Group of neurodegenerative disorders
Medical condition
Pontocerebellar hypoplasia
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Other names
| Non-syndromic pontocerebellar hypoplasia
|
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Pontocerebellar hypoplasia is inherited in an autosomal recessive manner
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Specialty
| Neurology
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Treatment
| Unknown
|
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Pontocerebellar hypoplasia
(
PCH
) is a heterogeneous group of rare
neurodegenerative disorders
caused by genetic
mutations
and characterised by progressive
atrophy
of various parts of the
brain
such as the
cerebellum
or
brainstem
(particularly the
pons
).
[1]
Where known, these disorders are inherited in an
autosomal recessive
fashion. There is no known cure for PCH.
[2]
Signs and symptoms
[
edit
]
There are different signs and symptoms for different forms of pontocerebellar hypoplasia, at least six of which have been described by researchers. All forms involve abnormal development of the brain, leading to slow development, movement problems, and
intellectual impairment
.
[2]
-
Facial features
(dysmorphism) of patients with one form of pontocerebellar hypoplasia due to mutations in the CASK gene. A and B: patient at 1 year (A) and 4 years (B). C: patient, 18 months. D: patient, 13 years. E: patient, 13 years. F: patient, 12 years. Note minor facial dysmorphism: round face, small chin, well-drawn eyebrows in the younger patients; longer face, high and large nasal bridge, long nose, protruding
maxilla
, in the older patients.
-
Magnetic resonance imaging
(MRI) examples of patients with pontocerebellar hypoplasia with
CASK
mutations. A.
Sagittal
images showing different degrees of
hypoplasia
(incomplete formation) of the
pons
and
vermis
(parts of the brain). Numbers represent different patients. Figure 9a shows an MRI of a patient at age 4 months and figure 9b shows the same patient at age 11 years. There is no progression of the lesions between successive MRI in patient 9. Note that in all patients, the pons is very small but has a relative sparing of its bulging, mainly in its superior part. Hypoplasia predominates at the lower part of the pons. Vermis hypoplasia is very variable, severe in patient 13, very slight in patient 10-11-12 and also predominates at the inferior part. B.
Coronal
images showing varying degrees of
cerebellar
hemispheric
(one of two halves of a part of the brain) hypoplasia. Hemispheres are frequently asymmetric. Note that the vermis does not protrude from the hemispheres indicating similar involvement of the vermis and the hemispheres. This pattern is different from that of PCH2 in which the vermis is relatively spared leading to the classic image of a "dragonfly", the protruding vermis being the body of the dragonfly and the hemispheres, the wings.
The following values seem to be aberrant in children with
CASK gene
defects:
lactate
,
pyruvate
,
2-ketoglutaric acid
,
adipic acid
, and
suberic acid
which seems to support the thesis that CASK affects mitochondrial function.
[3]
Causes
[
edit
]
Pontocerebellar hypoplasia is caused by mutations in genes including Sepsecs gene,
VRK1
(PCH1);
TSEN2
,
TSEN34
(PCH2);
RARS2
(PCH6); and
TSEN54
(PCH2 and PCH4). The genes associated with PCH3 and PCH5 have not yet been identified.
[2]
The mutated genes in PCH are
autosomal
recessive
, which means that parents of an affected child each carry only one copy of the damaged gene. In each parent the other copy performs its proper function and they display no signs of PCH. A child inheriting two damaged copies of the gene will be affected by PCH.
[2]
Mechanism
[
edit
]
Mutations in the genes that cause PCH produce faults in the production of chemicals, usually enzymes, that are required for the development of nerve cells (
neurons
) and for properly processing
RNA
, which is needed for any cell to function normally. The exact mechanism by which PCH affects the development of the cerebellum and pons is not well understood.
[2]
Diagnosis
[
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]
Classification
[
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]
Pontocerebellar hypoplasia is classified as follows:
[4]
Type
|
OMIM
|
Gene
|
Locus
|
Distinctive features
|
Alternate names
|
PCH1A
|
607596
|
VRK1
|
14q32
|
Infantile onset
anterior horn
cell degeneration resulting in progressive
muscle atrophy
; resembles infantile
spinal muscular atrophy
[5]
|
Spinal muscular atrophy
with pontocerebellar hypoplasia (SMA-PCH)
|
PCH1B
|
614678
|
EXOSC3
|
9p13.2
|
Cerebellar and
spinal motor neuron
degeneration beginning at birth and resulting in
decreased body tone
,
respiratory insufficiency
, muscle atrophy, progressive
microcephaly
and global
developmental delay
[6]
|
|
PCH2A
|
277470
|
TSEN54
|
17q25.1
|
Dyskinetic movements,
seizures
(frequently)
|
Volendam neurodegenerative disease
|
PCH2B
|
612389
|
TSEN2
|
3p25.2
|
|
|
PCH2C
|
612390
|
TSEN34
|
19q13.42
|
|
|
PCH2D
|
613811
|
SEPSECS
|
4p15.2
|
|
Progressive cerebello-cerebral atrophy (PCCA)
|
PCH2E
|
615851
|
VPS53
|
17p13.3
|
Profound
mental retardation
, progressive
microcephaly
, spasticity, and early-onset
epilepsy
[7]
|
|
PCH2F
|
617026
|
TSEN15
|
1q25.3
|
Variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity
|
|
PCH3
|
608027
|
PCLO
|
7q11?q21
|
Seizures,
short stature
,
optic atrophy
, progressive
microcephaly
, severe
developmental delay
; described only in a handful of cases.
[8]
|
CLAM-PCH
,
cerebellar atrophy with progressive microcephaly
|
PCH4
|
225753
|
TSEN54
|
17q25.1
|
Severe prenatal form of PCH2 with
excess fluid in the amniotic sac
,
muscle contractures
,
brief involuntary muscle twitching
,
brief episodes without breathing
, and early death following birth
|
|
PCH5
|
610204
|
TSEN54
|
17q25.1
|
Severe prenatal form, described in one family
|
Olivopontocerebellar hypoplasia (OPCH)
|
PCH6
|
611523
|
RARS2
|
6q15
|
Severe
encephalopathy
in the newborn with
hypotonia
, and inconstantly: intractable seizures,
edema
, increased
lactate
blood levels,
mitochondrial respiratory chain defects
|
|
PCH7
|
614969
|
TOE1
|
1p34.1
|
Hypotonia
,
apneic
episodes, seizures,
vanishing testis
[9]
[10]
|
|
PCH8
|
614961
|
CHMP1A
|
16q24.3
|
Severe psychomotor retardation, abnormal movements,
hypotonia
, spasticity, and variable visual defects
[11]
|
|
PCH9
|
615809
|
AMPD2
|
1p13.3
|
Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin
corpus callosum
, and delayed
myelination
[12]
|
|
PCH10
|
615803
|
CLP1
|
11q12.1
|
Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination
[13]
|
|
Pontine and cerebellar hypoplasia is also observed in certain phenotypes of
X-linked mental retardation
? so called
MICPCH
.
Another gene that has been associated with this condition is coenzyme A synthase (
COASY
).
[14]
Treatment
[
edit
]
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.
(
December 2017
)
|
Outcomes
[
edit
]
The severity of different forms of PCH varies, but many children inheriting the mutated gene responsible do not survive infancy
[15]
or childhood; nevertheless, some individuals born with PCH have reached adulthood.
[2]
See also
[
edit
]
References
[
edit
]
- ^
Millen KJ, Gleeson JG (February 2008).
"Cerebellar development and disease"
.
Curr Opin Neurobiol
.
18
(1): 12?9.
doi
:
10.1016/j.conb.2008.05.010
.
PMC
2474776
.
PMID
18513948
.
- ^
a
b
c
d
e
f
"Pontocerebellar hypoplasia"
.
Genetics Home Reference
. U.S. National Library of Medicine. December 2009
. Retrieved
20 September
2014
.
- ^
Mukherjee, K; Slawson, JB; Christmann, BL; Griffith, LC (2014).
"Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry"
.
Frontiers in Molecular Neuroscience
.
7
: 58.
doi
:
10.3389/fnmol.2014.00058
.
PMC
4075472
.
PMID
25071438
.
- ^
Online Mendelian Inheritance in Man
(OMIM):
[1]
- ^
Online Mendelian Inheritance in Man
(OMIM):
607596
- ^
Online Mendelian Inheritance in Man
(OMIM):
614678
- ^
Online Mendelian Inheritance in Man
(OMIM):
615851
- ^
Online Mendelian Inheritance in Man
(OMIM):
608027
- ^
Anderson, C; Davies, JH; Lamont, L; Foulds, N (April 2011). "Early pontocerebellar hypoplasia with vanishing testes: A new syndrome?".
American Journal of Medical Genetics Part A
.
155A
(4): 667?72.
doi
:
10.1002/ajmg.a.33897
.
PMID
21594990
.
S2CID
37977323
.
- ^
Namavar, Y; Barth, PG; Poll-The, BT; Baas, F (2011).
"Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia"
.
Orphanet Journal of Rare Diseases
.
6
: 50.
doi
:
10.1186/1750-1172-6-50
.
PMC
3159098
.
PMID
21749694
.
- ^
Online Mendelian Inheritance in Man
(OMIM):
614961
- ^
Online Mendelian Inheritance in Man
(OMIM):
615809
- ^
Online Mendelian Inheritance in Man
(OMIM):
615803
- ^
van Dijk T, Ferdinandusse S, Ruiter JPN, Alders M, Mathijssen IB, Parboosingh JS, Innes AM, Meijers-Heijboer H, Poll-The BT, Bernier FP, Wanders RJA, Lamont RE, Baas F (2018) Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Eur J Hum Genet doi: 10.1038/s41431-018-0233-0
- ^
Basson MA, Wingate RJ (September 2013).
"Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences"
.
Front Neuroanat
.
7
: 29.
doi
:
10.3389/fnana.2013.00029
.
PMC
3759752
.
PMID
24027500
.
External links
[
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Classification
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External resources
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