Pontocerebellar hypoplasia

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Not to be confused with Cerebellar hypoplasia.
Pontocerebellar hypoplasia
Other namesNon-syndromic pontocerebellar hypoplasia
Pontocerebellar hypoplasia is inherited in an autosomal recessive manner
SpecialtyNeurology
TreatmentUnknown

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare

autosomal recessive fashion. There is no known cure for PCH.[2]

Signs and symptoms

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]

  • 6 children's faces
    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.
  • 23 examples of Magnetic resonance imaging
    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

2-ketoglutaric acid, adipic acid, and suberic acid which seems to support the thesis that CASK affects mitochondrial function.[3]

Causes

Pontocerebellar hypoplasia is caused by mutations in genes including Sepsecs gene,

TSEN54 (PCH2 and PCH4). The genes associated with PCH3 and PCH5 have not yet been identified.[2]

The mutated genes in PCH are

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

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

Classification

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
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,
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
mitochondrial respiratory chain defects
PCH7 614969 TOE1 1p34.1
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
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

Outcomes

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

References

  1. PMID 18513948
    .
  2. ^ a b c d e f "Pontocerebellar hypoplasia". Genetics Home Reference. U.S. National Library of Medicine. December 2009. Retrieved 20 September 2014.
  3. PMID 25071438
    .
  4. ^ Online Mendelian Inheritance in Man (OMIM): [1]
  5. ^ Online Mendelian Inheritance in Man (OMIM): 607596
  6. ^ Online Mendelian Inheritance in Man (OMIM): 614678
  7. ^ Online Mendelian Inheritance in Man (OMIM): 615851
  8. ^ Online Mendelian Inheritance in Man (OMIM): 608027
  9. S2CID 37977323
    .
  10. PMID 21749694
    .
  11. ^ Online Mendelian Inheritance in Man (OMIM): 614961
  12. ^ Online Mendelian Inheritance in Man (OMIM): 615809
  13. ^ Online Mendelian Inheritance in Man (OMIM): 615803
  14. ^ 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
  15. PMID 24027500
    .

External links
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