Autosomal recessive Bethlem myopathy

F. Gualandi, A. Urciuolo, E. Martoni, P. Sabatelli, S. Squarzoni, M. Bovolenta, S. Messina, E. Mercuri, A. Franchella, A. Ferlini, P. Bonaldo, L. Merlini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1883-1891
Number of pages9
JournalNeurology
Volume73
Issue number22
DOIs
Publication statusPublished - Dec 2009

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Collagen
Muscles
Mutation
Fibroblasts
Skin
Muscle Weakness
Genetic Counseling
Genetic Association Studies
Contracture
Muscular Diseases
Amino Acid Substitution
Wrist
Basement Membrane
Ankle
Fingers
Bethlem myopathy
Alleles
Electrons
Genes

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Gualandi, F., Urciuolo, A., Martoni, E., Sabatelli, P., Squarzoni, S., Bovolenta, M., ... Merlini, L. (2009). Autosomal recessive Bethlem myopathy. Neurology, 73(22), 1883-1891. https://doi.org/10.1212/WNL.0b013e3181c3fd2a

Autosomal recessive Bethlem myopathy. / Gualandi, F.; Urciuolo, A.; Martoni, E.; Sabatelli, P.; Squarzoni, S.; Bovolenta, M.; Messina, S.; Mercuri, E.; Franchella, A.; Ferlini, A.; Bonaldo, P.; Merlini, L.

In: Neurology, Vol. 73, No. 22, 12.2009, p. 1883-1891.

Research output: Contribution to journalArticle

Gualandi, F, Urciuolo, A, Martoni, E, Sabatelli, P, Squarzoni, S, Bovolenta, M, Messina, S, Mercuri, E, Franchella, A, Ferlini, A, Bonaldo, P & Merlini, L 2009, 'Autosomal recessive Bethlem myopathy', Neurology, vol. 73, no. 22, pp. 1883-1891. https://doi.org/10.1212/WNL.0b013e3181c3fd2a
Gualandi F, Urciuolo A, Martoni E, Sabatelli P, Squarzoni S, Bovolenta M et al. Autosomal recessive Bethlem myopathy. Neurology. 2009 Dec;73(22):1883-1891. https://doi.org/10.1212/WNL.0b013e3181c3fd2a
Gualandi, F. ; Urciuolo, A. ; Martoni, E. ; Sabatelli, P. ; Squarzoni, S. ; Bovolenta, M. ; Messina, S. ; Mercuri, E. ; Franchella, A. ; Ferlini, A. ; Bonaldo, P. ; Merlini, L. / Autosomal recessive Bethlem myopathy. In: Neurology. 2009 ; Vol. 73, No. 22. pp. 1883-1891.
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AU - Urciuolo, A.

AU - Martoni, E.

AU - Sabatelli, P.

AU - Squarzoni, S.

AU - Bovolenta, M.

AU - Messina, S.

AU - Mercuri, E.

AU - Franchella, A.

AU - Ferlini, A.

AU - Bonaldo, P.

AU - Merlini, L.

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N2 - 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.

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