TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan.

The clinical features of a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (ALS) are reported. Weakness initially affected the bulbar musculature, with later involvement of the extremities. Genetic studies failed to detect any mutations of the Cu/Zn superoxide dismutase-1 (SOD1) and Dynactin1 (DCTN1) genes, but revealed a single base pair change from wild-type adenine to guanine at position 1009 in TAR-DNA-binding protein (TDP-43), resulting in a methionine-to-valine substitution at position 337. The immunohistochemical study on autopsied brain of the proband's aunt showed TDP-43-positive cytoplasmic inclusions in the anterior horn cells of the spinal cord and in the hypoglossal nucleus, as well as glial cytoplasmic inclusions in the precentral gyrus, suggesting that a neuroglial proteinopathy was related to TDP-43. In conclusion, a characteristic clinical phenotype of familial ALS with initial bulbar symptoms occurred in this family with TDP-43 M337V substitution, the pathomechanism of which should be elucidated.