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). Where known, these disorders are inherited in an autosomal recessive fashion. There is no known cure for PCH.

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.

Causes 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.

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.

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.

Diagnosis Classification

Pontocerebellar hypoplasia is classified as follows:

Type OMIM Gene Locus Distinctive features Alternate names PCH1A VRK1 14q32 Infantile onset anterior horn cell degeneration resulting in progressive muscle atrophy; resembles infantile spinal muscular atrophy Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) PCH1B 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 PCH2A TSEN54 17q25.1 Dyskinetic movements, seizures (frequently) Volendam neurodegenerative disease PCH2B TSEN2 3p25.2 PCH2C TSEN34 19q13.42 PCH2D SEPSECS 4p15.2 Progressive cerebello-cerebral atrophy (PCCA) PCH2E VPS53 17p13.3 Profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsyPCH2FTSEN151q25.3Variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity PCH3 PCLO 7q11–q21 Seizures, short stature, optic atrophy, progressive microcephaly, severe developmental delay; described only in a handful of cases. CLAM-PCH, cerebellar atrophy with progressive microcephaly PCH4 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 TSEN54 17q25.1 Severe prenatal form, described in one family Olivopontocerebellar hypoplasia (OPCH) PCH6 RARS2 6q15 Severe encephalopathy in the newborn with hypotonia, and inconstantly: intractable seizures, edema, increased lactate blood levels, mitochondrial respiratory chain defects PCH7 TOE1 1p34.1 Hypotonia, apneic episodes, seizures, vanishing testis PCH8 CHMP1A 16q24.3 Severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects PCH9 AMPD2 1p13.3 Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination PCH10 CLP1 11q12.1 Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination

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).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

Outcomes The severity of different forms of PCH varies, but many children inheriting the mutated gene responsible do not survive infancy or childhood; nevertheless, some individuals born with PCH have reached adulthood.

See also Mental retardation and microcephaly with pontine and cerebellar hypoplasia

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