Genetic analysis in families with amyotrophic lateral sclerosis

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Amyotrophic lateral screlosis (ALS) is a fatal neurodegenerative disease caused by selective death of motor neurons. Pathological studies of postmortem ALS patients revealed motor neuron loss in the anterior horn of the spinal cord, the nucleus of brainstem and the cortex. Approximately 10% of cases of ALS are inherited, usually as an autosomal dominant trait. Mutations of the cytosolic cupper-zinc superoxide dismutase (Cu/Zn SOD) gene were detected in about 25% of patients with familial ALS and until now more than 70 different mutations are known. In this study, we carry out a linkage analysis using a large Japanese family with ALS to identify loci that contain genes whose defects cause ALS.We did not detect any genetic linkage to the known locus of motor neuron diseases and now going on a genome-wide linkage analysis. In addition, we identified a novel missense mutation of the Cu/Zn SOD gene (Leu126Ser) in a Japanese family with ALS that included a patient with the homozygous mutation. The expression of the Cu/Zn SOD polypeptide in erythrocytes was markedly reduced in the case with the homozygous mutation compared to those with the heterozygous mutation. We speculated that this reduction of the mutant Cu/Zn SOD molecule may be related to the severe clinical phenotype of the case.