Congenital pontocerebellar atrophy and telencephalic defects in

Acta Neuropathol (2007) 114:387–399
DOI 10.1007/s00401-007-0248-z
ORIGINAL PAPER
Congenital pontocerebellar atrophy and telencephalic defects
in three siblings: a new subtype
Jules G. Leroy · Gilles Lyon · Catherine Fallet ·
Jeanne Amiel · Claudine De Praeter ·
Caroline Van Den Broecke · Piet Vanhaesebrouck
Received: 28 October 2006 / Revised: 30 May 2007 / Accepted: 4 June 2007 / Published online: 13 July 2007
© Springer-Verlag 2007
Abstract We report three siblings, two of whom had a
neuropathological study, with a new subtype of congenital
ponto-cerebellar atrophy (PCH). In addition to the brain
stem and cerebellar anomalies common to all types of this
heterogeneous condition, there were unique developmental
defects in the telencephalon: absence of the claustrum,
diVuse cortical changes particularly in the insula and an
extremely small brain. In an attempt to shed some light on
the pathogenesis of this developmental disorder, we have
analyzed the pattern of brain stem and cerebellar abnormalities in ours and in previously reported patients with PCH,
to possibly distinguish primary from secondary eVects of
the mutant gene upon the cerebellar circuitry, and compared our patients’ cerebellar and cerebral defects to those
of some other human brain malformations and to mutant
mice with both hindbrain and forebrain anomalies.
Although this and previous observations of familial
J. G. Leroy (&) · C. De Praeter · C. Van Den Broecke ·
P. Vanhaesebrouck
Departments of Pediatrics, Neonatology and Pathology,
Ghent University Hospital, De Pintelaan 185,
9000 Ghent, Belgium
e-mail: juliaan.leroy@ugent.be
G. Lyon
Department of Child Neurology,
Hôpital R. Debré, University of Paris, Paris, France
G. Lyon · J. Amiel
Department of Clinical Genetics,
Hôpital Necker–Enfants Malades,
University of Paris, Paris, France
C. Fallet
Department of Neuropathology,
Hôpital Ste. Anne, University of Paris, Paris, France
congenital PCH with apparent autosomal recessive inheritance spawn the endeavor to compare and classify patients
into subgroups, any Wnal classiWcation must await identiWcation and molecular characterization of the causal gene(s).
Keywords Congenital olivo-ponto-cerebellar atrophy
(COPCA) · Pontocerebellar hypoplasia (PCH) ·
Telencephalic dysplasia · Familial micrencephaly ·
Neocerebellar developmental defect ·
Autosomal recessive inheritance
Introduction
Congenital pontocerebellar hypoplasia (PCH), also termed
congenital olivopontocerebellar atrophy (COPCA) is the
name given to a group of rare, autosomal recessive developmental disorders of unknown pathogenesis with severe
expression in the neonate and young infant. This syndrome
is characterized by a speciWc constellation of morphologic
anomalies: atrophy of the pontine basis with a major reduction of pontocerebellar neurons, small middle cerebellar
peduncles, atrophy (i.e. reduction in size with neuronal
degeneration) or hypoplasia (i.e. small size without tissue
necrosis) of the neo-cerebellum with relative preservation
of the vermis and Xocculonodular lobes and various
changes in the dentate nucleus and inferior olives. In
patients reported up to now, the cerebrum is smaller than
normal without speciWc or consistent histologic anomalies.
In many reports, the reason for using either “atrophy” or
“hypoplasia” is not explained. Although these terms
express evident morphologic diVerences–essentially in
the neocerebellum–it seems highly probable that both
processes, which may coexist in the same patient, are the
result of the same genetic defect. According to clinical and
123
388
neuropathological criteria, Barth [3–5] has isolated two
main categories of this condition: PCH type 1 with concomitant evidence of spinal muscular atrophy and PCH
type 2 in which dystonia is a major feature (Tables 1, 2).
Other patients with acute neurological signs and a rapidly
fatal course have been reported under various denominations, which we provisionally group under the heading
“severe neonatal form” (Table 3).
The three siblings here reported, two of them with a neuropathology study, had some clinical features of the latter
group, but diVer markedly from the patients in all previous
reports on non-syndromic PCH with complete neuropathological description, because of their unique telencephalic
abnormalities.
Clinical reports
Patient 1. This male infant was born at 38-week gestation
to healthy nonconsanguineous parents. Prior to this pregnancy, there was a Wrst trimester abortion and the second
pregnancy resulted in a healthy boy. The third pregnancy
was complicated at 33 weeks by polyhydramnios and a
decelerating growth rate of the biparietal diameter
(BPD). Birth weight was 2,850 g, length 50 cm, occipitofrontal circumference (OFC) 30 cm. The newborn
required immediate ventilatory support. He had no suction reXex and showed generalized hypertonia and intermittent tonic seizures. Ophthalmologic examination,
routine laboratory investigations and metabolic studies
were normal. A CT scan showed severe reduction of the
cerebral volume and much widened subarachnoidal
spaces. The karyotype was 46 XY. The tonic convulsions
gradually led to status epilepticus, signiWcant O2-desaturation and fatal outcome within the Wrst day of life. Only
gross post-mortem examination was performed. The
brain weighed 70 g.
Patient 2. At 29 weeks, the next pregnancy was also
complicated by polyhydramnios and decelerating growth
rate of the BPD. Fetal movements, abdominal circumference and femoral length remained normal. Induction of
labor at 40 weeks resulted in the delivery of a female infant
with birth weight 4,000 g, length 52 cm and OFC 32 cm.
Apgar scores were 5 and 8 at 1 and 5 min respectively, but
soon respiratory support was required. The suction reXex
could not be elicited. All routine laboratory tests yielded
normal results. The karyotype was 46, XX. Ultrasonographic abnormalities and CT Wndings in the brain were
identical to those of patient 1. The small size of the brain
was again disproportionate to the near normal head circumference. Over the next few days, the infant showed increasing generalized hypertonia and seizures. On day 5 status
epilepticus led to intractable desaturation and fatal out-
123
Acta Neuropathol (2007) 114:387–399
come. A complete post-mortem examination of the central
nervous system was performed.
Patient 3. During the Wfth pregnancy a deceleration of
the PBD growth was noticed at 30 weeks, although fetal
movements, abdominal circumference and femoral length
remained normal. A female infant was born at 37 weeks
with birth weight 3,225 g, length 48 cm and OFC 31 cm.
The Apgar scores were 6 and 9 at 1 and 5 min. The suction
reXex absent initially, remained deWcient. DiYculty of oral
feeding was compounded by tonic seizures associated with
spells of apnea, bradycardia and O2-desaturation. An exaggerated startle response (hyperacousis) was noticed. All
laboratory examinations were normal. MRI imaging
(Fig. 1) of the brain showed gross abnormalities congruent
with those in the previously deceased sibs. The patient succumbed on day 22 during an episode of convulsions. A
complete post-mortem examination of the CNS was performed.
Materials and methods
Brains were Wxed in 10% formaldehyde for 20 days. They
were then cut in the coronal plane. Sections of whole hemispheres and brain stem with cerebellum were embedded in
paraYn. ParaYn blocks were cut in 7 m sections. The latter were stained with hemalunphloxin, cresyl violet and
luxol fast blue. Sections were also stained immunohistochemically with primary monoclonal antibodies: Vimentin
(1:100 Dako, USA), NeuroWlament Protein (1:100 Dako,
clone 2F11), Calbindin (1:10 000, Swart, Switzerland),
Map-2 (1:100, Sigma, clone HM32) or Reelin (GoVinet
AL, Department of pharmaceutical chemistry, University
of Louvain Medical school, Brussels, Belgium) [19] and
with a polyclonal antibody to Pax6 (Rabbit 1/150e, Dako,
Covance, USA). They were also immunostained with a
polyclonal antibody to GFAP (1:200–1:400, Dako, USA).
The universal immunostaining system streptavidin-peroxydase kit Immunotech (Coulter) was used to develop these
reactions. Slide-mounted sections were incubated for
30 min in citrate buVer at 98°C in a microwave oven and
rinsed in distilled water. After washing in PBS the slides
were treated with Protein Blocking Agent (PBA) for 5 min
(100 l/slide) at room temperature without rinsing. Subsequently, they were incubated for 60 min at room temperature with the primary antibody Vimentin, GFAP, MAP2 or
Reelin, rinsed twice in PBS and incubated with the biotinylated secondary antibody for 30 min at room temperature.
In order to complete the reactions, slides were rinsed twice
(each time 5 min) in PBS, incubated in Streptavidin–Peroxydase Complex for 45 min, rinsed twice in PBS and covered for 5 min with a freshly prepared DAB solution
(100 l/slide). Hematoxylin was used as the counterstain.
M
Sex
neuronal loss
++
+
[a,b]
+
+
+
[a,d]
+
+
[a,c]
++
++
+
+
nl
+
++
+
+
+
+
40
F
2
[5]
+
+
F
1
(36)
[6]
+
+
+
+
32
F
1
(42)(x)
+
+
[a,d]
+
+
[f]
++
+
+
450
+
nl
+
+
+
300
+
[a,c]
++
++
+
+
520
[b]
§
+
+: present; –: absent; blank: not mentioned, irrelevant, absent?; nl: normal; * 2 sibs also aVected; (x) sibs
SMA: spinal muscular atrophy; aut: autolysis
[1] pyramidal signs, hypertonia; [2] pyramidal signs, vocal cord paralysis, blindness; [3] blindness? vocal cord paralysis; cousin with SMA;
[4] clubfeet; hip dislocation; cardiomyopathy; [5] horizontal nystagmus; [6] pyramidal signs; no swallowing; cleft palate; hypoplastic ovaries;
[7] seizures
[a] normal cortex and basal ganglia; [b] thin corpus callosum; [c] atrophy, gliosis of white matter; [d] gliosis in thalamus; [e] brain atrophy;
[f] neuronal loss in striatum
(spinal cord § brainstem and thalamus)
SMA: neuronal degeneration
Cerebrum
neuronal loss
Inferior olives: poorly convoluted
–
+
+
Dentate nucleus: “typical” clusters
§
+
475
[4]
+
+
40
M
1
(16)
[7]
+
+
+
+
+
38
F
2
+
+
+
33 [3 months]
+
40
F
1
(28)(x)
+
[e]
+
++
–
[a]
++
++
2 months 6 months 1 month 2 years 1 months 1 month 3 months
Ventral pons atrophy/hypoplasia
+
350
+
[3]
++
+
Neocerebellar atrophy/hypoplasia
880
4 days 3 months
[2][3]
+
“DiVuse” cerebellar atrophy/hypoplasia
603
6 months 22 months
Brain weight (g)
Neuropathology
Age at death
[1]
+
+
+
Other
+
+
Developmental retardation
–
+
+
+
38
F
1
(21)
36 [6 weeks] nl
40
F
1
(29)*
Arthrogryposis
SMA
Neurological signs/symptoms
+
+
Facial dysmorphic features
Hypoventilation/apnea (respir. failure)
41
M
1
(63)
46 [22 months] 33.5
40
M
1
(45)
OFC (cm) at birth or at [age]
Polyhydramnios
Term of pregnancy (weeks)
+
1
Patient number
Clinical data
(44)
Reference number
Table 1 Patients reported with congenital Olivo-Ponto-Cerebellar atrophy Barth type I
[7]
+
+
+
40
F
3
+
aut
aut
aut
+
[f]
+
–
++
+
17 weeks 1 month
+
+
F
2
Acta Neuropathol (2007) 114:387–399
389
123
123
1
F
Patients number
Sex
[11 months] [15 months]
+
at [age]
Microcephaly
15 months
–
+
+
+
+
735
2.5 years
+
+
+
[24 months]
42
40
M
1
–
–
[c,e] [f]
+
+
+
+
+
s
+
+
+
1
(54) (9)
[h,i]
§
+
+
+
1,000
37
40
M
2
+
+
+
+
–
+
6 months
+
+
+
+
[18 months] [6 months]
49.5
40
M
1
(49)(x)
3.5 years 18 months
+
+
+
+
40
F
1
(31)
31
40
F
1
+
+
+
+
+
+
+
+
+
[3 months] [bi]
36
40
F
1
(52)
+
+
+
+
+
F
1
(3,5,27)
+
+
+
F
2
+
+
+
F
1
(56)
+
+
+
M
1
(59)
+
+
+
M
1
(30)
[c,h]
+
+
+
+
+
+
760
–
[c]
–
§
+
+
+
535
[g,h]
+
+
+
395
–
[a,h]
+
+
+
+
+
[j]
§
+
+
–
+
+
+
1,050
[a,c]
–
++
+
+
558
–
+
+
12 months 30 months 16 months 1.2 years 9.2 years 3 years 30 months 18 months
+
+
+
+
40
M
3
(27)
+: present; –: absent; blank: not mentioned, irrelevant, absent?; bi: birth; s: small;
*: dysmorphic features not reported; arthrogryposis: not reported; polyhydramnios not observed; respiratory failure not reported
[a] thin corpus callosum; [b] microgyric segment; heterotopias; [c] no signiWcant histologic changes; [d] large putamen; [e] no arcuate nucleus; [f] cleft putamen/insula; [g] thalamus: neuronal
loss; gliosis; [h] atrophy; gliosis white matter; [i] no pyramidal tract; [j] poor cortical lamination
–
[c,d,e]
[a,b]
–
+
SMA lesions
–
+
+
Neuronal loss
+
+
Cerebrum atrophy/
hypoplasia
Abno. convolutions;
fragmented
Inferior olives
Neuronal loss
“Typical clusters”
+
+
Ventral pons
atrophy/hypoplasia
Dentate nucleus
+
Neocerebellar
atrophy/hypoplasia
+
610
+
Brain weight (g)
Neuropathology
+
Developmental retardation +
Age at death
11 months
Pyramidal signs
+
+
+
+
Hypertonia
+
+
Dystonia
Seizures
+
40
Neurological
signs/symptoms
40
38
OFC (cm)
F
1
(12,13)
Term of pregnancy (weeks) <40
Clinical data*
(11)
Reference number
Table 2 Patients reported with congenital Olivo-Ponto-Cerebellar atrophy, Barth type II
390
Acta Neuropathol (2007) 114:387–399
M
Sex
+
+
Arthrogryposis
Early respiratory failure +
+
+
+
+
27
+
36
M
2
297
+
+
+
27
35
M
2
1
+
+
+
+
27 34
M F
3
+
+
+
+
37
F
2
+
+
+
25
+
30
F
1
–
[b]
+
+
+
+
+
[c]
+
–
+
+
–
[b]
+
–
+
–
+
–
[b]
+
–
+
–
+
+
104
–
[c]
++
+
++
++
+
+
160
[c,d,f]
++
+
++
+
+
375
[e]
++
+
+
+
+
+
145
[e]
++
+
+
+
+
+
135
++
+
+
+
+
+
63
[c,d]
++
++
++
++
198
+
135
–
[c,h]
+
+
++
–
[c,h]
+
+
++
+
+
140
+
+
+
+
25
+
30
F
2
+
+
+
+
33
F
1
(20)
–
[b,c]
+
++
+
175
[j]
+
+
+
[i]
–
175
+
+
+[3]
+
–
32
38
F
1
48(x)
F
3
M
1
+[3]
–
+[3]
–
18[2]
[j]
+
+
+
[i]
–
[j]
+
+
+
[i]
–
105* 32.5**
–
+
+
+
–
32
+
40
F
2
–
+
+
+
–
31
–
37
F
3
+
+
70
–
[g]
+
+
+
+
+
+
74
–
[g]
+
+
+
+
+
+
78
1 day 5 days 22 days
–
+
+
–
30
+
27[1] 20[1] (1) 38
F
2
This report(x)
+: present; –: absent; blank: no data or item irrelevant; pm: post-mortem; (x): sibs; (x)(x) identical twins;
* Pregnancy interrupted at 27 weeks, ** at 20 weeks gestation: see corresponding norms in (48)
[a] ischemic changes; [b] no signiWcant microscopic abnormalities;[c] gliosis in white matter § basal ganglia; [d] thin corpus callosum; [e] mild microgyria, no separation caudate nucleus; [f]
heterotopias; [g] no claustrum, cortical dysgenesis; [h] simpliWed gyri; [i] vermis most aVected; [j] irregular layer 2
[1] termination of pregnancy; [2] Normal: 16.7 cm (Ref. [48]); [3] fetal onset of seizures
SMA lesions
[remarks by original
authors]
[a]
+
Cerebrum
–
Neuronal loss
+
Poorly convoluted
Inferior olives
Neuronal loss
“Typical clusters”
Dentate nucleus: A/H
+
+
140
+
+
+
27
+
39
M
1
+
+
+
360
+
+
+
+
+
38
37
M
1
(14)(x)(x)
Ventral pons atrophy/
hypoplasia
+
150
+
+
+
+
+
36
F
3
(40)(x)
++
+
180
+
+
+
+
<p3
+
38
M
2
(35)(x)
DiVuse cerebellar A/H,
vermis A/H
Neocerebellar atrophy/ +
hypoplasia (A/H)
Brain weight (g)
Neuropathology
+
+
+
+
<p3
+
37
F
1
(60)
+
+
+
+
+
29
+
36
F
1
(1)(x)
9 days 10 days 1 day 9 days 1 day 1 day 3 months 12 months 18 days 3,5 months 5 months 6 days ** 4 days 14 days 7 weeks 7 weeks 5 days 3 days 1 day 1 day
+
+
+
33
+
39
M
1
(64)(x)
Age at death
32
F
2
(50)
Dysmorphic features
Hypertonia;
Startle reXex
Seizures: multiple,
severe
+
32
Neurological signs/
symptoms
+
OFC at birth (cm)
37
F
1
(47)(x)
Polyhydramnios
Term of pregnancy
(weeks)
38
1
Patient number
Clinical data
(37)
Reference number
Table 3 Patients reported with congenital Olivo-Ponto-Cerebellar atrophy: “severe neonatal type”
Acta Neuropathol (2007) 114:387–399
391
123
392
Acta Neuropathol (2007) 114:387–399
Neuropathology Wndings
tip of the globus pallidus was approximately 10 mm, compared to 12 mm in a normal control. The transverse diameter
of the fully developed thalamus was approximately 5 mm
instead of 7 mm in a control. The size of the amygdala was
not signiWcantly reduced. Arteries of the circle of Willis
had a normal conWguration.
Macroscopic examination
Microscopic examination
The neocerebellar hemispheres were very small, the vermis
and Xocculonodular lobes more moderately reduced in size
(Figs. 1, 3a). In the midbrain, the cerebral peduncles were
small. The ventral aspect of the pons was Xattened (Fig. 1).
The diameter of each bulbar pyramid was approximately of
1 mm, compared to 2 mm in a normal control. The spinal
cord was thin.
The post-Wxation brain weights in patients 2 and 3, both
born at term, were 74 and 78 g, respectively (normal: 350–
450 g). In either patient, Wndings were remarkably consistent. The meninges were thickened. Cortical convolutions
were small and simpliWed but their general pattern was
retained with recognizable primary, secondary and tertiary
Wssures. Sulci were enlarged. There was incomplete opercularisation of the lower part of the sylvian Wssure. At the
level of the insula, only a very thin band of tissue could
be distinguished on the external surface of the putamen
(Fig. 2b). The volume of the central and intra-axial white
matter was much reduced. The internal capsule was thin.
The corpus callosum, on a frontal plane through the anterior nucleus of the thalamus (Fig. 2b), was approximately
1 mm thick (normal control = 2 mm). The fornix, optic
tracts and olfactory tracts were identiWed. Lateral ventricles
were enlarged. The periventricular germinal matrix was
thick for age (Fig. 2a, b). In contrast to the important volumetric reduction of the cerebral cortex and white matter
(pallium), the size of the striatum and globus pallidus
(Fig. 2b) did not diVer signiWcantly from normal: the distance between the external surface of the putamen and the
The very small neocerebellar hemispheres had a smooth
surface with only few shallow undulations (Fig. 3a). There
were various degrees of cortical alteration. In some areas,
the laminar organization was recognizable but Purkinjé
cells were absent except for an occasional, isolated, calbindin and MAP-2 positive cell. The thin external granular
layer had a normal structure. The internal granular layer
was very sparsely populated (Fig. 3b). The shallow molecular layer contained apparently normal GFAP labeled radial
glial Wbers (Fig. 3c). Large reactive astrocytes were present. In other areas, the molecular layer had vanished completely to the eVect that remnants of the external and
internal granular layers were contiguous. Finally, in the
most atrophic regions (Fig. 3d), only a few granular cells
remained within a dense glial network. Macrophages were
present. The dentate nucleus was small, fragmented and
reduced to a few irregular clusters of normal appearing neurons. There was no gliosis. There were no signiWcant
microscopic changes in the vermis and Xocculonodular
lobes (Fig. 3e). In the atrophic neocerebellar white matter, a
dense reactive gliosis was present; no axons were immunostained with neuroWbrillary protein. In this regard, the vermis and Xocculonodular lobes were normal (Fig. 3f). There
were no ectopic Purkinjé cells.
In the midbrain, the cranial nerve nuclei, nucleus ruber
and substantia nigra had a normal structure. The cerebral
peduncles were present. In the underdeveloped ventral part
of the pons, the number of neurons in the pontine-nuclei
were considerably reduced; only very few small aggregates
Fig. 1 Neuroimaging. a Neurologically normal neonate. T2-weighted
MRI; axial plane at sella turcica showing normal anatomy of pons and
cerebellum.b Patient 3. T1-weighted axial MRI at level of hypophysis,
showing atrophy of basis pontis (arrowhead) and of cerebellar hemispheres (arrow); T2-weighted images not available. c Normal neonatal
brain (same subject as in a). T2-weighted axial section of cerebral
hemispheres and basal ganglia at striatal plane. Insular cortex and subjacent white matter (arrow) with thin claustrum therein clearly visible.
d Patient 3. T1-weighted axial plane at level of striatum. Severe atrophy of cerebral cortex and white matter. Insular structures not covering
the mass of basal ganglia (arrowhead). Considerably enlarged peripheral CSF spaces
All sections were examined under the Eclipse E800
Nikon light microscope. Some were selected for photographic recording.
123
Acta Neuropathol (2007) 114:387–399
393
Fig. 2 Cerebrum (patient 3). a Ten-days-old newborn. Normal brain
(420 g at term). Frontal section (level slightly anterior to that in b).
Note insular cortex (arrowhead), claustrum (arrow). b Patient 3 (at
term brain weight 78 g). Frontal section of cerebral hemispheres at the
level of anterior thalamic nuclei, amygdala, optic tracts. Atrophy of
central and intra-axial white matter. Large cortical sulci and sylvian
Wssure. Insular cortex (arrows) very thin and unconvoluted dorsally,
absent ventrally. No claustrum. Near normal size of striatum and globus pallidus and amygdala (see text). Thick periventricular germinal
matrix. c Higher magniWcation of b. Insular cortex (arrow) thin, unconvoluted in dorsal segment, practically devoid of neurons ventrally.
No claustrum. Very thin white matter band (arrowhead) between
cortex and putamen (white arrowhead). d Higher magniWcation of c.
Neuronal depopulation and marginal gliosis of insular cortex (arrow).
No claustrum in white matter band (arrowhead) separating cortex from
putamen. e Heterotopic streaks of neurons in central white matter
(arrow). Dense gliosis of white matter. (a) cresyl violet-luxol. (b–e)
cresyl violet stain
of these cells remained (Fig. 4a). There were no ectopic
pontine neurons. The remaining ponto-cerebellar axons
were thin and fragmented (Fig. 4b). The transversally sectioned bundles of the pyramidal tract were small and so
were the middle cerebellar peduncles. The VIth, VIIth and
vestibular nuclei were normal. In the medulla, the inferior
olives were reduced to a few isolated clumps of normal
appearing neurons (Fig. 4c). There was no indication of
neuronal degeneration or gliosis, and the nuclei of the
other cranial nerves showed no abnormality. No microscopic changes were detected in the pyramids. Only a few
neurons remained in the arcuate nuclei, and the site of
severe gliosis (Fig. 4c). In the thin spinal cord, the anterior horn cells and other gray structures were normal
(Fig. 4d), and the main Wber tracts could be readily discerned.
123
394
Acta Neuropathol (2007) 114:387–399
Fig. 3 Cerebellum (patient 2). a Horizontal section through the cerebellum and upper medulla. Marked reduction in size of neo-cerebellum
with very thin cortical band (arrows). Relative preservation of vermian
and Xocculonodular structures. b Neocerebellar cortex, mildly aVected
segment. Normal structure of the external granular layer. Shallow
molecular layer (arrow). No Purkinjé cells. Sparsely populated internal
granular layer (arrowhead). c Neocerebellar cortex, moderately aVected segment. Radial glial Wbers (Bergmann glia) are seen crossing the
molecular layer to reach the external granular layer. Internal granule
cells somewhat sparse. No Purkinjé cell evident. d Neocerebellar cortex, severely aVected segment. Very thin, partially destroyed external
granular layer (arrow). No molecular layer. Reactive astrocytes in
depopulated internal granular layer. e Vermis. Normal cytoarchitecture
of cortex. f Cerebral white matter. Immunostaining of nerve Wbers
(axons) in archicerebellum (white arrow), not in atrophic neocerebellar
white matter (arrowhead). (a, b, d, e) cresyl violet stain; (c) GFAP, cresyl
violet; (f) NeuroWlament protein (NFP)
In all parts of the cerebral neocortex, the most superWcial
layers (second and third layer) were composed of irregular
clumps or bands of adjacent, at times coalescent neurons;
no radial arrangement was discernable at this level (Fig. 5a,
b). Reactive astrocytes were present. In the lower neocortical segment (layers IV–VI), the cyto-architecture showed
no signiWcant change. In the molecular layer, numerous
Cajal-Retzius cells labeled with reelin and MAP2, were
observed (Fig. 5b). There was no trace of a subpial granular
layer. The cortex of the superior temporal gyri was irregularly undulated. Thin bands or islands of neurons appeared
occasionally in the molecular layer, possibly as a result of a
section artefact (Fig. 5c). The most striking cortical abnormalities were seen in the region of the insula (Fig. 2b–d). In
its upper third, the insular cortex was very thin and unconvoluted. In its lower part, nearly all neurons were either
absent or grouped in minute islets; reactive astrocytes were
present. There was no claustrum and consequently, the
insula and putamen were separated only by a narrow band
of white matter (Fig 2c, d). The hippocampus was normal
except for a limited loss of pyramidal cells in Sommer’s
sector in patient 3. The amygdala had a normal structure.
The striatum and globus pallidus (Fig. 2b) showed no
microscopic alteration. There was no signiWcant cell loss in
the thalamus.
In the atrophic central and intra-axial white matter,
dense gliosis and streaks of elongated heterotopic neurons
were observed (Fig. 2e). No myelinated Wbers were
123
Acta Neuropathol (2007) 114:387–399
395
Fig. 4 Brain stem (patient 2).
a Pons—Basis Pontis. Near
absence of pontine nuclei
neurons. A few remain (arrow).
DiVuse gliosis. b Basis pontis.
Rare pontocerebellar axons, thin
and fragmented (arrows).
c Medulla. Inferior olives are
reduced to small unconvoluted
masses of neurons (arrows).
Pyramidal tracts (white
arrowhead). Gliosis in arcuate
nuclei (black arrowhead).
d Upper spinal cord—Anterior
horn cells are present (arrow).
(a, c, d), cresyl violet stain;
(b) Bodian stain
Fig. 5 Neocortex. (patient 3).
a Frontal cortex. Disorganized
cytoarchitectonics of superWcial
cortical layers. Irregular aggregates of dark, partly coalescent
neurons. b Immunostaining of
neurons and dendrites in frontal
cortex. Compare to a. Note
Cajal-Retzius cells (arrow).
c Temporal cortex. Irregular
undulations of upper layers
(arrow). Bands or round aggregates of neurons in molecular
layer (arrowhead). (a, c) cresyl
violet stain. (b) MAP-2 stain
detected. A thin internal capsule was identiWed. The corpus
callosum and the optic tracts had a normal microscopic
structure. The periventricular matrix was thick for age
(compare Fig. 2a, b). The ependymal lining of the cerebral
ventricles was normal.
Discussion
As their molecular basis is still unknown, diVerent forms
of idiopathic congenital olivopontocerebellar atrophy/hypoplasia are classiWed according to clinical and neuropathologic
123
396
criteria. Two among them have been delineated by Barth
[4]. In PCH type 2, the most coherent group [3, 5, 9, 11–13,
27, 30, 31, 49, 52, 54, 56, 59] and Table 2, initially
described by Brun [11], a major and practically constant
feature is dystonia. Motor and mental development is very
limited, and head circumference is reduced. Most children
die in late infancy or early childhood; a few live longer.
Survival beyond the third year of life has been reported in
some patients in whom no post-mortem examination had
been performed [2, 5, 17].
In PCH type-1 patients [16, 21, 22–28, 29, 36, 42–45,
53, 63] and Table 1, degeneration of the spinal and brain
stem motor neurons and of some thalamic neurons is associated with the typical olivopontocerebellar defects. Clinical evidence of SMA is usually but not consistently present.
In some of these subjects with obvious developmental
delay, brain weight is normal for age or only moderately
reduced. The initial patient with this type of PCH was
described by Norman [43] and a second one by Norman
and Kay [45]. Involvement of the SMN1 gene locus on
5q11.2-q13.3 has been excluded in two families with PCH
type 1 [22, 53].
We concur with Barth [6] who stated that some patients
with idiopathic congenital PCH were diYcult to classify.
The clinical features in our patients–intractable seizures,
excessive startle response, central hypoventilation, polyhydramnios, marked reduction of brain volume and neonatal
death–diVer from the ones in PCH1 and in PCH2, but are
comparable to a number of patients previously reported
under various denominations [1, 14, 20, 35, 37, 40, 47, 48,
50, 60, 64] listed in Table 3.
Some of the latter have recently been labeled PCH4 by
Patel et al. [48] who also used PCH5 to designate the clinical and neuropathological characteristics in three sibs with
prenatal seizures and marked vermian predominance of cerebellar lesions. The term PCH3 had been used previously
as well to name the condition reported in three siblings, two
of whom had MRI Wndings of diVuse atrophy of the central
nervous system at 12 and 6 years of age, respectively, and
one a large cisterna magna and an atrophic cerebellum [46,
51]. Linkage to chromosome 7q11-21 was found [51]. A
generalized atrophy of the central nervous system also
characterized the patients reported by Zelnik et al. [66].
Because of the considerable volumetric reduction of the
entire central nervous system revealed by the available
MRI documents and the lack of any neuropathology study,
the basic morphologic criteria necessary for the delineation
of a new type of congenital PCH were not fulWlled in these
patients. In order to avoid further confusion of terminology,
we propose to refer to the fairly coherent assembly of
patients listed in Table 3 as to the “severe neonatal type” of
congenital non-syndromic PCH, especially at present with
the apparently monogenic cause(s) still unidentiWed.
123
Acta Neuropathol (2007) 114:387–399
While displaying the characteristic brain stem and cerebellar changes common to all types of PCH as well as the
clinical features of the “severe neonatal form” (Table 3),
our patients present in addition extreme micrencephaly and
unique developmental abnormalities in the cerebral cortex
that clearly sets them apart. A small brain is, with few
exceptions, featured in all types of PCH. However, in our
patients the reduction of brain size at term (74 and 78 g
compared to the normal of at least 350 g), was far more
pronounced than in PCH1 and PCH2 (Tables 1, 2) and even
more extreme than in the patients grouped here into the
“severe neonatal category”. The micrencephaly was essentially the consequence of the volumetric reduction of
the neo-cortex and hemispheric white matter (Pallium),
whereas the size of the Striatum and Globus pallidus was
practically normal (Fig. 2) and that of the thalamus only
moderately reduced.
In striking contrast, the reduction of head size was only
mild. This discrepancy remains unexplained, but supports
the contention that in neonates and young infants, reduction
of occitipofrontal circumference is not always directly correlated with reduction of brain volume.
Small brains weighing at term less than 100 g and called
“microbrains” [24] occur in other conditions. They have
been associated with various types of cortical dysplasia in
congenital malformation syndromes such as the Neu-Laxova syndrome and in cases of autosomal recessive lissencephaly with cerebellar defects. Microbrains have also been
observed in infants with a normal cortical pattern [24, 38].
In addition to the considerable volumetric reduction, the
cerebrum of our patients showed unique neocortical and
subcortical (pallial) abnormalities: absence of the claustrum, neuronal depletion in the insula, and cytoarchitectonic changes of the superWcial, late migrating, layers in the
other regions of the neocortex (Figs. 2, 5). This constellation of cerebral anomalies is not reported in any type of
PCH, where only minor and unspeciWc changes have occasionally been observed (Tables 1, 2). It supports the contention that our patients represent a hitherto unrecognized
severe variant of PCH.
Absence of the claustrum, a subcortical structure with
connections to many cortical areas [26] is rare in congenital
cerebral malformations. It is, however, in our experience
also a feature of lissencephaly type 1. It has been observed
as well in a patient with congenital microcephaly of
unknown causation, in association with widespread degeneration of late migrating neurons, particularly in the insula
and without signiWcant cerebellar and brainstem anomalies
(Miller 2002 personal communication).
In an attempt to shed some light on the pathogenesis of
the apparently autosomal recessive developmental disorder
presented, we have adhered to two lines of thought. First,
we have compared the pattern of brain stem and cerebellar
Acta Neuropathol (2007) 114:387–399
abnormalities in our patients with the ones in previously
reported patients with PCH in order to sort potentially
primary from secondary eVects of the mutant gene(s) upon
the cerebellar circuitry [57]. Second, we have carefully
weighted our patients’ cerebellar and cerebral defects
against the CNS anomalies in mutant mice with both hindbrain and forebrain anomalies on the one hand, and against
some other human cerebral developmental anomalies on
the other.
In our patients, the number of ponto-cerebellar neurons
(neurons in pontine nuclei) were considerably reduced, and
the neo-cerebellar granule cell layer to which these neurons
project was depopulated. As a similar reduction of the number of pontine nuclei is found also in cases of PCH in which
neo-cerebellar granule cells are apparently not aVected, a
primary eVect of the causal mutation upon ponto-cerebellar
neurons is probable. It is of note that the neurons in the
pontine nuclei remain intact in the so-called “primary
degeneration of the granule cell layer” [43] an apparently
autosomal recessive condition in humans. In mice lacking
the Math1 gene [7, 62], the ponto-cerebellar neurons
(mossy Wbers) are defective, as in PCH, but the cerebellar
external granular layer is lacking, which is not the case
here.
In the “atrophic” neocerebellum in our patients the least
aVected segments maintained a recognizable cortical lamination, but Purkinjé cells were extremely rare and the internal granular layer was very sparsely populated. To the
contrary, the relatively thin external granular layer retained
its normal histologic structure (Fig. 3b), tangential migration of granule cells apparently having been preserved.
Radial glial Wbers were present in the shallow molecular
layer (Fig. 3c). Similar Wndings were recorded in all types
of congenital PCH [4, 11, 14, 29, 35, 37, 47, 50, 63]. The
few residual Purkinjé cells were Calbindin positive and
MAP2 positive suggesting that these cells degenerated
following normal diVerentiation and migration. A similar
interpretation has been oVered previously [47]. It can therefore be assumed that the loss of Purkinjé cells probably represents another primary eVect of the mutant gene and the
depopulation of the internal granule cells a secondary phenomenon, as Purkinjé cells to which they project and pontine nuclei from which they receive aVerent Wbers, are both
deWcient. The normal appearing external granular layer in
some areas of the neocerebellum and in the vermis and the
presence of “GFAP labeled” glial Wbers in the cerebellar
molecular layer (Fig. 3c), are also in favor of this hypothesis.
The dentate nucleus was small, fragmented and reduced
to irregular clusters of normal appearing neurons. This
characteristic pattern and other less frequent alterations are
observed in PCH irrespective of the presence or severe
reduction in number of neocerebellar Purkinjé cells. Hence,
it can hardly be ascribed to an arrest in the fetal develop-
397
ment of this nucleus [32], as had been postulated by Brun
[11].
The inferior olives were reduced to a few isolated
clumps of normal appearing neurons (Fig. 4c). This typical
change as well as other histopathologic alterations observed
in PCH–ranging from neuronal loss in a normally convoluted nucleus to marked disruption of its usual pattern—are
diYcult to interpret. Although these facts may represent a
primary, albeit variable developmental dysplasia, they
could alternatively be the consequence of early neuronal
degeneration of an initially normal nucleus, as appears to
be the case in the “Staggerer” mutant mouse [65]. A striking polymorphism of olivary morphology is also found in
other developmental disorders such as dentate-olivary dysplasia [34].
While concluding this section, we postulate that degeneration of Purkinjé cells, ponto-cerebellar neurons and possibly dentate nucleus cells are direct consequences of the
gene mutation, although we are fully aware that either
mechanism or sequence of the multiple developmental
anomalies cannot be ascertained conclusively by any type
of post-mortem study of the human CNS.
Designation of a candidate mutant gene as the cause
of any type of congenital PCH depends either on human
linkage data or on the study of mutant genes in the mouse
with similar neurodevelopmental defects [15, 61]. Present
genetic studies in humans have not yet characterized any
signiWcant linkage to a chromosomal site or any potentially
causal gene in congenital PCH. Linkage to chromosome 7
was found only in a generalized developmental CNS anomaly in siblings in whom morphologic criteria of congenital
PCH have not been formally documented [51].
In reviewing the morphologic defects in several strains
of mutant mice with both cerebellar and cerebral malformations, we found that developmental anomalies in the
Pax6sey/Pax6sey mutant mouse [23, 58] including absence
of the claustrum, dysgenesis of the insular cortex, defective
migration of neocortical neurons, poor foliation and cytocortical anomalies in the cerebellum, and disruption of
ponto-cerebellar neurons, were strikingly similar to the
ones found in our patients, absence of eye changes notwithstanding. However, our cytoimmunochemical studies using
a Pax6 antibody showed in the cerebellum and cerebral cortex of our patients and in controls, similar staining intensity
and pattern prompting the conclusion of similar Pax6 gene
expression in both.
The reeler mouse [33] and other recently described
mutant mice also display developmental defects in both the
rhombencephalon and the cerebral cortex. This is the case
of the dreher mutant mouse (drJ) due to a mutation in the
Lmx1a gene [18, 25, 39], and of the developmental defect
produced by a mutation in the Lhx2 gene [8, 41]. The pallial changes in murine mutants of the homeobox transcription
123
398
factors Emx1 and Emx2 [10, 55] diVer from the ones
observed in our patients. Moreover, in the latter type of
mutant mice, cerebellar defects are lacking. As the phenotypic expression diVers markedly from the dysgenesis of
cerebral cortex and cerebellum documented here, the candidate genes cited are unlikely orthologs of the gene causing
the type of congenital PCH at hand. However, careful comparison of the neuropathological consequences in either
newly discovered or genetically engineered murine mutants
with the CNS Wndings in patients with congenital PCH will
continue to be helpful in sorting primary from secondary
roles of speciWc cell lineages in cerebellar development.
Congenital PCH is probably not as rare an autosomal
recessive defect in humans as assumed from the literature
data, because familial occurrences are largely overrepresented particularly among the patient reports dating from
the era preceding eVective neuro-imaging (Tables 1, 2, 3).
More reports even of isolated cases with congenital PCH
are much needed provided they include complete neuropathology documentation. Possible complacency in the
neonatal intensive care units by mere reliance on ultrasonography-based diagnosis in early succumbing infants may
be a challenge to the goal of elucidating the monogenic
causes of abnormal cerebellar development. Hopefully, this
report on only one of several types of PCH may expedite
successful molecular steps in the investigations for achieving that goal.
Acknowledgements The authors thank the family for the permission
granted to study the patients and for their persevering conWdence in
them. They express gratitude to Dr. H. Zoghbi, Department of Molecular and Human Genetics, to Dr. D. Armstrong, Department of Neuropathology, Baylor College of Medicine, Houston, Texas, to Dr. JJ
Hauw and Dr. Ch. Duyckaerts, Department of Neuropathology, Hôpital de la Salpétrière, Paris, to Dr. M. Wassef, Directeur de Recherche
CNRS, Paris, France and to Dr. Ph. Evrard, Department of Pediatric
Neurology, Hôpital R. Debré, Paris and Dr. C. Verney, Inserm U 676,
Hôpital R. Debré, for valuable advice and/or critical review of the manuscript. Thanks go to Dr. V. Meersschaut and to Mrs. M-L. Duyts,
Department of Radiology, Ghent University Hospital, for the comparative neuroimaging and excellent photographic recording respectively.
The authors owe much gratitude to Mr. L. Draon, Department of Child
Neurology, Hôpital R. Debré, Paris, for expert photographic and digital production skills applied to all illustrations. Also, the dedication and
careful secretarial assistance of Mrs. A. Gailly, Paris and of Mrs.
K. Buchanan, Greenwood Genetic Center (GGC), Greenwood, South
Carolina, deserve authors’ sincere acknowledgement. JGL expresses
gratitude for the hospitality oVered by the Department of Molecular
and Human Genetics, Houston, Texas and by the GGC during his
recurrent episodes as a visiting scholar.
References
1. Albrecht S, Schneider MC, Belmont J, Armstrong DL (1993) Fatal
infantile encephalopathy with olivopontocerebellar hypoplasia
and micrencephaly. Report of three siblings. Acta Neuropathol
(Berl) 85:394–399
123
Acta Neuropathol (2007) 114:387–399
2. Barbot C, Carneiro G, Melo J (1997) Pontocerebellar hypoplasia
with microcephaly and dyskinesia: report of two cases. Dev Med
Child Neurol 39:554–557
3. Barth PG, Vrensen GFJM, Uylings HBM, Oorthuys JW, Stam FC
(1990) Inherited syndrome of microcephaly, dyskinesia and pontocerebellar hypoplasia: a systemic atrophy with early onset.
J Neuro Sci 97:25–42
4. Barth PG (1993) Pontocerebellar hypoplasias. An overview of a
group of inherited neurodegenerative disorders with fetal onset.
Brain Dev 15:411–422
5. Barth PG, Blennow G, Lenard H-G, Begeer JH, van der Kley JM,
Hanefeld F, Peters AC, Valk J (1995) The syndrome of autosomal
recessive pontocerebellar hypoplasia, microcephaly and extrapyramidal dyskinesia (pontocerebellar hypoplasia type 2): compiled
data from ten pedigrees. Neurology 45:311–317
6. Barth PG (2000) Pontocerebellar hypoplasia- how many types?
Eur J Paediatr Neurol 4:161–162
7. Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR,
Guo Q, Matzuk MM, Zoghbi HY (1997) Math 1 is essential for
genesis of cerebellar granule neurons. Nature 390:169–172
8. Bertuzzi S, Porter FD, Pitts A, Kumar M, Agulnik A, Wassif C,
Westphal H (1999) Characterization of Lhx9, a novel LIM/homeobox gene expressed by the pioneer neurons in the mouse cerebral
cortex. Mech Dev 81:193–198
9. Biemond A (1955) Hypoplasia ponto-neocerebellaris with malformation of the dentate nucleus. Folia Psychiatr Neurol Neurochir
Ned 58:2–7
10. Bishop KM, Rubinstein GL, O’Leary DD (2002) Distinct actions
of Emx 1, Emx 2, and Pax 6 in regulating speciWcation of areas in
the developing neocortex. J Neurosci 22:7627–7638
11. Brun R (1917) Zur Kenntnis der Bildungsfehler des Kleinhirns.
Schweiz Arch Neurol Psychiatr 1:61–123
12. Brun R (1918a) Zur Kenntnis der Bildungsfehler des Kleinhirns.
Schweiz Arch Neurol Psychiatr 2:48–105
13. Brun R (1918b) Zur Kenntnis der Bildungsfehler des Kleinhirns.
Schweiz Arch Neurol Psychiatr 3:13–88
14. Chavez-Vischer V, Pizzolato GP, Hanquinet S, Maret A, Bottani
A, Haenggeli CA (2000) Early fatal pontocerebellar hypoplasia in
premature twin sisters. Eur J Paediatr Neurol 4:171–176
15. Chizhikov V, Millen KJ (2003) Development and malformations
of the cerebellum in mice. Mol Genet Metab 80:54–65
16. Chou SM, Gilbert EF, Chun RW, Laxova R, TuZi GA, SuWt RL,
Krassinot N (1990) Infantile olivopontocerebellar atrophy with
spinal muscular atrophy (infantile OPCA+ SMA). Clin Neuropathol 9:21–31
17. Coppola G, Muras I, Pascotto A (2000) Pontocerebellar hypoplasia 2 (PCH2): report of two siblings. Brain Dev 22:188–192
18. Costa C, Harding B, Copp AJ (2001) Neuronal migration defects
in the dreher (Mlx1a) mutant mouse: role of disorders of the glial
limiting membrane. Cereb Cortex 6:498–505
19. De Bergeyck V, Naerhayzen B, GoVinet AM, Lambert de Rouvroit C (1998) A panel of monoclonal antibodies against Reelin,
the extracellular matrix protein defective in Reeler mutant mice.
J Neurosci Methods 82:17–24
20. De Koning TJ, De Vries LS, Groenendaal F, Ruitenbeek W, Jansen
GH, Poll-Thé BT, Barth PG (1999) Pontocerebellar hypoplasia
associated with respiratory-chain defects. Neuropediatrics 30:93–95
21. De Leon GA, Grover WD, D’Cruz CA (1984) Amyotrophic cerebellar hypoplasia. A speciWc form of infantile spinal atrophy. Acta
Neuropathol (Berl) 63:282–286
22. Dubowitz V, Daniels RJ, Davies KE (1995) Olivopontocerebellar
hypoplasia with anterior horn cell involvement (SMA) does not
localize to chromosome 5q. Neuromuscul Disord 5:25–29
23. Engelkamp D, Rashbass P, Seawright A, Van Heyningen V (1999)
Role of Pax 6 in development of the cerebellar system. Development 126:3585–3596
Acta Neuropathol (2007) 114:387–399
24. Evrard Ph, Lyon G, Gadisseux JF (1984) Le développement prénatal
du système nerveux et ses perturbations. Progrès Neonatol 4:71–85
25. Failli V, Bachy I, Retaux S (2002) Expression of the LIM-homeodomain gene Lmx1a (dreher) during development of the mouse
nervous system. Mech Dev 118:225–228
26. FilimonoV IN (1966) The claustrum, its origin and development.
J Hirnforsch 8:503–528
27. Gadisseux JF, Rodriguez J, Lyon G (1984) Pontocerebellar
hypoplasia. A probable consequence of prenatal destruction of the
pontine nuclei and a possible role of phenytoin intoxication.
Clin Neuropathol 3:160–167
28. Görgen-Pauli U, Sperner J, Reiss I, Gehl HB, Reusche E (1999)
Familial pontocerebellar hypoplasia type 1 with anterior horn cell
disease. Eur J Paediatr Neurol 3:33–38
29. Goutières F, Aicardi J, Farkas E (1977) Anterior horn cell disease
associated with pontocerebellar hypoplasia in infants. J Neurol
Neurosurg Psychiatr 40:370–378
30. Grellner W, Rohde K, Wilske J (2000) Fatal outcome in a case of
pontocerebellar hypoplasia type 2. Forensic Sci Int 113:165–172
31. Gross H, Kaltenbäck E (1959) Über eine kombinierte progressive
pontocerebellare systematrophie bei einem kleinkind. Dtsch Z
Nervenheilkd 179:388–400
32. Gudovi R, Marinkovi R, Aleksi S (1987) The development of the
dentate nucleus in man. Anat Anz Iena 163:233–238
33. Hamburgh M (1963) Analysis of the postnatal developmental
eVects of « Reeler », a neurological mutation in mice. A study in
developmental genetics. Dev Biol 19:165–185
34. Harding BN, Boyd SG (1991) Intractable seizures from infancy
can be associated with dentate-olivary dysplasia. J Neurol Sci
104:157–165
35. Hashimoto K, Takeuchi Y, Kida Y, Hasegawa H, Kantake M,
Sasaki A, Asanuma K, Isumi H, Takashima S (1998) Three
siblings of fatal infantile encephalopathy with olivopontocerebellar
hypoplasia and microcephaly. Brain Dev 20:169–174
36. Kamoshita S, Takei Y, Miyao M, Yanagisawa M, Kobayashi S,
Saito K (1990) Pontocerebellar hypoplasia associated with infantile motor neuron disease (Norman’s disease). Pediatr Pathol
10:133–142
37. Kawagoe T, Jacob H (1986) Neocerebellar hypoplasia with systemic
combined olivopontodentatal degeneration in a 9-day-old baby: contribution to the problem of relations between malformation and systemic degeneration in early life. Clin Neuropathol 5:203–208
38. Lyon G (1995) Congenital malformation of the brain. In: Levene
MI, Lilford RJ (eds) Fetal and neonatal neurology and surgery,
2nd edn. Churchill Livingstone, London, pp 193–214
39. Millonig JH, Millen KJ, Hatten ME (2000) The mouse Dreher
gene Lmx1a controls formation of the roof plate in the vertebrate
CNS. Nature 403:764–769
40. Mitra AG, Salvino AR, Spence JE (1999) Prenatal diagnosis of
fatal infantile olivopontocerebellar hypoplasia syndrome. Prenat
Diagn 19:375–378
41. Monuki ES, Porter FD, Walsch CA (2001) Patterning of the dorsal
telencephalon and cerebral cortex by a roof plate-Lhx2 pathway.
Neuron 32:591–604
42. Muntoni F, Goodwin F, Sewry C, Cox P, Cowan F, Airaksinen E,
Patel S, Ignatius J, Dubowitz V (1999) Clinical spectrum and diagnostic diYculties of infantile pontocerebellar hypoplasia type 1.
Neuropediatrics 30:243–248
43. Norman RM (1940) Primary degeneration of the granular layer of
the cerebellum: an unusual form of familial cerebellar atrophy
occurring in early life. Brain 63:365–379
44. Norman RM (1961) Cerebellar hypoplasia in Werdnig-HoVmann
disease. Arch Dis Child 36:96–101
45. Norman RM, Kay JM (1965) Cerebello-thalamo-spinal degeneration in infancy: an unusual variant of Werdnig-HoVmann disease.
Arch Dis Child 40:370–378
399
46. Parisi MA, Dobyns WB (2003) Human malformations of the midbrain and hindbrain: review and proposed classiWcation scheme.
Mol Genet Metab 80:36–53
47. Park SH, Becker-Catania S, Gatti RA, Crandall BF, Emelin JK,
Vinters HV (1998) Congenital olivopontocerebellar atrophy: report of two siblings with paleo- and neocerebellar atrophy. Acta
Neuropathol (Berl) 96:315–321
48. Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D (2006)
Severe, fetal-onset form of olivopontocereballar hypoplasia in
three sibs: PCH Type 5? Am J Med Genet 140A:594–603
49. PeiVer J, PfeiVer RA (1977) Hypoplasia pontocerebellaris. J Neurol 215:241–251
50. Pittella JE, Nogueira AM (1990) Pontocerebellar hypoplasia: report of a case in a newborn and review of the literature. Clin Neuropathol 9:33–38
51. Rajab A, Mochida GH, Hill A, Ganesch V, Bodell A, Riaz A,
Grant PE, Shugart YY, Walsh CA (2003) A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurol
60:1664–1667
52. Robain O, Dulac O, Lejeune J (1987) Cerebellar hemispheric
agenesis. Acta Neuropathol (Berl) 74:202–206
53. Rudnik-Schöneborn S, Wirth B, Röhrig D, Saule H, Zerres K
(1995) Exclusion of the gene locus for spinal muscular atrophy on
chromosome 5q in a family with infantile olivopontocerebellar
atrophy (OPCA) and anterior horn cell degeneration. Neuromuscul Disord 5:19–23
54. Scherer HJ (1933) Beiträge zur pathologischen Anatomie des
Kleinhirns. III. Genuine Kleinhirnatrophien. Ztschr Ges Neurol
Psychiatr Orig 145:335–349
55. Shinozaki K, Yoshida M, Nakamura M, Aizawa S, Suda Y (2004)
Emx 1 and Emx 2 cooperate in initial phase of archipallium development. Mech Dev 121:475–489
56. Simonati A, Dalla Bernardina B, Colombari R, Rizzuto N (1997)
Pontocerebellar hypoplasia with dystonia: clinicopathological
Wndings in a sporadic case. Childs Nerv Syst 13:642–647
57. Sotelo C, Mariani J (1999) Research strategies for the analysis of
neurological mutants in mice. In: Crassio WE, Gerlai RT (eds)
Handbook of molecular genetic techniques for brain and behavior
research. Techniques in the behavioral and neural sciences, vol 13.
Elsevier Science, Amsterdam, pp 132–146
58. Stoykova A, Treichel D, Hallonet M, Gruss P (2000) Pax 6 modulates the dorsoventral patterning of the mammalian telencephalon.
J Neurosci 20:8042–8050
59. Uhl M, Pawlik H, Laubenberger J, Darge K, Baborie A, Korinthenberg R, Langer M (1998) MR Wndings in pontocerebellar
hypoplasia. Pediatr Radiol 28:547–555
60. Vossbeck S, Scheuerle A, Bechinger D, Pohlandt F (1997)
Olivopontocerebral hypoplasia—case report of a neurodegenerative
disease manifesting at birth with fatal outcome. Klin Pädiat
209:137–140
61. Wang VY, Zoghbi HY (2001) Genetic regulation of cerebellar
development. Nat Rev Neurosci 2:484–491
62. Wang VY, Rose MF, Zoghbi HY (2005) Math 1 expression redeWnes the rhombic lip derivatives and reveals novel lineages within
the brain stem and cerebellum. Neuron 48:31–43
63. Weinberg AG, Kirkpatrick JP (1975) Cerebellar hypoplasia in
Werdnig-HoVmann disease. Dev Med Child Neurol 17:511–516
64. Young ID, McKeever PA, Squier MV, Grant J (1992) Lethal
olivopontoneocerebellar hypoplasia with dysmorphic features in
sibs. J Med Genet 29:733–735
65. Zanjani HS, Herrup K, Guastavino JM, Delaye-Bouchaud N,
Mariani J (1994) Development of the inferior olivary nucleus in
Staggerer mutant mice. Dev Brain Res 82:18–28
66. Zelnik N, Dobyns WB, Forem SL, Kolodny EH (1996) Congenital
pontocerebellar atrophy in three patients: clinical, radiologic, and
etiologic considerations. Neuroradiology 38:684–687
123