SIGMAR1 variants in ALS-PD complex cases: a case report of a novel mutation and literature review

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons, with occasional involvement of the extrapyramidal system. Mutations in the sigma non-opioid intracellular receptor 1 (SIGMAR1) gene have been identified as one of the causes of ALS. Here, we present a case of a 49-year-old man diagnosed with ALS-Parkinson's disease (PD) complex. The patient exhibited bradykinesia and tremor, and whole-exome sequencing revealed homozygous mutations in the SIGMAR1 gene (c.446-2A > T). In addition, we conducted an investigation into the clinical and molecular phenotype of previously reported variants of SIGMAR1 associated with ALS. This case report aims to raise awareness among physicians regarding atypical phenotypes of amyotrophic lateral sclerosis and to encourage further research on the factors leading to SIGMAR1 mutations in patients.

Keywords: Parkinson’s disease; SIGMAR1; amyotrophic lateral sclerosis; genotype; phenotype.

Figure 1

(A) Atrophy of bilateral calves more pronounced distally giving a “stork leg” appearance akin to Charcot-Marie-Tooth disease. (B) Planovalgus deformities of both feet.

Figure 2

Filtering steps for the variant calls in whole-exome sequencing.

Figure 3

(A) Splice site mutation in the SIGMAR1 identified in our patient. Sanger sequencing was performed using cDNA generated from the patient. (B) Mutation in the SIGMAR1 identified in our patient’s mother. (C) Mutant pedigree map of familial mutations. Circles = females; squares = males; and slashes = deceased.

Figure 4

Mutation site of SIGMR1. The previously reported mutation site was located in exons and 3′-UTR, and the mutation site was located in intron.