Abstract

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have recently been found to be one of the most frequent causes of autosomal recessive axonal Charcot-Marie-Tooth (CMT2) and distal hereditary motor neuropathy (dHMN). This study was performed to explore the frequency of SORD mutations and correlations of the phenotypic-genetic spectrum in a relatively large Chinese cohort. In this study, we screened a cohort of 485 unrelated Chinese patients with hereditary neuropathy by using Sanger sequencing, next generation sequencing, or whole exome sequencing after PMP22 duplication was initially excluded. SORD mutation was identified in five out of 78 undiagnosed patients. Two individuals carried the previously reported homozygous c.757 delG (p.A253Qfs*27) variant, and three individuals carried the heterozygous c.757delG (p.A253Qfs*27) variant together with a second novel likely pathogenic variant, including c.731 C>T (p.P244L), c.776 C>T (p.A259V), or c.851T>C (p.L284P). The frequency of SORD variants was calculated to be 6.4% (5/78) in unclarified CMT2 and dHMN patients. All patients presented with distal weakness and atrophy in the lower limb, two of whom had minor clinical sensory abnormalities and small fiber neuropathy. Our study provides further information on the genotype and phenotype of patients with SORD mutations.

Highlights

  • Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies that share common characteristics of distal muscle wasting, sensory loss, and decreased deep tendon reflexes [1]

  • Numbness and episodic pain of the distal limb and a positive pinprick test were observed in patients 1 and 5; these two patients with minor sensory involvement were classified as having CMT2, and the other three cases were consistent with distal hereditary motor neuropathy (dHMN)

  • We identified four sorbitol dehydrogenase (SORD) variants from five unrelated patients in a cohort of 485 Chinese patients with hereditary neuropathy

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Summary

Introduction

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies that share common characteristics of distal muscle wasting, sensory loss, and decreased deep tendon reflexes [1]. CMT can be classified as demyelinating (CMT1) and axonal (CMT2) according to motor nerve conduction velocity (MCV) in the upper limb nerve. CMT is closely related to distal hereditary motor neuropathies (dHMNs), which manifest only as motor involvement with or without minor sensory involvement. Two disorders are sharing many causative genes (e.g., HSPB1, HSPB27, BSCL2, DCTN1) [2], and they represent a continuum from pure motor neuropathy to motor and sensory neuropathy [1]. To date, >100 genes have been identified to be related to hereditary neuropathies.

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