Autosomal recessive Bethlem myopathy

BACKGROUND: Bethlem myopathy is a well-defined clinical entity among collagen VI disorders, featuring proximal muscle weakness and contractures of the fingers, wrists, and ankles. It is an early-onset, slowly progressive, and relatively mild disease, invariably associated to date with heterozygous dominant mutations in the 3 collagen VI genes. We have characterized the clinical, laboratory, and genetic features of autosomal recessive Bethlem myopathy in 2 unrelated patients. METHODS: This study is based on clinical, histochemical, immunocytochemical, and electron microscope evaluation of the muscle and dermal fibroblasts, CT imaging of the muscles, and biochemical and molecular analysis. RESULTS: Both patients carry a truncating COL6A2 mutation (Q819X; R366X) associated with missense changes in the partnering allele lying within the C2 domain of the alpha2(VI) chain (D871N; R843W-R830Q). They show decreased amounts of collagen VI in the basal lamina of muscle fibers and in dermal fibroblast cultures and altered behavior of collagen VI tetramers. Biochemical studies supported the pathogenic effect of identified amino acid substitutions, which involve strictly conserved residues. CONCLUSIONS: The reported patients illustrate the occurrence of Bethlem myopathy with a recessive mode of inheritance. This observation completes the hereditary pattern in collagen VI myopathies with both Ullrich congenital muscular dystrophy and Bethlem myopathy underlined by either recessive or dominant effecting mutations. This finding has relevant implications for genetic counseling and molecular characterization of patients with Bethlem myopathy, as well as for genotype-phenotype correlations in collagen VI disorders.