Pontocerebellar hypoplasia

Pontocerebellar hypoplasia
Other namesNon-syndromic pontocerebellar hypoplasia
Autosomal recessive - en.svg
Pontocerebellar hypoplasia is inherited in an autosomal recessive manner
SpecialtyNeurology
TreatmentThere is no known treatment.

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

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]

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

Pontocerebellar hypoplasia is caused by mutations in genes including 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

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]

TypeOMIMGeneLocusDistinctive featuresAlternate names
PCH1A607596VRK114q32Infantile onset anterior horn cell degeneration resulting in progressive muscle atrophy; resembles infantile spinal muscular atrophy[5]Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH)
PCH1B614678EXOSC39p13.2Cerebellar 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]
PCH2A277470TSEN5417q25.1Dyskinetic movements, seizures (frequently)Volendam neurodegenerative disease
PCH2B612389TSEN23p25.2
PCH2C612390TSEN3419q13.42
PCH2D613811SEPSECS4p15.2Progressive cerebello-cerebral atrophy (PCCA)
PCH2E615851VPS5317p13.3Profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy[7]
PCH2F617026TSEN151q25.3Variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity
PCH3608027PCLO7q11–q21Seizures, short stature, optic atrophy, progressive microcephaly, severe developmental delay; described only in a handful of cases.[8]CLAM-PCH, cerebellar atrophy with progressive microcephaly
PCH4225753TSEN5417q25.1Severe 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
PCH5610204TSEN5417q25.1Severe prenatal form, described in one familyOlivopontocerebellar hypoplasia (OPCH)
PCH6611523RARS26q15Severe encephalopathy in the newborn with hypotonia, and inconstantly: intractable seizures, edema, increased lactate blood levels, mitochondrial respiratory chain defects
PCH7614969TOE11p34.1Hypotonia, apneic episodes, seizures, vanishing testis[9][10]
PCH8614961CHMP1A16q24.3Severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects[11]
PCH9615809AMPD21p13.3Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination[12]
PCH10615803CLP111q12.1Severely 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

  • Mental retardation and microcephaly with pontine and cerebellar hypoplasia

References

  1. ^ 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.
  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. ^ 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.
  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. ^ 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.
  10. ^ 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.
  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. ^ 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

Classification
External resources

Media files used on this page

Pontocerebellar hypoplasia MRI 1750-1172-7-18-4-l.jpg
Author/Creator: Lydie Burglen, Sandra Chantot-Bastaraud, Catherine Garel, Mathieu Milh5, Renaud Touraine, Ginevra Zanni, Florence Petit, Alexandra Afenjar, Cyril Goizet, Sabina Barresi, Aurélie Coussement, Christine Ioos, Leila Lazaro, Sylvie Joriot, Isabelle Desguerre, Didier Lacombe, Vincent des Portes, Enrico Bertini, Jean-Pierre Siffroi, Thierry Billette de Villemeur and Diana Rodriguez. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet Journal of Rare Diseases 2012, 7:18 doi:10.1186/1750-1172-7-18, Licence: CC BY 2.0
MRI examples of patients with pontocerebellar hypoplasia. A. Sagittal images showing spectrum of vermis and pons hypoplasia. Number represents the number of the patient. Figure 9 shows MRI of patient 9 at age 4 months and figure 9b patient 9 at age 11 years. Note that in all patients, the pons is very small but has a relative sparing of his buldging, mainly in its superior part. Hypoplasia predominates at the inferior part of the pons. Vermis hypoplasia is very variable, severe in patient 13, very slight in patient 10-11-12 and predominates at the inferior part. V4 is open in most cases. B. Coronal images showing spectrum of cerebellar hemispheric hypoplasia. Number represents the number of the patient. 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 "dragonfly", the protruding vermis being the body of the dragonfly and the hemispheres, the wings. There is no progression of the lesions between successive MRI in patient 9.
Autosomal recessive - en.svg
Author/Creator: Domaina, Kashmiri and SUM1, Licence: CC BY-SA 3.0
Autosomal recessive inheritance (English version)
Pontocerebellar hypoplasia Orphanet 1750-1172-7-18-3-l.jpg
Author/Creator: Lydie Burglen, Sandra Chantot-Bastaraud, Catherine Garel, Mathieu Milh5, Renaud Touraine, Ginevra Zanni, Florence Petit, Alexandra Afenjar, Cyril Goizet, Sabina Barresi, Aurélie Coussement, Christine Ioos, Leila Lazaro, Sylvie Joriot, Isabelle Desguerre, Didier Lacombe, Vincent des Portes, Enrico Bertini, Jean-Pierre Siffroi, Thierry Billette de Villemeur and Diana Rodriguez. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet Journal of Rare Diseases 2012, 7:18 doi:10.1186/1750-1172-7-18, Licence: CC BY 2.0
Facial features of patients with pontocerebellar hypoplasia with 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, protuding maxilla, in the older patients.