Pontocerebellar hypoplasia (PCH) represents a clinically and genetically heterogeneous group of genetic, autosomal recessive inherited neurodegenerative diseases, most of which start prenatally and therefore usually show early clinical symptoms. The leading symptoms are a severe motor and cognitive developmental disorder, often with muscle hypotonia, and a limited life expectancy. Despite cerebellar hypoplasia, corresponding symptoms such as ataxia hardly ever occur. Initially, mainly structures below the tentorium cerebelli (cerebellum and pons) are affected, but the cerebral cortex and/or basal ganglia may also be affected by atrophy. Neuroradiology shows a variable, but usually severe hypoplasia or atrophy of the cerebellum, which is especially prominent in the cerebellar hemispheres and the pons.
There are now 18 genes listed in the OMIM database whose mutations cause various subtypes of PCH. Most of the gene products are involved with RNA processing or RNA translation. In accordance with the now numerous genetic causes, the clinical symptoms have also expanded beyond the aforementioned leading symptoms. Based on the clinical symptoms and genetic causes, 12 subtypes are currently distinguished (as of 2019): PCH1 (PCH1 A to D), PCH2 (PCH2 A to F), PCH3 to 12.
The subgroups PCH1 and PCH2 were the first to be documented, and according to clinical criteria they differ in the degeneration of the anterior horn cells, with the result that PCH1 presents with muscle atrophy. Clinically, the leading symptom in patients with classic PCH1 is pronounced muscle hypotonia resulting in muscle atrophy comparable to other spinal muscular atrophies, as well as a severe global developmental disorder, a central visual impairment, swallowing and eating disorders, occasional seizures and microcephaly in some patients. Life expectancy is usually limited. PCH1A is caused by mutations in the VKRI gene, type 1B by mutations in the EXOSC3 gene. In type 2 there is a severe motor development disorder and almost no cognitive development. Furthermore, extrapyramidal movement disorders and progressive microcephaly occur. The other previously defined types 3 to 12 show different neurological symptoms of varying degrees of severity, with and without progression and partly associated brain malformations such as beam deficiency.
van Dijk et al. 2018 Orphanet J Rare Dis 13:92 / Rudnik-Schöneborn et al. 2014, Am J Med Genet C Semin Med Genet. 2014 166C(2):173 / Bierhals et al. 2013 Eur J of Med Genet 56:325 / Maricich et al. 2011 J of Child Neur 26:288