Autosomal recessive Bethlem myopathy
- 1 December 2009
- journal article
- case report
- Published by Ovid Technologies (Wolters Kluwer Health) in Neurology
- Vol. 73 (22), 1883-1891
- https://doi.org/10.1212/wnl.0b013e3181c3fd2a
Abstract
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 α2(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.This publication has 29 references indexed in Scilit:
- Identification and characterization of novel collagen VI non-canonical splicing mutations causing ullrich congenital muscular dystrophyHuman Mutation, 2009
- Autosomal recessive myosclerosis myopathy is a collagen VI disorderNeurology, 2008
- Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severityAnnals of Neurology, 2008
- Exon skipping mutations in collagen VI are common and are predictive for severity and inheritanceHuman Mutation, 2008
- A refined diagnostic algorithm for Bethlem myopathyNeurology, 2008
- Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathiesProceedings of the National Academy of Sciences of the United States of America, 2008
- Molecular consequences of dominant Bethlem myopathy collagen VI mutationsAnnals of Neurology, 2007
- Primary collagen VI deficiency is the second most common congenital muscular dystrophy in JapanNeurology, 2007
- Structural Basis of Type VI Collagen Dimer FormationJournal of Biological Chemistry, 2003
- A Heterozygous Splice Site Mutation in COL6A1 Leading to an In-Frame Deletion of the α1(VI) Collagen Chain in an Italian Family Affected by Bethlem MyopathyBiochemical and Biophysical Research Communications, 1999