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Pontocerebellar Disorders
Introduction
Autosomal recessive pontocerebellar hypoplasias (PCHs) are a group of severe neurodegenerative disorders affecting the cerebellum and pons. This disease appears in fetal or neonatal life with subsequent pontocerebellar degeneration, progressive microcephaly, and atrophy of the cerebral cortex. Most affected individuals have profound motor and cognitive deficits. Life expectancy generally lasts into infancy or childhood, though there are reports of some individuals with PCH who live into adulthood. At the time of this publication, Online Mendelian Inheritance in Man cites 10 known PCH subtypes (PCH1-10).
Disorder
Definition
Individuals affected by PCH are typically diagnosed in the neonatal period because of profound motor and cognitive delay. The phenotype and life expectancy vary based on PCH subtype. However, most individuals with PCH share common clinical manifestations including profound motor and cognitive delay, movement disorders, epilepsy, hypotonia, feeding difficulties requiring gastrostomy, and respiratory distress.
Prevalence and Epidemiology
Autosomal recessive PCH is rare and the prevalence is unknown. Several genetically isolated communities with founder mutations are reported in the literature. One such founders' community in the Netherlands has a carrier frequency of PCH2 of 14.3%.
Etiology and Pathophysiology
PCH is inherited in an autosomal recessive manner. Several gene mutations have been isolated among individuals affected by PCH including TSEN54 , RARS2 , EXOSC3 , and PCLO . PCH2 is the most common PCH subtype and is caused by a mutation in TSEN54 ; other TSEN- related PCH disorders include PCH4 and 5. Of note, TSEN54 , TSEN2 , and TSEN34 encode the transfer ribonucleic acid (tRNA) splicing endonuclease complex subunits whereas RARS2 mutation, which is implicated in PCH6, encodes mitochondrial arginyl tRNA synthetase. However, it is unclear why the cerebellum and pons are most severely affected, unlike other structures that also rely heavily on protein synthesis.
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