Characterizing SOD1 mutations in Spain: The impact of genotype, age and sex in the natural history of the disease

Abstract Background and purpose The aim of this study was to describe the frequency and distribution of SOD1 mutations in Spain, and to explore factors contributing to their phenotype and prognosis. Methods Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. Results In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all five exons of SOD1 , including seven novel mutations. A total of 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. The frequency of this mutation varied considerably among regions, due to founder events. The most frequent mutation was p.Gly38Arg ( n = 58), followed by p.Glu22Gly ( n = 11), p.Asn140His ( n = 10), and the novel p.Leu120Val ( n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp[Estimate] = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (hazard ratio 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated with faster disease progression (exp[Estimate] = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs. 301 months). Conclusions These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.