2026 Volume 43 Issue 3 Pages 264-267
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic cause identified for familial ALS and remain one of the most extensively studied. In Japan, SOD1 variants account for approximately 30% of familial ALS and a small proportion of sporadic cases. The disease mechanism is thought to involve toxic gain–of–function of structurally unstable mutant SOD1 proteins, leading to intracellular aggregation, oxidative stress, and motor neuron degeneration.
Clinically, SOD1–associated ALS (SOD1–ALS) shares many features with sporadic ALS but often shows variant–dependent characteristics, including differences in age at onset, progression rate, and predominance of lower motor neuron signs. Limb onset, particularly distal lower limb weakness, is common.
Tofersen, an antisense oligonucleotide targeting SOD1 mRNA, has been developed to reduce SOD1 protein expression in the central nervous system. Clinical studies demonstrated reductions in cerebrospinal fluid SOD1 and neurofilament biomarkers, and early treatment may provide clinical benefit. SOD1–ALS thus represents an important model for gene–targeted therapy and precision medicine in neurodegenerative diseases.
