Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder. The majority of cases are sporadic ALS (SALS), with 5-10% being familial ALS (FALS), and are inherited mostly as autosomal dominant. Mutations in Cu/Zn superoxide dismutase (SOD1) and the TAR DNA-binding protein (TARDBP) gene are the most commonly known cause of ALS. We analyzed these genes in 61 Italian ALS patients using high-resolution melting analysis to confirm the role of SOD1 and TARDBP in the physiopathology of ALS. The screenings showed a single mutation in SOD1 (Asp109Tyr) and three in TARBDP (Ala382Thr, Gly295Ser, Gly294Val) in five unrelated ALS patients. This report enlarges the spectrum of clinical phenotypes associated with genetic mutations in SOD1 and TARDBP genes confirming the variability of phenotypes associated with the same mutation and emphasizes the importance of genetic analysis. The different genotype-phenotype correlations suggest the implication of other factors possibly influencing clinical manifestation of the disease, such as an epigenetic or epistatic effect with other genes not yet identified.