AMYOTROPHIC lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord^1,2. Its cause is unknown and it is uniformly fatal, typically within five years³. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade^4,5. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar^4,6,7. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8,9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O^–₂ to O₂ and H₂O₂ (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders¹¹, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.