FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is inherited in ten percent of cas es as a Mendelien trait. Familial ALS (FALS) is genetically heterogene ous and transmitted either as an autosomal dominant (DFALS) or an auto somal recessive (RFALS) trait. Fifteen percent of DFALS families have mutations in the gene for Cu,Zn superoxide dismutase (SOD1) which is c oded on chromosome 21. These mutations result in decreased SOD1 activi ty and shortened half-life of the protein in most instances. Several o bservations suggest that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather t han by the decrease of SOD1. activity. Possible mechanisms of the nove l neurotoxic function of mutated SOD1 are discussed. The role of event ual neurofilament involvement in the pathogenesis of ALS is also discu ssed. The locus for one form of RFALS has been mapped to chromosome 2q 33. FALS can also be associated with dementia and the gene locus for o ne form of hereditary ALS-dementia syndrome maps to chromosome 17q21-2 2. (C) 1996 Wiley-Liss, Inc.