# Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies

## TL;DR

Pontocerebellar hypoplasia type 1 is a rare neurodegenerative disorder linked to specific genetic variants and can present with a range of neurological symptoms.

## Contribution

This paper clarifies the genetic and clinical features of PCH1 and its association with neuromuscular disorders.

## Key findings

- PCH1 is associated with recessive variants in genes like VRK1 and EXOSC3.
- PCH1 can present with neuromuscular disorders resembling ALS or SMA.
- PCH1 gene functions include RNA metabolism and mitochondrial regulation.

## Abstract

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders.