Molecular genetic study of familial ALS in Japan

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We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with four different missense point mutations in exons 2,4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine^<46> by arginine (H46R), leucine^<84> by valine (L84V), isoleucine^<104> by phenylalanine (I104F), and valine^<148> by isoleucine (V148I), in five Japanese families. Although features of progressive neurogenic muscular atrophy was common in patients of these families, patients of each family showed characteristic clinical features. In addition, spinal cords of sporadic cases with amyotrophic lateral sclerosis (ALS) and normal controls were immunohistochemically examined using antibodies for nitrotyrosine (NT) and Cu/Zn superoxide dismutase (SOD). Immunoreactivity for NT was densely detected in the motor neurons of ALS while that was not or was only minimally detected in those of controls. The staining was also found in the axons on motor neurons of ALS,but was not found in the controls. In contrast, although immunoreactivity for Cu/Zn SOD of the motor neurons was dense in the motor neurons, that was not different between the ALS and controls.These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene showed each clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.Furthermore, nitration of protein tyrosine residue is upregulated in motor neurons of the spinal cord of ALS.