PT  - JOURNAL ARTICLE
AU  - Horga, Alejandro
AU  - Tomaselli, Pedro J.
AU  - Gonzalez, Michael A.
AU  - Laurà, Matilde
AU  - Muntoni, Francesco
AU  - Manzur, Adnan Y.
AU  - Hanna, Michael G.
AU  - Blake, Julian C.
AU  - Houlden, Henry
AU  - Züchner, Stephan
AU  - Reilly, Mary M.
TI  - <em>SIGMAR1</em> mutation associated with autosomal recessive Silver-like syndrome
AID  - 10.1212/WNL.0000000000003212
DP  - 2016 Oct 11
TA  - Neurology
PG  - 1607--1612
VI  - 87
IP  - 15
4099  - http://n.neurology.org/content/87/15/1607.short
4100  - http://n.neurology.org/content/87/15/1607.full
SO  - Neurology2016 Oct 11; 87
AB  - 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.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