EPIDEMIOLOGY OF MUTATIONS IN SUPEROXIDE-DISMUTASE IN AMYOTROPHIC-LATERAL-SCLEROSIS

We registered 366 families in a study of dominantly inherited amyotrop hic lateral sclerosis. Two hundred ninety families were screened for m utations in the gene encoding copper-zinc cytosolic superoxide dismuta se (SOD1). Mutations were detected in 68 families. The most common SOD 1 mutation is an alanine for valine substitution in codon 4 (50%). We present clinical and genetic data concerning 112 families with 395 aff ected individuals. The clinical characteristics of patients with famil ial amyotrophic lateral sclerosis arising from SOD1 mutations are simi lar to those lacking SOD1 defects. Mean age at onset was earlier (Wilc oxon test, P = 0.004) in the SOD1 group (46.3 years [standard deviatio n, 12.5] vs 50.5 years [11.5] in the non-SOD1 group). Bulbar onset was associated with a later onset age. The presence of either of two muta tions, G37R and L38V, predicted an earlier age at onset. Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with th e non-SOD1 group at early survival times (Wilcoxon test, p = 0.0007). The presence of one mutation, A4V, correlated with shorter survival. G 37R, G41D, and G93C mutations predicted longer survival. This informat ion suggests it will be productive to investigate other genetic determ inants in amyotrophic lateral sclerosis and to use epidemiological cha racteristics of the disease to help discern molecular mechanisms of mo tor neuron cell death.