Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation

Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only 15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%.

In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next-generation sequencing and subsequent Sanger sequencing of SORD.

Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals.

This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.