Age at onset and genetic risk for Spinocerebellar ataxia type 2

Rev Cubana Genet Comunit 2008;2(2) 23-28
ARTÍCULO ORIGINAL
Age at onset and genetic risk for Spinocerebellar ataxia type 2
Edad de inicio y riesgo genético en la Ataxia espinocerebelosa tipo 2
Luis Enrique Almaguer Mederos,I Milena Paneque Herrera,II Carlos Leyva Proenza,IIIYanetza González
Zaldivar,IV Edilberto Martínez Góngora,V Dany Cuello Almarales, VI Luis Velásquez Pérez. VII
Abstracts
Resumen
Spinocerebellar ataxia type 2 is a neurodegenerative disorder
that reaches the highest worldwide prevalence in Holguín
province, Cuba. To obtain probabilistic estimates of the
risk of having inherited the disease causing mutation with
dependence of the age for at-risk descendants with a priori
risk of 50% or 25%. Medical records were reviewed from
the 748 affected patients belonging to 101 spinocerebellar
ataxia type 2 families. Molecular testing was made by
PCR. The mean age at onset was 33 years, and 50% of the
patients became symptomatic before being 31 years old.
The empiric risk for 7-year-old or younger children remains
at 50%, but in the cases of 65 years old or more, the risk
decreases up to approximately 0%. There is a progressive
decrease in the genetic risk for spinocerebellar ataxia type
2 at-risk descendants as the individual gets older. These
data are presented as an aid for genetic counseling of atrisk individuals.
La Ataxia espinocerebelosa tipo 2 (SCA2) es una
enfermedad neurodegenerativa que alcanza las mayores
tasas de incidencia y de prevalencia en Holguín, Cuba.
Obtener estimados probabilísticos del riesgo dependiente
de la edad, de haber heredado la mutación causante de
la SCA2. Fueron revisadas las historias clínicas de 748
pacientes afectados pertenecientes a 101 familias con
SCA2. El diagnóstico molecular fue realizado por PCR.
La edad de inicio promedio fue de 33 años, y el 50% de
los pacientes fueron asintomáticos antes de los 31 años de
edad. El riesgo empírico fue del 50% para individuos con
7 años de edad o menos, pero en los casos con 65 años
o más, el riesgo disminuyó hasta casi un 0%. Existe una
disminución progresiva del riesgo genético para la SCA2 a
medida que avanza la edad del individuo. Los resultados son
presentados como un apoyo para el asesoramiento genético
de individuos en riesgo.
Keywords: Presymptomatic diagnosis, spinocerebellar
ataxia type 2, genetic counseling, risk estimation,
polyglutamine disorders.
Palabras clave: Diagnóstico presintomático, ataxia
espinocerebelosa tipo 2, asesoramiento genético, estimación
de riesgo, enfermedades poliglutamínicas.
Recibido: 16 de enero de 2008
Aprobado: 12 marzo de 2008
Introduction
Spinocerebellar Ataxia type 2 (SCA2) belongs to a
group of hereditary neurodegenerative diseases caused
by the expansion of a CAG repeat tract in coding regions
of novel genes which are translated into polyglutamine
stretches containing proteins. This group includes
Huntington’s disease (HD), spinal and bulbar muscular
atrophy (SBMA), dentatorubral-pallidoluysian atrophy
(DRPLA), and the spinocerebellar ataxias (SCA) type 1,
type 3 or Machado-Joseph disease, type 6, type 7, type
12, and type 17.1
Of all these conditions, HD it is the most common
and well known,2 while SCA3 is the most common
autosomal dominant ataxia syndrome in the world
accounting for about one third of autosomal dominant
cerebellar ataxias (ADCAs), and reaching its highest
prevalence in the Azores Islands of Portugal.3 Similarly
BSc.-Biology; Assistance Professor. E-mail: leam@cristal.hlg.sld.cu
MSc.-Genetic Counseling. paneque@cristal.hlg.sld.cu
III.
MD cproenza@cristal.hlg.sld.cu
IV.
BSc-Microbiology. yanetza@ataxia.hlg.sld.cu
V.
MD-Neurology. edy@infomed.sld.cu
VI.
MSc.-Neuroscience. danny@ataxia.hlg.sld.cu
VII.
MD, PhD. Titular Professor. lvp@ataxia.hlg.sld.cu
I.
II.
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Age at onset and genetic risk for Spinocerebellar ataxia type 2
SCA2 is broadly distributed and is the second most
common ADCA, accounting for about 12% of cases
in Europe, mainland China and Taiwan, and reaching
its highest worldwide prevalence in Holguín province,
Cuba.4, 5
These mutations show very high penetrance, and they
follow an autosomal dominant inheritance pattern,
meaning that each descendant from an affected patient
has an a priori genetic risk of 50%. However, it has
been proven that the empiric risk of having inherited
the mutation causing HD or SCA3 lessens with
advancing age. This fact has significant implications in
the genetic counseling of at- risk individuals. Accuracy
and precision achieved in the estimate of the genetic
risk of developing a certain hereditary illness will have
a very important impact on decision making linked
to health, reproductive, financial matters, and family
planning.
Therefore we undertook a survey of the age of onset in
a cohort of SCA2 patients from Holguín province and
made a comparison with published estimates carried
out for HD and SCA3.
Methods
Subjects
For the purposes of this investigation we retrospectively
assembled data conformed by a total of 748 SCA2
cases belonging to 101 unique families studied during
a genetic survey realized on the worldwide largest and
genetically homogenous SCA2 population in Holguín,
Cuba, since 1990. The diagnosis of SCA2 was made
on the basis of molecular testing. Age at onset was
determined according to subjective complains of the
diagnostic symptoms gait ataxia, dysarthria, dysmetria,
adiadochokinesia and intention tremor. The study
protocol was approved by the institutional review
board and informed consent was obtained from each
study participant or their guardians.
Molecular testing for SCA2
Genomic DNA was isolated from peripheral blood
leucocytes using a standard protocol.6 The SCA2
CAG repeat was assessed by PCR amplification
with the previously published UH10 and UH13
oligonucleotide primers,7 followed by polyacrilamide
gel electrophoresis in an ALFExpress II apparatus
(Amersham Biosciences). Cases with 32 or more
repeats were designated SCA2 gene carriers in
accordance with published association with disease
expression.8
Statistical Analysis
For statistical analysis a comparison of means for the
age at onset between male and female patients was
performed with F test. The frequencies shown, as well
as the statistics of central tendency and dispersion,
were calculated with the software SPSS version 10.0
for Windows.
We have made a Bayesian analysis for risk calculation.
We start our Bayesian analysis with two mutual
exclusive hypotheses, the first one is that the consultant
is a carrier for SCA2 mutation and the second
hypothesis is that he/she is a non-carrier. A generalized
Bayesian analysis formula could be represented as:9
P = αβi/[αβi + (1- α) γ],
[1]
The prior probability of being a SCA2 mutation
carrier is designated as α, and the prior probability of
not being a SCA2 mutation carrier is designated as
(1 - α). As the SCA2 follows an autosomal dominant
inheritance pattern, both hypothesis have a 0.50 prior
probability in the case of asymptomatic individuals
with an a priori risk of 50%. Corresponding figures
in the case of asymptomatic individuals with an a
priori risk of 25% are 0.25 and 0.75 for α and (1 - α),
respectively. The probability of not being sick at an
specific age would occur if we assume that the at-risk
descendant is a SCA2 mutation carrier is designated
as βi (βi was calculated starting from the accumulative
relative frequency for age at onset (see Figure 2); βi
equals one minus accumulative relative frequency for
age at onset). The probability of not being sick at a
specific age would occur if we assume that the at-risk
descendant is not a SCA2 mutation carrier is designated
as γ (γ=1). This way, a more practical formula in the
case of asymptomatic individuals with an a priori risk
of 50% will be:
P = βi/[βi +1].
[2]
In a similar way, a more practical formula in the case
of asymptomatic individuals with an a priori risk of
25% will be:
P = βi/[βi +3].
[3]
Results
General characterization of the study sample
In this cohort, the age at onset showed an asymmetrical
distribution, with a skewness (S.E) of 0.33 (0.09) and
a kurtosis (S.E) of -0.56 (0.18), indicating a slightly
displaced to the left and a more flatted distribution
than a normal one. Non-normality of the age at onset
distribution was confirmed by Shapiro-Wilk’s test
(SW-W=0.7; p<0.001); however, visual examination of
the data suggests a distribution very close to normality
( Figure 2).
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Luis Enrique Almaguer Mederos
Figure 1. Distribution of age at onset frequencies in
Cuban SCA2 patients
Figure 2. Accumulative frequency for the age at onset
in SCA2 Cuban patients
Table 1. Life table risk for asymptomatic individuals with an
a priori risk of 50% for the SCA2
Age (years old)
Risk (%)
Age (years old)
Risk (%)
≤7
50
38-39
24
8-12
49
40
21
13-15
48
41
20
16-17
47
42-43
19
18
46
44
18
19
45
45-46
16
20
44
47
15
21
43
48
14
22-23
42
49
12
24
41
50
10
25-26
39
51-52
9
27
38
53
8
28
37
54-55
7
29
36
56
6
30-31
33
57
5
32
32
58-59
4
33
31
60
3
34
29
61
2
35
27
62-64
1
36
37
26
25
≥ 65
~0
The mean [±SD] age at onset was 32.5±13.8 years
old, varying in a wide range from 2 to 68 years old.
The standard error of the mean was 0.51, and the
95% confidence interval moves from 31.54 to 33.53
years old. The observed median age at onset was 31
years old, and the most frequent value was 30 years
old, representing 5.84% of the total sample.
Of the patients studied, 51.1 % are males with a
mean [±SD] 31.8 ± 13.9 years of age at onset, on
average, they became symptomatic approximately
one year earlier than women (mean [±SD]=33.2 ±
13.5 years); these differences are not statistically
significant (F= 1.92; P = 0.166) (Figure 1).
Bayesian Risk dependent of the age for the
SCA2.
The calculation of the cumulative frequency for
the age at onset of the disease showed that 50%
of patients became symptomatic before being 31
years of age; 25% of the cases became symptomatic
approximately before being 21 years old, while
98% were symptomatic by the age of 61.
The calculation of the Bayesian risk for
asymptomatic individuals with an a priori risk of
50% or 25% indicated the existence of a progressive
decrease in the genetic risk as the individual gets
older. Thus, while for 7-year-old or younger
children the empiric risk remains in 50% in the case
of asymptomatic individuals with an a priori risk of
50%, the 30-year-old individuals have an empiric
risk of 33%, and in the cases of 65-year-old or
older individuals, the empiric risk decreases up to
approximately 0% (Table 1). Similarly, in the case
of asymptomatic individuals with an a priori risk of
25%, while for 9-year-old or younger children the
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Age at onset and genetic risk for Spinocerebellar ataxia type 2
empiric risk remains in 25%, 30-year-old individuals
have an empiric risk of 14%, and in the cases of 63year-old or older individuals, the empiric risk decreases
up to approximately 0% (Table 2).
Table 2. Life table risk for asymptomatic individuals
with an a priori risk of 25% for the SCA2
Age (years old)
Risk (%)
≤9
25
10-14
24
15-17
23
18
22
19
21
20-22
20
23-24
19
25
18
26-27
17
28-29
16
30-31
14
32-33
13
34
12
35-36
11
37-38
10
39
9
40-41
8
42-44
7
45-47
6
48
5
49-50
4
51-54
than 60 of about 10% each has been reported.13 Also
for SCA3 the rare occurrence of juvenile or older than
60 cases has been described.12 However, for SCA2 a
higher frequency of juvenile onset had been noted, with
cases developing the disease before being 25 years
reaching approximately 40%, and those developing
disease before being 14 years reaching approximately
11%.10 In our cohort, corresponding figures are 31%
and 6,6% for onset before 25 and 14 years respectively;
a frequency of only 2% for cases older than 60 was
noted. This distribution confirms the earlier age-ofonset of SCA2 in comparison with these other two
polyglutamine diseases. As it was previously reported
for the SCA314 and also for the SCA2,5 we do not
find statistically significant differences in age at onset
between men and women.
In SCA2 there is an a priori risk of 50% of transmission
from the affected individual to each of their children.
However, the empiric risk of having inherited the gene
of the illness decreases along with the individual’s
age. For HD and for SCA3, decreased empiric risk
is too slow as to obtain sufficiently low risks during
the reproductive phase of life.12, 15On the contrary,
Table 3. Comparison of genetic risk in three
CAG repeat expansion disorders
Age (years
old)
Risk (%)
SCA2
SCA3*
HD**
10
49
49
-
15
48
48
-
20
44
47
50
3
25
39
45
49
55-57
2
58-61
1
30
33
41
48
≥63
~0
35
27
36
46
40
21
29
43
45
16
22
38
50
10
14
32
55
7
9
25
60
3
2
19
65
0
1
13
70
-
0
6,2
Discussion
Spinocerebellar ataxia type 2 is considered a late onset
disease, although the age when the first symptoms
appear is very inter- and intra-familiarly variable.10The
age at onset shows a broad distribution, where in
most individuals the illness appears from the third to
the fourth decades of life; a similar image has been
described for HD,11 and for SCA3.3, 12 For HD, a
frequency of juvenile cases and of individuals older
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Luis Enrique Almaguer Mederos
decreased genetic risk is quite marked in SCA2. We
find that individuals with a 50% a priori risk and 25
years of age have a 39% empiric risk of inheriting the
mutated gene of the illness, for 35-year-old individuals
we have estimated a 27% empiric risk, while for those
being 45 years old, the risk was only 16% (Table 3).
These differences in the empiric risk for these
illnesses could be explained on the basis of the
neuropathological and molecular distinctive features
and favor the hypothesis that for ataxin-2 the flanking
translated sequences are less protective against the gain
of function produced by the polyglutamine expanded
tract, giving an explanation for the appearance of
a significant number of SCA2 juvenile cases, and
the relatively quick decrease in the empiric risk for
asymptomatic individuals with a 50% a priori risk.16-18
As our risk estimates are based on the age at onset
distribution in Cuban SCA2 population, and age at
onset is influenced by genetic and environmental
factors, differences in age at onset distributions should
be expected between diverse SCA2 populations in the
world, due to dissimilar genetic and environmental
backgrounds. So caution should be taken in order
to apply these probabilistic estimates to other SCA2
populations in the world.
In conclusion, the relatively quick decrease in the
empiric risk for SCA2 in affected families could be
reassuring for many of risk descendants of reproductive
age. Genetic counseling based on these estimates
might be helpful as it may assist the patient in making
more rational decisions, regarding family planning,
reproduction, financial, and health matters.
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