Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy

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.

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

“…In this dHMN patient cohort, the rate of genetic diagnosis was achieved in 36.7% (33/90) of families through a comprehensive genetic investigation including the recently reported SORD and NOTCH2NLC genes. These rates are similar to the other published series screened by NGS techniques from worldwide, 3 , 6 , 7 , 8 , 9 , 10 which proved once again the genetic heterogeneity of dHMN, and a large part of dHMN patients still remain uncertain in genetic diagnosis.…”

“…With the progression of high‐throughput next‐generation sequence (NGS), more than 30 genes have been associated with dHMN representative of the great genetic heterogeneity 5 . Nevertheless, it still remains difficult and elusive to genetic diagnosis of dHMN, because the causative variants have been identified in only 20.0–47.8% of affected index patients with different ethnic origins 6–10 . Recently, GGC repeat expansion in the 5′ untranslated region (5’UTR) of the NOTCH2NLC gene has been associated with distal motor neuropathy and rimmed vacuolar myopathy 11 .…”

“… 5 Nevertheless, it still remains difficult and elusive to genetic diagnosis of dHMN, because the causative variants have been identified in only 20.0–47.8% of affected index patients with different ethnic origins. 6 , 7 , 8 , 9 , 10 Recently, GGC repeat expansion in the 5′ untranslated region (5’UTR) of the NOTCH2NLC gene has been associated with distal motor neuropathy and rimmed vacuolar myopathy. 11 Additionally, some patients with CAG repeat expansion in the Ataxin‐2 (ATXN2) gene also can affect motor neuropathy independently.…”

Association of SORD mutation with autosomal recessive asymmetric distal hereditary motor neuropathy

“…dHMN accounted for a small proportion of inherited peripheral neuropathy. Considering the wide phenotypic and genetic heritability the diagnostic rate in dHMN ranges from 14 to 39% [ 1 , 5 , 11 , 19 , 20 ]. Low diagnostic rate in dHMN indicates the presence of an unidentified mutation in novel candidate genes.…”

“…Sorbitol dehydrogenase deficiency with peripheral neuropathy is associated with mutations in the SORD gene. To our knowledge, around 16 bi-allelic mutations in the SORD gene have been identified [ 16 – 20 ]. SORD-related neuropathy has been reported as one of the most frequent causes of autosomal recessive CMT2 and dHMN [ 17 ].…”