Abstract
Objective:To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor–1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene.Methods:We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations.Results:In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN.Conclusions:We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies.
Highlights
MethodsWe used whole-exome sequencing to investigate the proband
In the proband, we identified a homozygous missense variant (c.194T.A, p.Leu65Gln) in exon 2 of sigma nonopioid intracellular receptor–1 gene (SIGMAR1) as the probable causative mutation
ALS 5 amyotrophic lateral sclerosis; CMT 5 Charcot-Marie-Tooth disease; distal hereditary motor neuropathies (dHMN) 5 distal hereditary motor neuropathy; dHMN-J 5 distal hereditary motor neuropathy and pyramidal features identified in the Jerash region of Jordan; ER 5 endoplasmic reticulum; ExAC 5 Exome Aggregation Consortium database; HSP 5 hereditary spastic paraplegia; MAF 5 minor allele frequency; MRC 5 Medical Research Council; s1R 5 sigma-1 receptor; SIGMAR1 5 sigma nonopioid intracellular receptor–1 gene; UTR 5 untranslated region; wholeexome sequencing (WES) 5 whole-exome sequencing
Summary
We used whole-exome sequencing to investigate the proband. A larger cohort of 16 unrelated dHMN patients was screened for SIGMAR1 mutations. The proband and 16 additional patients screened for SIGMAR1 mutations were identified from those attending neuropathy clinics at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. The proband was investigated as part of a larger study to determine the genetic etiology in patients with inherited neuropathies using wholeexome sequencing (WES). WES, Sanger sequencing, and in silico analysis methods are detailed in the supplementary material at Neurology.org. The study had ethical approval from the National Hospital for Neurology & Neurosurgery/Institute of Neurology Joint Research Ethics Committee. All patients gave written informed consent for genetic testing
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