Škarica Mario, Acsadi Gyula, Živković Sasha A
Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA.
Division of Neurology, Connecticut Children's Medical Center, St. Hartford, CT 06106, USA.
Genes (Basel). 2025 May 15;16(5):585. doi: 10.3390/genes16050585.
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.
脑桥小脑发育不全是一种罕见的神经退行性综合征，其特征为脑桥和小脑严重发育不全或萎缩，可能与其他脑畸形、小头畸形、视神经萎缩、肌张力障碍、共济失调和神经肌肉疾病相关。目前，除脑桥和小脑发育不全外，根据临床表现以及独特的放射学和生化特征，已鉴别出17种脑桥小脑发育不全变体。PCH1被定义为与脊髓前角变性相关并伴有肌无力和肌张力减退的脑桥小脑发育不全变体，与VRK1、EXOSC3、EXOSC8、EXOSC9和SLC25A46基因的隐性变体相关。神经肌肉表现临床上可能表现为肌萎缩侧索硬化症（ALS）、运动神经病（HMN）或神经元病（非5q脊髓性肌萎缩症；SMA）或感觉运动性多发性神经病（HMSN）。与PCH1相关基因的生理功能包括RNA代谢调节、线粒体分裂和神经元迁移。总体而言，与PCH1基因变体相关的复杂表型范围从脑桥小脑发育不全及相关神经发育障碍合并神经肌肉疾病到孤立的神经肌肉疾病，其预后各不相同，孤立的神经肌肉疾病通常起病较晚，预后较好。对脑桥小脑发育不全的发病机制及其与运动神经元病和周围神经病的关联的进一步了解，可能为我们提供有价值的见解，并为神经退行性疾病带来潜在的新治疗靶点。
