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A refined diagnostic algorithm for Bethlem myopathy

Lookup NU author(s): Dr Debbie Hicks, Dr Anne Lampe, Dr Rita Barresi, Dr Richard Charlton, Professor Hanns Lochmuller, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby


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OBJECTIVE: Mutations in COL6A1, COL6A2, and COL6A3, the genes that encode the extracellular matrix component collagen VI, lead to Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). Unlike UCMD, BM is difficult to diagnose because of its clinical overlap with other contractural phenotypes and the lack of sensitivity of standard muscle biopsy immunohistochemical diagnostic techniques. METHODS: We appraised two potential techniques for the diagnosis of BM: dual immunofluorescence (IF) for collagen VI and basal lamina-located perlecan in muscle, and immunofluorescent labeling of collagen VI in skin biopsy-derived fibroblast cultures, which was conducted in 40 patients by blinded investigators and correlated with genetic findings. RESULTS: Dual IF was indistinguishable from normal controls in most BM patients. However, abnormalities in the IF labeling pattern of collagen VI were detected in more than 78% of genetically confirmed BM patient fibroblast cell lines. In addition, in a group of patients with unknown diagnosis studied prospectively, the fibroblast IF technique was highly predictive of the presence of a COL6A mutation, providing a positive predictive value of 75%, a sensitivity and negative predictive value of 100%, and a specificity of 63%. CONCLUSIONS: Immunofluorescent labeling of collagen VI in fibroblast cultures is a useful addition to current diagnostic services for Bethlem myopathy (BM). It can be used to guide molecular genetic testing, the gold standard diagnostic technique for BM, in a cost-effective and time-saving manner. ©2008AAN Enterprises, Inc.

Publication metadata

Author(s): Hicks D, Lampe AK, Barresi R, Charlton RG, Fiorillo C, Bonnemann CG, Hudson J, Sutton R, Lochmüller HKM, Straub VW, Bushby KMD

Publication type: Article

Publication status: Published

Journal: Neurology

Year: 2008

Volume: 70

Issue: 14

Pages: 1192-1199

Print publication date: 01/04/2008

ISSN (print): 0028-3878

ISSN (electronic): 1526-632X

Publisher: Lippincott Williams & Wilkins


DOI: 10.1212/01.wnl.0000307749.66438.6d

PubMed id: 18378883


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Funder referenceFunder name
Wellcome Trust
G0601943Medical Research Council