Amyotrophic lateral sclerosis (ALS; Lou Gehtig's disease) is a fatal motor neuron degenerative syndrome that is inherited in approximately 10% of cases and sporadic in about 90%. The clinical and pathological features of the familial (FALS) and sporadic (SALS) forms ate indistinguishable [11. About one-fourth of FALS cases are associated with mutations in sodl, the gene that encodes copperlzinc superoxide dismutase (CuZnSOD). Results of transgenic mouse and cell culture studies point to a dominant, toxic gain of function for these mutations [2, 31. The cause of SALS is unknown.

About 50 different sod] mutations have been identified in FALS families [4]. Most of the mutations lead to single amino acid substitutions. These mutations are located throughout the protein structure, although most are clustered at the protein's P-barrel turns and at the dimerization interface (Fig). FALS-associated mutations in CuZnSOD have been predicted to lead to a more open structure of the enzyme, with increased access to the active site channel [5]. The mutations pro-duce variable effects on the level of SOD activity, which are not correlated with the severity of the disease [GI.