Pontocerebellar hypoplasia


Pontocerebellar hypoplasia 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. 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.
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.

Causes

Pontocerebellar hypoplasia is caused by mutations in genes including VRK1 ; TSEN2, TSEN34 ; RARS2 ; and TSEN54. 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 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:
TypeOMIMGeneLocusDistinctive featuresAlternate names
PCH1AVRK114q32Infantile onset anterior horn cell degeneration resulting in progressive muscle atrophy; resembles infantile spinal muscular atrophySpinal muscular atrophy with pontocerebellar hypoplasia
PCH1BEXOSC39p13.2Cerebellar and spinal motor neuron degeneration beginning at birth and resulting in decreased body tone, respiratory insufficiency, muscle atrophy, progressive microcephaly and global developmental delay
PCH2ATSEN5417q25.1Dyskinetic movements, seizures Volendam neurodegenerative disease
PCH2BTSEN23p25.2
PCH2CTSEN3419q13.42
PCH2DSEPSECS4p15.2Progressive cerebello-cerebral atrophy
PCH2EVPS5317p13.3Profound mental retardation, progressive microcephaly, spasticity, and early-onset epilepsy
PCH2FTSEN151q25.3Variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity
PCH3PCLO7q11–q21Seizures, short stature, optic atrophy, progressive microcephaly, severe developmental delay; described only in a handful of cases.CLAM-PCH, cerebellar atrophy with progressive microcephaly
PCH4TSEN5417q25.1Severe 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
PCH5TSEN5417q25.1Severe prenatal form, described in one familyOlivopontocerebellar hypoplasia
PCH6RARS26q15Severe encephalopathy in the newborn with hypotonia, and inconstantly: intractable seizures, edema, increased lactate blood levels, mitochondrial respiratory chain defects
PCH7TOE11p34.1Hypotonia, apneic episodes, seizures, vanishing testis
PCH8CHMP1A16q24.3Severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects
PCH9AMPD21p13.3Severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination
PCH10CLP111q12.1Severely 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.

Treatment

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.