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.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- CMT=
- Charcot-Marie-Tooth disease;
- dHMN=
- distal hereditary motor neuropathy;
- dHMN-J=
- distal hereditary motor neuropathy and pyramidal features identified in the Jerash region of Jordan;
- ER=
- endoplasmic reticulum;
- ExAC=
- Exome Aggregation Consortium database;
- HSP=
- hereditary spastic paraplegia;
- MAF=
- minor allele frequency;
- MRC=
- Medical Research Council;
- σ1R=
- sigma-1 receptor;
- SIGMAR1=
- sigma nonopioid intracellular receptor–1 gene;
- UTR=
- untranslated region;
- WES=
- whole-exome sequencing
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by MRC.
↵* These authors contributed equally to this work.
Supplemental data at Neurology.org
- Received March 29, 2016.
- Accepted in final form June 24, 2016.
- © 2016 American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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