Two Cases of Sporadic Amyotrophic Lateral Sclerosis With Contrasting Clinical Phenotypes: Genetic Insights

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects individuals of diverse racial and ethnic backgrounds. There is currently no cure for ALS, and the number of efficient disease-modifying drugs for ALS is limited to a few, despite the large number of clinical trials conducted in recent years. The latter could be attributed to the significant heterogeneity of ALS clinical phenotypes even in their familial forms. To address this issue, we conducted postmortem genetic screening of two female patients with sporadic ALS (sALS) and contrasting clinical phenotypes. The results demonstrated that despite their contrasting clinical phenotypes, both patients had rare pathologic/deleterious mutations in five genes: ACSM5, BBS12, HLA-DQB1, MUC20, and OBSCN, with mutations in three of those genes being identical: BBS12, HLA-DQB1, and MUC20. Additional groups of mutated genes linked to ALS, other neurologic disorders, and ALS-related pathologies were also identified. These data are consistent with a hypothesis that an individual could be primed for ALS via mutations in a specific set of genes not directly linked to ALS. The disease could be initiated by a concerted action of several mutated genes linked to ALS and the disease's clinical phenotype will evolve further through accessory gene mutations associated with other neurological disorders and ALS-related pathologies.

Keywords: amyotrophic lateral sclerosis; clinical heterogeneity; next generation sequencing; postmortem genetic screening; whole exome sequencing.

Figure 1. Distribution of rare pathologic/deleterious variants in D1 and D2 among the following categories: red - variants linked to amyotrophic lateral sclerosis (ALS) (Group II); blue - variants linked to other neurological disorders (Group III); yellow - variants linked to ALS-related pathology (Group IV); and beige - ungrouped variants. Numerals represent the total number of variants in the respective categories.