Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (<i>SOD1, TARDBP, FUS, C9orf72</i>) and phenotype in ALS. Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis. A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (<i>SOD1</i>, n=65; <i>FUS</i>, n=43; <i>TARDBP</i>, n=27; <i>C9orf72</i>, n=37). <i>SOD1</i> mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). <i>C9orf72</i> expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). <i>SOD1</i> and <i>FUS</i> mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with <i>SOD1</i> mutations, <i>C9orf72</i> expansions and those carrying pathogenic <i>FUS</i> mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with <i>C9orf72</i> expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128). Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease's progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.