A Family of Bethlem Myopathy Caused by a Heterozygous COL6A1 Mutation

Collagen-VI-related myopathies are caused by mutations in the COL6A1, COL6A2, and COL6A3 and are known to have a wide phenotypic spectrum, including Bethlem myopathy, Ullrich congenital muscular dystrophy, intermediate phenotype, and limb-girdle muscular dystrophy. These patients present with joint hyperextensibility and/or contractures as well as skin changes and muscle weakness, and so clinicians need to notice those extramuscular symptoms in order to achieve a correct diagnosis. We describe the clinical, pathological, and radiological features in a family with Bethlem myopathy caused by a COL6A1 mutation.

Molecular Genetic Diagnosis of a Bethlem Myopathy Family with an Autosomal-Dominant COL6A1 Mutation, as Evidenced by Exome Sequencing

BACKGROUND: We describe herein the application of whole exome sequencing (WES) for the molecular genetic diagnosis of a large Korean family with dominantly inherited myopathy. CASE REPORT: The affected individuals presented with slowly progressive proximal weakness and ankle contracture. They were initially diagnosed with limb-girdle muscular dystrophy (LGMD) based on clinical and pathologic features. However, WES and subsequent capillary sequencing identified a pathogenic splicing-site mutation (c.1056+1G>A) in COL6A1, which was previously reported to be an underlying cause of Bethlem myopathy. After identification of the genetic cause of the disease, careful neurologic examination revealed subtle contracture of the interphalangeal joint in the affected members, which is a characteristic sign of Bethlem myopathy. Therefore, we revised the original diagnosis from LGMD to Bethlem myopathy. CONCLUSIONS: This is the first report of identification of COL6A1-mediated Bethlem myopathy in Korea, and indicates the utility of WES for the diagnosis of muscular dystrophy.

A Family of Bethlem Myopathy

Bethlem myopathy (BM) is an early-onset benign autosomal dominant myopathy characterized by proximal muscle weakness and multiple contractures. It is caused by mutations in the three genes encoding collagen VI, which is a ubiquitous extracellular matrix protein forming a microfibrillar network in close association with the basement membrane. Here, we present a family with BM which is the first reported Korean case.