psychiatry at the University of Cambridge, UK and he is the UK PWS Association President. With his
colleagues, he has published extensively on various aspects of PWS and is co-coordinator of the European
PWS research project.
Tony Holland
MBBS, MRCPsych, M.Phil
Douglas House
18b Trumpington Road
Cambridge
CB2 2AH UK
Ajh1008@cam.ac.uk
Ioana Ispas
Ioana is advisor for Bioethics Genomics and Health at Romanian Ministry of Education and Research and
part time researcher at CA, member of National Ethics Research Council (appointed by Order nr
967/12.05.2007 of Minister of Education ,Research and Youth ) who has gained important managerial
experience and organizational skills in running goal oriented projects for many years. She is member of
UNESCO – Romania Bioethics Commission and European experts groups, dealing with the ethics as well
as administration and management of research projects. Regarding her professional background she
studied Biochemistry in Bucharest and has a master degree in Molecular Biology. She has an important
experience in bioethics having training courses in ethics in biotechnology (Paris, Oxford, Brno) and ethics
in nanobiotechnology (Oxford) as well as short stages in ethics in genetic testing (Cardiff and London ).
She awarded a fellowship in GMO detection methods and risk assessment in Excellence Centre for Plant
Biotechnology Bulgaria (FP5 project) and Italy (Ispra-Institute for Consumer Protection and ICGEBVenice) . She worked as scientist and assistant professor in Biochemistry at University of Bucharest and
University of Ecology for more than 9 years. She worked in the field of research for European Institutions
namely European Commission in Brussels as well as evaluator for Framework Programme 6.
Furthermore she has years of experience in project management and administration and she has been
involved in the administrative and organisational coordination of more than 5 European research projects
,part of some still ongoing. She provides advice on ethics for scientists who are applying for national or
international research projects and she is in charge with updating national regulations in terms of ethical
review and elaborating the code of conduct for research activities in life sciences. She has more then 20
papers presented at international events in bioethics.
Ioana Ispas
Advisor for Bioethics,Genomics and Health
Ministry of Education and Research
National Authority for Scientific Research
European Integration and International Cooperation Division
21-25 Mendeleev Street, District 1, 010362, Bucharest, ROMANIA
Tel: +4021.212 77 91 Fax: +4021.318.30.53
iispas@mct.ro or ioana_isp@yahoo.com
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Elli Korth
Elli Korth was born in Buenos Aires on the 1st of November of 1952. Her parents are German. She
studied in the German school in Buenos Aires, and was raised in the German and Argentine culture. She
studied tourism and travel around the world. Knowing people and understanding the way they think were
always her interests. In 1977, she married Alex Korth and in 1982, her first daughter was born, Mariela.
She had lack of oxygen and when the neurologist came to see her, he looked at her and diagnosed PWS.
This diagnosis could not be confirmed right away as she has unapparent diasomy. And the test did not
show deletion. At that time there was no other test available. In 1985, Sofia was born and in 1988, Juan.
At that time with the beginning of Internet (Alex is an expert) they got in touch with the British Assoc.
and they informed them about the World Conference in Frambu. After that Conference, they were in
touch with IPWSO and either Alex or Elli attended each of the conferences. In 1998, they started a
Shelted Farm and that had to close a few years later due to the economic situation in Argentina. They still
live in the Farm with their children. Mariela loves it. In Minnesota she was elected part of the Board of
Directors and has been serving in IPWSO since then, representing Latin America, where they worked
hard to start Associations also in other countries.
Elli Korth
Forli 680 Loma Verde
1625 Escobar Argentina
Tel: + 54 3488 493499 Mobile: +54 9 11 4035 3241
ellikorth@hotmail.com
ellik@datamarkets.com.ar
Shuan-Pei Lin, MD
Shaun-Pei Lin is the Director of Division of Genetics, Departments of Pediatrics and Medical Research at
Mackay Memorial Hospital.
He is the Assistant Professor of the Department of Infant and Child Care, National Taipei College of
Nursing, and Department of Early Childhood Care and Education, Mackay Medicine, Nursing and
Management College.
He is a board member of IPWSO, the Taiwan Human Genetics Society, the Taiwan Pediatric Association
and Taiwan Foundation for Rare Disorders (TFRD); Medical Consultant of PWSA-Taiwan.
He is a member of the Deliberation Committee for Rare Diseases and Orphan Drugs, Department of
Health, Taiwan.
Dr. Shuan-Pei Lin
Department of Pediatrics, Mackay Memorial Hospital
92 Chung-Shan North Road, Sec. 2
Taipei 10449 Taiwan
Tel: 886-2-2543-3535 ext. 3090 Fax: 886-2-2543-3642
Marianne Lindmark
Marianne Helgogaard is a registered Clinical Dietitian, educated at the University of Gothenborg, Sweden
and at the University of Oslo, Norway. She has a Masters in Clinical Dietetics from the University of
Oslo in Norway.
Marianne Lindmark has been working at Frambu, a National Centre for Rare Disorders in Norway since
2002. At the centre she meets and gives nutritional counseling to families and caregivers of persons with
PWS from all over Norway. Since 2003 she has been involved in Frambu’s multidisciplinary descriptive
study of young children with PWS in Norway.
She is the author of the nutritional chapter in the Norwegian booklet, “Prader Willis Syndrome” (2003).
Marianne Lindmark
FRAMBU national centre for rare disorders
Sandbakkeveien 18
1404 Siggerud, Norway
Tel: + 47 64856000
mal@frambu.no
168
Georgina Loughnan
Georgina Loughnan has worked for Metabolism & Obesity Services, Royal Prince Alfred Hospital, a
major teaching hospital in Sydney, Australia, for the past 24 years. Trained as a physiotherapist, for the
past 22 years she has treated clients for weight loss management. In 1991, with one client, she began a
clinic for adults with Prader-Willi Syndrome. The PWS Clinic has now seen 61 adolescent and adult
clients with genetically diagnosed PWS, 40 of whom attend regularly. The PWS Clinic offers clients full,
ongoing medical care under the direction of endocrinologists. Support and training in PWS is given to
parents, careers and significant others who are involved with the PWS client. Concentrating on clients
with PWS is now the major part of Georgina’s work although she still counsels other clients with
intellectual disabilities and those with mental illness, for weight management.
Georgina Loughnan
Metabolism & Obesity Services
and Prader-Willi Syndrome Clinic
Royal Prince Alfred Hospital
Camperdown NSW Australia
Tel: 61 2 95154230 Fax: 61 2 95155820
georgie@email.cs.nsw.gov.au
Jackie Mallow
Jackie Mallow has worked in a residential setting since 1985. She has worked directly with children and
adults who have been dually diagnosed. She has extensive training, experience, and education in the
areas of behavior/crisis management, and program/staff development. She has worked exclusively with
individuals with Prader-Willi syndrome since 1996, providing educational training, support, guidance and
consultation nationwide. Jackie is the Admissions/Consultative Services Director for Prader-Willi Homes
of Oconomowoc, on the board of directors for PWSA-Wisconsin since 1997, and was newly elected in
2006 to the Board of Directors for PWSA-USA. She is the chairperson for the newly developed PWSAUSA Care Providers Advisory Board. Since 1997 she has enjoyed sharing her knowledge as a presenter at
the National and International level for PWSA (USA)/IPWSO, as well as her ability to grow through the
experience and knowledge of others she has met over the years.
“I have worked with many children, adults, families, providers, and professionals who have had to meet
numerous challenges none of these compare to the struggles an individual with PWS and those who care
for them must face. It may also be said, that I have never seen a group of families, providers, and
professionals be more supportive, dedicated and tireless in their efforts to making a difference in the lives
of those touched by Prader-Willi syndrome.
Jackie Mallow
Prader-Willi Homes of Oconomowoc
Director of Admission
& Consultative Services
PO Box 278
Dousman, WI 53118
(262)569-5515
169
Marcovici Tamara-Marcela
Marcela graduated in the Faculty of Medicine in Timişoara, Romania in 1988, with a Pediatrics speciality.
She is an Assistant Professor in the 1st Pediatric Clinic of „Victor Babes” University of Medicine and
Pharmacy Timisoara, Ph. D. and she is performing her activities as a pediatric specialist at “Louis
Ţurcanu” Emergency Children's Clinical Hospital Timisoara. She is a member of European Society of
Human Genetics and of the Romanian Society of Medical Genetics.
As a pediatrician she has had a great interest in rare diseases in children.
She has a very close collaboration with the Medical Genetics Department of University of Medicine and
Pharmacy Timisoara in performing an adequate diagnosis and genetic counseling.
Marcovici Tamara-Marcela
M. Kogalniceanu Street no.4 Apt. 7
300133 Romania, Timisoara,
Office: +40-256-203394 Home: +40-256- 286490 Mob: +40-256-0723694950
t_marcovici@yahoo.com
Marginean Otilia MD, PhD
In 1985 Otilia graduated from the University of Medicine and Pharmacy “Victor Babes” in Timisoara,
Romania Faculty of General Medicine. He received a Master in Paediatric, Specialist Endocrinology. He
is married and has one daughter and one son.
Marginean Otilia
Tel: 0723-577-013
otiliamarginean@yahoo.com
Jean Phillips-Martinsson
IPWSO Honorary President, founder, President 1991-1998
Swedish PWSA International Delegate, founder, President 1986-1996
Trustee PWSA (UK) Management Board
Jean’s son, Anders, was not diagnosed with PWS until 1984 when he was 14 yrs. old. She was English,
married to Sven and living in Sweden - a country with only 9 million people, speaking a language only
used by them and a handful of Finns. They were warned that they were probably alone in Sweden with
the diagnosis PWS. So, from that day onwards, she set herself the task of discovering other families,
even if it meant "going international" to find them. There must be others out there somewhere! Together
they would become strong! Luckily she was working internationally, as she'd done all her working life.
For 6 years she worked in Paris, with the OEEC (Organisation for European Economic Cooperation) as
Information Officer and English/French interpreter. She even participated in the initial meetings for the
creation of the European market. In 1962, as a freelance journalist, she jumped at the opportunity to
cover a 3-week assignment in Sweden. She stayed 32 years, having met Sven on a skiing holiday in
Romania 41 years ago! Anders was born in 1970 but, in this land of equal opportunity, she was able to
work from home and set up the Cross-Cultural Relations Centre. Amongst the multi-national managers
who attended her workshops and lectures to develop cultural awareness and international communication
skills were Pharmacia (now Pfizer), Astra and Glaxo. Little did she know how useful these contacts
would become! In 1989, her book on the Swedes was published and became a best-seller. This too
helped open doors with Swedish subsidiaries around the world.
After her workshops, many of them invited her to stay on in their countries, to give talks about being the
mother of a son with PWS, and arranged for her to visit their contacts in hospitals etc. Due to this, she
was able, in 1991, to realise her dream. The first International PWS Conference was held in the
Netherlands, where some 200 participants gathered and IPWSO was founded. Nobody asked the eternal
question "What is PWS? I've never heard of it"!
Prader-Willi Association in Sweden (PWSF) www.prader-willi.se
Jean Phillips-Martinsson
Farthings, 44 Warwick Park
Tunbridge Wells, Kent TN2 5EF, UK
Tel: 44-(0)1892-549492 jeanpws@compuserve.com
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Désirée Moharamzadeh
In 2005, Désirée received her Doctorate of Medicine at the University Vita-Salute San Raffaele, Milan,
Italy. Her graduation project was on “Progression of Scoliosis in patients with Prader-Willi Syndrome
treated with Growth Hormone Therapy” (110/110), under the supervision of Dr. Maurizio de Pellegrin.
From 2006 to present she was a resident in the Orthopaedics’ and Traumatology Programme (1st school)
at the University of Milan.
From 2004 to the present, she has been researching Prader-Willi Syndrome: scoliosis progression during
treatment with growth hormone at the Hospital San Raffaele, Milan.
In Sept. 2005, she participated in the XII National Congress of the Italian Society of Pediatric
Orthopedics’ and Traumatology (SITOP), Anacapri Lecture – “La scoliosi nella Sindrome di PraderWilli”.
Désirée Moharamzadeh
Istituto Ortopedico Gaetano Pini
Piazza Cardinal Ferrari 1
Milano, Italy
Tel: +39 339 2068470
desiree.moharamzadeh@gmail.com
Mariona Nadal
Mariona Nadal (Barcelona 1980) is the sister of two children, the youngest with PWS (born 1998,
diagnosed 2002). She is a Software Engineer graduated from the Polytechnic University of Madrid (19982003) and an Expert in Web Accessibility and Usability by the University of Alcalá de Henares (20052006). She has been a volunteer and member of the Board of the Prader-Willi Syndrome Association
from Madrid, Spain (AMSPW) since 2004.
Professional experience: Software engineer, in several companies, since 2003. Programmer, in several
companies, 2001-2003.
Related achievements: Delegated of Technology and Communications of the AMSPW. Voluntary
instructor in the activities “Fridays’ Workshops”, “Leisure and Free Time”, “Course of Computer
Alphabetisation” and “Kiddies to Play” of the AMSPW. She is the Webmaster of the Web site
www.amspw.org. She is a co-writer, designer and editor of the Web site www.amspw.org, the quarterly
bulletins amspw.org, leaflets, posters and brochures elaborated by the AMSPW. Lectures “Internet:
Virtual Prader-Willi” and “Activities: the importance of contact between families” at the National PWS
Conference of Chile (2006). Collaborator in the lectures presented by the AMSPW in the IV LatinAmerican PWS Conference, Buenos Aires: “Pilot Experience of Animated Therapy” (Buenos Aires,
Argentina, 2005) and in III Rare Diseases and Orphan Drugs Conference: “Virtual Support Groups”
(Mendoza, Argentina, 2006).
Related honors: Honorary Mention in the Prizes Bip Bip 2006. She was a finalist in the Prizes Day of
Internet 2005.
Mariona Nadal
Asociación Madrileña para el Síndrome de Prader-Willi (AMSPW)
C/ Las Naciones 15, 4º Iz.
28006 Madrid, Spain
Tel: (+34) 91 435 22 50
http://www.amspw.org
amspw@amspw.org
Elke Neumann
Elke Neumann was born on 5.9.1962. She is a state qualified educator and responsible Team manager for
a group of children with PWS in Langenstein, Germany since April 2005.
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Christel Nourissier
The first of Christel Nourissier’s four children was born with a rare disease. Amélie is now 30 years old.
Together with her family, Christel faced a 16 years delay for diagnosis, the lack of professional
knowledge of her daughter’s health and behaviour problems, the lack of recognition of her special needs
at school, and the absence of a patient group in France until 1997. Today her strongest wish for the future
is: no family living with a rare disease in Europe should have to go through this any more.
Christel Nourissier was elected director of Eurordis, Rare Diseases Europe, in 2000, representing the
newly established Alliance Maladies Rares in France, and became Secretary General in 2003. Since 2000,
she has been involved in all Eurordis European projects, in the organisation of the European Conferences
on rare diseases Paris 2003, and Luxembourg 2005 with the support of the European Commission. She
has been actively associated to the growth of Eurordis, particularly in the new members States, and
represents people living with rare diseases in many European institutions and platforms. She is also
advocating for patients rights and compensation of disabilities in France.
Christel Nourissier, EURORDIS General Secretary
2, rue Montfleury
78000 Versailles, France
Tel: 33-1-39-54-93-37
pwf.nourissier@wanadoo.fr
christel.nourissier@eurordis.org
Grethe Østergaard
Grethe Østergaard is a social education worker who graduated from school in 1989. Since then, she has
been working solely with physically, mentally and socially handicapped persons.
In 1999 she was a part of a team that established a group home for five young adults with PWS. In 2003
they built a new house especially for people with PWS. The house is designed to meet the demands of
people with PWS as much as possible. It is the only PWS group home in Denmark. Living in the home,
there are 8 clients between the ages of 18 and 31. There are 12 employees taking care of the group. Since
2002 Grethe Østergaard has been the manager of the house.
Grethe Østergaard, Social education worker/Manager
”Grankoglen”
Region Midt, Denmark
Grankoglen Granbakkevej 22B 8961 Allingåbro
www.grankoglen.dk
Tel : + 45 87867766 goe@granbakken.aaa.dk
Dorthe Pedersen
Dorthe Pedersen was born in 1958. She was educated in 1984 as a social educationist. In Danish, the
word is “pædagog”. Further education (1998): sociology at the Danish pedagogical university.
She has worked with people with Prader-Willi syndrome since 1992, and she was a member of the board
in the Danish Prader-Willi organisation and on the Danish advisory board for a number of years, and she
is still involved in educating staff, parents and even young adults with PWS. Among other things she has
been the leader of the Danish PWS organisations “family weekends” for several years. She has been
participating in the international conferences since Oslo 1995 – but unfortunately she “missed” the one in
New Zealand 2004. In Minneapolis 2001, she had a speech during the carers and provider day, about a
survey done in Denmark – the subject was occupational therapy. Here she volunteered for the children’s
program as well. She has been a co-writer of the first book about PWS, which was published in Denmark
last year. She is looking forward very much to being part of the first international conference in Romania,
to explore Cluj with the children and the volunteers, and to be with people, as interested in the persons
who have Prader-Willi syndrome, as she is herself.
Dorthe Pedersen
Høvevej 47
4550 Asnæs, Denmark
Tel: 0045 29 21 64 49 dorthepedersen@mail.tele.dk
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Rika du Plooy
Rika du Plooy majored in Speech Therapy and Audiology from the University of Pretoria (South Africa)
in 1968. She was a tutor at the same University until 1980. Rika is married to Izak and they have a
twenty-four year old daughter with Prader-Willi Syndrome. Rika has been involved in the PWS
Association of South Africa since it was established in 1990. She is currently the chairperson of the
association and also parent delegate to IPWSO.
267 Middelberg Street
Muckleneuk
0002 Pretoria, South Africa
Tel/Fax: +27 (0) 123440241
rikadup@mweb.co.za
Thomas Polomsky
Thomas Polomsky was born on 23.10.78. He works with different priorities as an occupational therapist
in Naumburg, Germany since March 2004.
Maria Pop
She is a primary pediatrician, doctor of medicine since 2003, member of Romanian Society of Medical
Genetics and European Society of Human Genetics.
She works in Timisoara Pediatric Clinic III of the „Louis Turcanu” Emergency Children Hospital and she
teaches at the University of Medicine and Farmacy “Victor Babes” Timisoara. Between 2005 and 2006
she was in USA for research and she specializes in using the modern genetics techniques (PCR) for
diagnosis in acute hepatitis in children. She is married and has two daughters.
Maria Pop
Timisoara Pediatric Clinic III
Str. Iosif Nemoianu, 2
Tel: 0256 2032303
Maria Puiu
In 1985, Maria obtained her MD from the Medical University in Timisoara, Romania and then her PhD in
1994 from the University of Medicine and Pharmacy in Bucharest, Romania. She then went on to get her
specialist degrees in pediatric medicine from Clinical Pediatrics (Romania) and medical genetics from Gr.
Alexandrescu Hospital (Romania). Maria followed these degrees with a fellowship in clinical genetics
and prenatal cytogenetics at Hospices Civiles de Lyon (France).
Maria is a member of Romanian Society of Medical Genetics (SRGM), a member of European Society of
Human Genetics (ESHG) and an Expert Evaluator CNCSIS, VIASAN, CEEX. She has also done
research on the optimization of diagnosis and management of patients with mental retardation by
introducing the MLPA test in the evaluation protocol; the impact on the quality of life of functional food
with bioactive antioxidant components in breast
She also worked for the Romanian National Alliance for Rare Diseases (RONARD) and studied
management optimization for children with Lymphoblastic Acute Leukemia by using molecular
cytogenetics techniques (FISH).
Maria Puiu
Department of Medical Genetics
University of Medicine and Pharmacy Victor Babes
Piata E. Murgu nr. 2
Timisoara, Romania 300041
Tel. (work): +40-256-220-479 Fax: +40-256-220-479
maria_puiu@umft.ro
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Kai Fr. Rabben
Kai Fr. Rabben was born in Oslo, Norway in 1951. In 1971, he graduated college and then, in 1979,
obtained his medical education at Vrije Universiteit in Brussels, Belgium. Between 1981 and 1987, Kai
worked as a pediatrician specialist for hospitals in Lidkøping, Sweden and Kärnsjukhuset in Skövde,
Sweden. In the mean time, Kai obtained his pediatrician practicing licenses in both Sweden and Norway.
Kai also has experience in child and adolescent psychiatry and has studied the medicine of infectious
diseases in both Lidkøping and Skövde (Sweden). He was also a consulting physician at the children’s
hospital in Skövde, Sweden until 1987. After which he became a pediatrician, and later the chief
physician, at the hospital in Kristiansund, Norway from 1987 until 1995. Following that, Kai was
employed as pediatric consultant at Frambu, a national center for rare disorders in Norway.
Kai is also a member of the advisory board for the Norwegian PWS association, and a member of the
Norwegian project team of “Joint Nordic Study on the Effects of Growth Hormone Treatment in Adult
Patients with Prader-Willi Syndrome.” He is also the co-author of a Norwegian book publication about
PWS.
Kai Fr. Rabben, MD
Frambu
Sandbakkveien 18
N-1404 Siggerud, Norway
Tel. (work): +47 64856000
kra@frambu.no
kfrabben@broadpark.no
Professor Martin Ritzén
Paediatric Endocrinology, Karolinska Institute, Stockholm, Sweden
Professor emeritus
Active research interests particularly those relevant to PWS:
Professor Ritzén is a paediatric endocrinologist whose primary research interests is in steroid hormones
and growth. He initiated the first randomized controlled study of GH treatment of children with PWS, the
results of which laid the ground for acceptance of PWS as a legitimate indication for GH prescription in
large parts of the world. Along with his coworkers, other effects of GH treatment than growth have also
been studied, such at respiration, body composition, glucose metabolism, a.o.
He is the founder of the paediatric endocrinology unit at the Karolinska Hospital, past member and
chairman of the Medical Nobel Council, assoc. editor of Acta Paediatrica, a.o.
Karolinska University Hospital
Q2:08 SE 171 76
Stockholm, Sweden
Tel: +46 8 5177 2465 Fax: +46 8 5177 5128
martin.ritzen@ki.se
Dianne Rogers, B.A., B.Ed.
Dianne and her husband, Gary, have a daughter, Kate, born in 1999 with Prader-Willi syndrome. Dianne
has been a regional contact for the Canadian Prader-Willi Syndrome Organization since 2000 and served
as president from 2002-2006. Dianne, Gary and Kate reside in Prince Edward Island, Canada.
Dianne Rogers
PO Box 786
Kensington, PE C0B 1M0
Tel: 902.836.4452 Fax: 902.836.3056
gdrogers@route2.pe.ca
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René Römling
René Römling was born on 11.9.1978. She is a state qualified caretaker for mentally handicapped people,
working for a group of children with PWS in Langenstein, Germany since August 2005.
Ioana Rotaru
Ioana Rotaru is a pediatric medical specialist and is married with two children. From September 2005
until now she has been the medical director of the Rehabilitation, Treatment and Care Centre “ACASA”
Zalau, Romania. She is responsible for the Children’s Department at ACASA. She is also a member of
the homecare team at ACASA Foundation in Zalau.
Ioana Rotaru
ACASA Foundation
Str. Gheorghe Doja Nr. 161
Tel: 0260-661-384 or 0260-612-999 Fax: 0260-615-899
ioanarotaru2010@yahoo.com
Cristina Rusu
Cristina is a clinical geneticist and pediatrician. She is senior lecturer in Iasi University of Medicine and
Pharmacy, Medical Genetics Department. She is working in the field of Dysmorphology, her main
interest being mental retardation and developmental delay. She has done her PhD thesis on X-linked
mental retardation. She has introduced new techniques in Romania for the screening of mentally retarded
children (antiFMRP test for Fragile X Syndrome and MLPA test for subtelomeric rearrangements), as
project manager. The projects won in the national competition, the last one being qualified the first out of
almost 200 medical projects.
She was appointed as a board member of European Journal of Medical Genetics in 2005.
Cristina was treasurer of the Romanian Society of Medical Genetics (RSMG) between 1995 and 2006, in
2006 being elected vice-president of RSMG. She is president of the Public Relations Commission of
RSMG and she represents RSMG in the relationship with the European Society of Human Genetics.
Cristina is also married and has two children.
Cristina Rusu
University of Medicine and Pharmacy
Medical Genetics Department
Str Universitatii 16
Iasi 700115, Romania
Tel/ Fax: 00 40 232 272754 Mob 00 40 745 432077
Email abcrusu@gmail.com
Emilia Severin, PhD
Emilia is a Professor of Genetics.
She received her PhD from Carol Davila University of Medicine and Pharmacy, in Bucharest Romania.
She is a professional member of the European Society of Human Genetics (1998 – present), the American
Society of Human Genetics (2003 – present), and the Romanian Society of Medical Genetics (1998 –
present). The main theme of her research is currently focused in the genetic basis of inherited dental
defects, particularly those involving non-syndromic hypodontia. Her goal is to elucidate factors important
for tooth morphogenesis in humans and to understand how mutations within genes encoding these factors
contribute to dental anomalies.
Severin Emilia
Str. D. Gerota Nr. 19-21
020027 Bucharest, Romania
Tel: (021) 3180757 Fax: (021)2226398
severin@cis.ro
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Tiina Silvast
Tiina Silvast is the mother of 26 year Vappu, who has Prader-Willi syndrome. Vappu is still living at
home. In 1993, Tiina was one of the few people who helped to found a Prader-Willi association in
Finland. Since 1995, she has been president of the association. During many years she got to know a
great number of PWS people, most of them in the summer camps the association arranges for PWS
people every year. Tiina and her husband have been the leaders of the camps for 10 summers. She is
proud to have many Prader-Willi people as friends. At some point, Tiina also started to lecture in group
homes about PWS, especially about PWS behavior and its management as there wasn't any professional
specialized in PWS behavior in Finland, and still isn't.
Now, through her own company, Tiina lectures and educates others about Prader-Willi as part of her
work. She lectures mostly to professionals, but also to Prader-Willi families and families with PraderWilli children. She is also a graphic designer and designed the IPWSO logo in 1998.
Tiina Silvast
Prader-Willi Association Finland
Teekkarinkatu 15 B 17
Tampere, Finland 33720
Tel: +358 400 84 75 76
silvast.pws@elisanet.fi
Cristina Skrypnyk
Cristina is a medical geneticist working at the Clinical Children Hospital “Dr. G. Curteanu” Oradea. She
is also Assistant Professor at the University of Oradea, Faculty of Medicine, Genetics Department, has a
PhD title in Medical Genetics and her mainly researches are microdeletions and microduplications
syndromes. She is member of the Romanian Society of Medical Genetics and an active volunteer
member in the Rare Genetics Disorders Romanian Association, Prader Willi Syndrome Romanian
Association, Williams Syndrome Romanian Association and PKU Romania Association. Cristina is
married and has one child.
Cristina Skrypnyk
Tusnadului Streeet No 2, Bl. Q2, Ap. 22
BH 410304
Tel: 0722413662
cristinaskrypnyk@yahoo.com
Heinrich Schnatmann
Heinrich has a doctorate in Economy. He works for Internationales Bildungs- und Sozialwerk and
provides many services for Romanian Social Services. He worked with the counties of Iasi, BistritaNasaud, Sibiu, and Salaj in Romania to help people with disabilities, Prader-Willi Syndrome, and other
rare genetic diseases to start programs within the social field including group homes, and life skills
trainings. He supports the Technical University in Cluj-Napoca financially inturn becoming an Honorary
Professor of the University.
Heinrich Schnatmann
Internationales Bildungs- und Sozialwerk
Scherlingstraße 7-9
58640 Iserlohn
Tel: 02 304 / 222 80
Fax: 02 304 / 222 60
www.int-bsw.de
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Renata Sõukand
Renata Sõukand was born on 04.04.1974 and is Estonian. She has one child with PWS named Aira Pääsu
Kalle (18.08.05, PWS deletion). In 1999, she received her BSc in Pharmaceutical Sciences at Tartu
University, Faculty of Medicine. In 2003, she received her MSc in Environmental Sciences at Tartu
University, Faculty of Physics and Chemistry. Currently she is a doctoral student of Semiotics and
Cultural Theory at Tartu University, Faculty of Social Sciences.
From 1996 – 2000, she worked at Leks Insurance LTD, as an insurance consultant. From 2000 – 2004,
she worked at the Museum of Tartu University History, as a project manager, and currently she works at
the Estonian Literary Museum, Department of Folkloristics, as a researcher.
Renata Sõukand
Tähe 69-1, Tartu 50107 (home)
Tel: +372-50-22-394 (mobile)
renata@ut.ee
http://haldjas.folklore.ee/~renata
Dr. Hubert Soyer
Dr. Hubert was born on the 29th of March in 1955. He has been working as a teacher at an elementary
and secondary school for 5 years. He also has been working at a school for multiple auditoral
handicapped pupils for 15 years. Since 1994, He has been the director of an institution for mentally
challenged and physically handicapped people. Meanwhile, he studied psychology and reveived his
doctorate. Since 1995, He has been working with people with PWS. In the institution he works for, they
were the first in Germany to make a specific offer for PWS in grouphomes. They have been gaining
experience in PWS for more than ten years and have worked out a special treatment for this particular
syndrome in collaboration with the University of Eichstaett and other institutions in Germany.
Dr. Hubert Soyer
Regens Wagner Absberg
Marktplatz 1
91720 Absberg, Germany
hubert.soyer@regens-wagner.de
www.rw-absberg.de
Assoc. Prof. Dr. Rumen Stefanov, MD, PhD
Rumen Stefanov is the founder of the Information Centre for Rare Diseases and Orphan Drugs
(ICRDOD) in Bulgaria and an associate professor in public health and health management at the Medical
University of Plovdiv (Bulgaria). He is a Specialist in epidemiology and clinical trials on small
populations. Dr. Stefanov has more than 6 years professional experience in rare diseases, being a Marie
Curie fellow at the Mario Negri Institute (Italy) under the Program of EC “Quality of life and
management of living resources” in 2001. In 2003 – 2004, he was a visiting scientist at the Coordinating
Centre for Rare Diseases (Mario Negri Institute for Pharmacological Research, Italy). Dr. Stefanov is a
reviewer at the Cochrane Renal Group (Australia), member of the Task Force on Rare Diseases at DG
SANCO (EC, Luxembourg) and board member of the Central & Eastern European Genetic Network
(CEE GN). He is a chairperson of the working group formed by the Minister of Health of Bulgaria for
establishment of National Program on Rare Disease (2007-2011). Dr. Rumen Stefanov is fluent in
English, Italian, Russian and Bulgarian (native) languages and has more than 35 scientific publications in
leading Bulgarian and international medical journals.
Assoc.Prof. Rumen Stefanov, MD, PhD
Information Centre for Rare Diseases and Orphan Drugs (ICRDOD)
A project of the Bulgarian Association for Promotion of Education and Science
Office 46, Hall 7-East
International Plovdiv Fair,
Plovdiv, Bulgaria 4000
www.raredis.org
stefanov@raredis.org
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Dr. Jorgelina Stegmann
Jorgelina Stegmann is a medical doctor from Argentina. She is a specialist in Internal Medicine, with a
particular focus in psychoimmunoneuroendocrinology. Jorgelina works with adolescents and adults with
PWS and is the president of a SPINE Foundation in Argentina. She coordinates a group of seven
professionals from different disciplines: nutrition, rehabilitation, psychology, psycho pedagogy,
education, etc. Together, they do multidisciplinary work with families with people with PWS.
Fundacion SPINE
Araoz 2471 2"9" piso
C1425EFF
Ciudad de Buenos Aires
Tel: (0054)11 48 22 10 61 Fax: (0054) 11 48 22 07 64
www.spine.org.ar
fundacionspine@gmail.com
jstegmann@spine.org.ar
Kate Steinbeck
Kate Steinbeck is the Director of the Metabolism & Obesity Services at Royal Prince Alfred Hospital,
Sydney where the first adult & adolescent Prader Willi Clinic in Australia was established. She is also
involved in Prader Willi research including cardiovascular risk, appetite hormones and the behavioral
effects of HRT. Professor Steinbeck is a past President of the Australasian Society for the Study of
Obesity (ASSO). She was co-chair for the International Congress of Obesity held in Sydney in September
2006, and serves on a number of Committees for the International Association for the Study of Obesity.
She is a pediatric associate editor of the International Journal of Obesity and associate editor for the
International Journal of Pediatric Obesity.
A/Prof Kate Steinbeck
Endocrinology and Adolescent Medicine
Tel: 612 9515 9261 Fax: 612 9515 9266
Liviu Athos Tamas, M.D.
Liviu Athos Tamas was born in 1972, in Timişoara, Romania. In 1997, he graduated the Medical School
at Victor Babes University of Medicine and Pharmacy from Timisoara, Romania and after one year of
clinical practice, in 1999, he had joined the academic staff of the same university at the Biochemistry
Department in the position of Assistant Professor. In 2002, he started to study the genetics of cystic
fibrosis for his Ph.D. thesis which is entitled: The study of genetic structure at children with cystic
fibrosis from Romania. In 2004, as participant in a CNCSIS research grant study, he started to perform
genetic testing in cystic fibrosis. He performed the first prenatal diagnosis in cystic fibrosis in 2005, and
he continues performing the genetic tests in suspected patients from the National Centre of Cystic
Fibrosis from Timisoara. In 2007, he started to perform genetic testing in acute leukemia patients, as a
participant in a CEEX research grant. He is married and he has one child.
Liviu Athos Tamas
Victor Babes University of Medicine and Pharmacy
Biochemistry Department
2nd Eftimie Murgu Square
RO-300041, Timisoara
Tel: 00 40 744 764 737
tliviu33@yahoo.com
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Domenica Taruscio
Director of Rare Disease Unit (ISS), Scientific Responsible of the National Center Rare Diseases
(Istituto Superiore di Sanità),
Domenica Taruscio is the director of the Italian National Centre Rare Diseases, and is an M.D.
pathologist, specialized in bioethics and genetics; her efforts are directed mainly to tackle rare diseases
from science to society. Since 2000, she has been the Italian Member to the Orphan Drug Committee
(COMP) at the European Drug Agency (EMEA); the Italian contact point for the OECD for the quality
assurance of genetic testing. In particular, in 1989-91 she underwent post-doctoral training at the Dept. of
Human Genetics - Yale University (New Haven, USA) and, from 1992 to 1994, was a visiting researcher
at the Dept. of Pathology - Columbia University (New York, USA). She is currently responsible for the
National Centre for Rare Diseases at the Istituto Superiore di Sanita’ (Rome, Italy). She is member of the
following national and international working Groups and Committees:
(2000- Present): OECD Contact Point for “Genetic Testing Regulation in Italy”;
(2000-2009): Italian Member of Committee for Orphan Medical Products-COMP (EMEA);
(2001): Italian Member of OECD Steering Committee on Genetic Tests;
(2002-Present): Member of the Italian National Committee on Genetic testing of the Italian Ministry of
Health;
(2002-Present): Member of the Italian National Committee on “Task Force on rare diseases” of the Italian
Ministry of Health;
(2002): scientific expert at the Italian Commission on Drugs (CUF).
She is the Scientific Coordinator of a number of national and international projects on rare diseases, the
local organizer of the WHO-Europe meeting on folic acid and birth defects (Rome, ISS, 2002) and, in
particular the Scientific Coordinator of the project NEPHIRD (Network of Public Health Institutions on
Rare Diseases) funded by the EU Commission (DG-SANCO). She is the Italian Member at the
Committee on Orphan Medicinal Products (COMP) at the EMEA. She is a member of the Task Force on
Rare Diseases (DG-Sanco), an OECD expert (genetic testing), member of the European Molecular
Genetics Quality Network management board, and of the advisory board of Eurogentest (NoE). She is
co-author of several scientific publications.
Domenica Taruscio
Istituto Superiore di Sanità (ISS)
Viale Regina Elena
299-00161 Rome, Italy
Tel: +39 06 49904016 Fax: +39 06 49904370
taruscio@iss.it
http://www.iss.it/cnmr
Dr. Min-Chieh Tseng
Dr. Min-Chieh Tseng received his Ph.D. in Sociology at the University of Wisconsin-Madison, U.S. and
in 1991 he received his M.S. in Sociology, University of Wisconsin-Madison, U.S.
He has been employed since 2003, as an Associate Professor, Dep’t of Social Work, at National Taipei
University in Taiwan.
He is also the Vice President of the Taiwan Foundation for Rare Disorders, Taiwan.
He has worked in public service as a member of the Committee for Protecting the Handicapped, Ministry
of Interior, in Taiwan, and a member of Committee on Rare Diseases and Orphan Drug, Department of
Health, in Taiwan.
From 1999-2005, he was the Executive Director of the Taiwan Foundation for Rare Disorders.
From 2001-2005, he was the Deputy Executive Director of the Taiwan Health Reform Foundation, and
from 1997-2003, he was an Associate Professor, Department of Labor Relations, National Chung Cheng
University in Taiwan.
In 2006 he received the Public Service Award from the Department of Health in Taiwan, and in 2004, he
was the recipient of a Fulbright Scholarship, in the US.
Dr. Min-Chieh Tseng
Tel: 886-2-25210717 Exit 103 Fax: 886-2-25673560
mctseng@mail.ntpu.edu.tw or ex01@tfrd.org.tw
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Annick Vogels
Annick Vogels obtained her Medical Degree at the Catholic University of Leuven (Belgium). She had her
training in child psychiatry at the University Hospital of Leuven and at the Royal Hospital for sick
children in Bristol. She is a child psychiatrist at the Department for Human Genetics at the University
Hospital of Leuven where she is specialized in children and adults with a genetic disorders and
psychiatric problems.
In 2001, she completed her PhD on “Psychosis in Prader-Willi Syndrome” at the Catholic University of
Leuven. She is an international researcher on the topic of psychiatric problems in genetic syndromes
specifically on PWS.
Annick is a board member of the Flemish PWS association, and the professional delegate to the
International PWS organization of the Flemish PWS association and a member of the “Conseil
Scientifique Prader-Willi France”. She is an active member of the European Consortium on Prader-Willi
Syndrome. She is the coordinator of the multidisciplinary clinic for Prader-Willi patients in Leuven and
has a long term follow-up of more than 50 Prader-Willi patients.
Annick Vogels M.D. Ph.D.
Department of Human Genetics
University Hospital of Leuven
Herestraat 46
3000 Leuven, Belgium
Annick.Vogels@uzleuven.ac.be
Jackie Waters
Jackie Waters is the mother of a 29 year old woman with PWS who lives with her at home. She is Deputy
Chief Executive of the Prader-Willi Syndrome Association (UK), and has been with the Association, first
as a trustee and then as a paid worker, since 1987. She has written several books and articles about PWS,
mostly for parents, some of which have been translated into other languages. She is also responsible for
the PWSA (UK) News magazine and website, as well as organizing training days and conferences.
Jackie Waters, PWSA (UK)
125a London Road
Derby DE1 2QQ
Tel: +44 1332 365676
jwaters@pwsa.co.uk
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Map of Cluj-Napoca:
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The Romanian Prader-Willi Association and the International Prader-Willi Organization
would like to thank the following people and businesses for their efforts and contributions
to this important conference. This would not have been possible without the help, support,
and financial contribution of our friends, families, and associates. We appreciate all that
you have done for the progression, research, and sustainability of the activites all over the
world for PWS and other rare genetic diseases.
We would also like to take this opportunity to thank those people whom have been key
organizers, networkers, supporters, and friends to the Romanian Prader-Willi Association
to help us make this dream a reality for our association and the medical community here in
Romania including all of the Conference Committee Organizers with their hard work,
commitment, and boundless support throughout this process!
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•
•
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Giorgio Fornasier- IPWSO laison, IPWSO Director of Program Development
EURORDIS
Robert Brown- IPWSO Business and Systems Analyst
OrphanNet Europe
Tiberiu Dan- Executive Director RPWA
Marcela Papici- Simbotours Travel Agent
Thank You Sincerely,
Romanian Prader-Willi Association and the International Prader-Willi Syndrome
Organization
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