Although some mutations associate with very specific ALS clinical profiles (e.g., patients with the Ala4Val mutation in SOD1 usually have an aggressive form of ALS, whereas those with the homozygous Asp91Ala mutation tend to have a very slowly progressive disease with a generally ascending upper motor neuron phenotype), the majority of disease-causing genes show a high degree of phenotypic heterogeneity, with mutations in the same gene giving rise to different clinical entities, supporting a genetic basis for the observed clinical heterogeneity in ALS. This evidence concerns the gene SOD1 and amyotrophic lateral sclerosis.