Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in Cu/Zn superoxide dismutase gene: a possible new subtype of familial ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder that results in relentless damage to the motor neuron system. Although about 5-10% of cases are familial, the pathophysiologic process of ALS remains unknown. We identified a novel point mutation A to G in exon 2 of the Cu/Zn SOD gene, resulting in an amino acid substitution of histidine46 by arginine (H46R), in two Japanese familial ALS (FALS) families. The segregations of the mutation were evident. The enzymatic activities of Cu/Zn SOD of peripheral red blood cell lysate were reduced to about 80% in the affected members, compared with other non-affected family members. The patients in these families are clinically characterized by relative late onset, initial involvement in lower extremities, relative rare impairment of bulbar muscles and much slow progression of muscular weakness and atrophy, compared with other Japanese FALS cases who have no mutation in the Cu/Zn SOD gene. These findings suggest that the H46R mutation in Cu/Zn SOD gene is highly related to this unique subtype of FALS.