A FREQUENT ALA-4 TO VAL SUPEROXIDE DISMUTASE-1 MUTATION IS ASSOCIATEDWITH A RAPIDLY PROGRESSIVE FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS

Familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor neurons, is associated with mutations in the Cu/Zn superoxid e dismutase gene SOD1 in some affected families. We confirm a recently reported ala4-->val mutation in exon 1 of the SOD1 gene and report th at this mutation is both the most commonly detected of all SOD1 mutati ons and among the most clinically severe. By comparision with our othe r FALS families, the exon 1 mutation is associated with reduced surviv al time after onset: 1.2 years, as compared to 2.5 years for all other FALS patients. We also demonstrate that SOD1 is prominently expressed in normal motor neurons and that neural expression of SOD1 is not pre vented by this exon 1 mutation. Assays of SOD1 enzymatic activity in e xtracts from red blood cells, lymphoblastoid cells, and brain tissues revealed an approximately 50% reduction in activity of cytosolic SOD1 in patients with this mutation compared to normal individuals. By cont rast, patients with sporadic ALS had normal levels of SOD1 enzymatic a ctivity. Why this SOD1 mutation causes motor neuron death in FALS rema ins to be established. While it may be that FALS is a consequence of l oss of SOD1 function, it is also possible that motor neuron death in t his dominantly inherited disease occurs because the mutations confer a n additional, cytotoxic function on the SOD1 protein.