Molecular analysis and clinical diversity of distal hereditary motor neuropathy

Background and purpose Distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders. The purpose of this study was to identify the genetic distribution of dHMNs in a large cohort of Chinese patients and provide insight into the underlying common pathophysiology of dHMNs. Methods Multi-gene panel testing or whole-exome sequencing was performed in 70 index patients with clinically diagnosed dHMN between January 2007 and December 2018. The clinical features, Charcot-Marie-Tooth (CMT) neuropathy scores and electrophysiological data at diagnosis were recorded. Results Twenty-four causative mutations were identified in 70 index patients with dHMN (34.3%). Mutation in the HSPB1 gene was the most common cause of dHMN. Some CMT genes (MPZ, SH3TC2, GDAP1) were found to be related to dHMN with minor sensory involvement. Patients with a dHMN-plus phenotype (distal motor neuropathy and additional neurological deficits) carried variants in genes related to hereditary spastic paraplegia, amyotrophic lateral sclerosis and spinal muscular atrophy (FUS, KIF5A, KIF1B, ZFYVE26, DNAJB2). Conclusions Comprehensive genetic testing of dHMN patients allows for identification of the pathogenic mutation in one-third of cases. Pure motor neuropathies and motor neuropathies with minor sensory involvement share many genes with CMT disease. Causes for dHMN-plus phenotypes overlap with motor neuron disease.