Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness

Objective The fukutin gene (FKTN) is the causative gene for Fukuyama‐type congenital muscular dystrophy, characterized by rather homogeneous clinical features of severe muscle wasting and hypotonia from early infancy with mental retardation. In contrast with the severe dystrophic involvement of skeletal muscle, cardiac insufficiency is quite rare. Fukuyama‐type congenital muscular dystrophy is one of the disorders associated with glycosylation defects of α‐dystroglycan, an indispensable molecule for intra‐extra cell membrane linkage. Methods Protein and functional analyses of α‐dystroglycan and mutation screening of FKTN and other associated genes were performed. Results Surprisingly, we identified six patients in four families showing dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence, associated with a compound heterozygous FKTN mutation. One patient died by rapid progressive dilated cardiomyopathy at 12 years old, and the other patient received cardiac implantation at 18 years old. Skeletal muscles from the patients showed minimal dystrophic features but have altered glycosylation of α‐dystroglycan and reduced laminin binding ability. One cardiac muscle that underwent biopsy showed altered glycosylation of α‐dystroglycan similar to that observed in a Fukuyama‐type congenital muscular dystrophy patient. Interpretation FKTN mutations could cause much wider spectrum of clinical features than previously perceived, including familial dilated cardiomyopathy and mildest limb girdle muscular dystrophy. Ann Neurol 2006