Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare

neurodegenerative disorders A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

caused by genetic

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s and characterised by progressive

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

of various parts of the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

such as the

cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...

(particularly the

pons The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum. The pons is also called the pons Varolii ("bridge of Va ...

). Where known, these disorders are inherited in an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

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 Developmental disability is a diverse group of chronic conditions, comprising mental or physical impairments that arise before adulthood. Developmental disabilities cause individuals living with them many difficulties in certain areas of life, espe ...

. The following values seem to be aberrant in children with CASK gene defects: lactate,

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...

, 2-ketoglutaric acid,

adipic acid Adipic acid or hexanedioic acid is the organic compound with the formula (CH2)4(COOH)2. From an industrial perspective, it is the most important dicarboxylic acid: about 2.5 billion kilograms of this white crystalline powder are produced annuall ...

, 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 Serine/threonine-protein kinase VRK1 is an enzyme that in humans is encoded by the ''VRK1'' gene. This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. This gene is widely expressed in human ...

(PCH1);

TSEN2 tRNA-splicing endonuclease subunit Sen2 is an enzyme that in humans is encoded by the ''TSEN2'' gene. tRNA splicing is a fundamental process required for cell growth and division. SEN2 is a subunit of the tRNA splicing endonuclease, which catalyz ...

TSEN34 tRNA-splicing endonuclease subunit Sen34 is an enzyme that in humans is encoded by the ''TSEN34'' gene. tRNA splicing is a fundamental process required for cell growth and division. SEN34 is a subunit of the tRNA splicing endonuclease, which cata ...

(PCH2);

RARS2 RARS is an acronym for Robot Auto Racing Simulator. It is an open source 3D racing simulator Simulated racing or racing simulation, commonly known as simply sim racing, are the collective terms for racing game software that attempts to accu ...

(PCH6); and

TSEN54 TRNA splicing endonuclease subunit 54 is a protein that in humans is encoded by the TSEN54 gene. Function This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The c ...

(PCH2 and PCH4). The genes associated with PCH3 and PCH5 have not yet been identified. The mutated genes in PCH are

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

, 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 A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

) and for properly processing

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

, 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: Pontine and cerebellar hypoplasia is also observed in certain phenotypes of

X-linked mental retardation X-linked intellectual disability refers to medical disorders associated with X-linked recessive inheritance that result in intellectual disability. As with most X-linked disorders, males are more heavily affected than females. Females with one aff ...

– so called MICPCH. Another gene that has been associated with this condition is coenzyme A synthase (

COASY Bifunctional coenzyme A synthase is an enzyme that in mammals is encoded by the ''COASY'' gene that catalyses the synthesis of coenzyme A from 4'-phosphopantetheine. Function COASY is an enzyme that catalyzes the last two steps in the synthesis ...

).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

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.

References

External links

{{CNS diseases of the nervous system Neurodegenerative disorders Neurogenetic disorders Autosomal recessive disorders Rare syndromes