Genetic localization of Bethlem myopathy

Bethlem myopathy (early-onset benign autosomal dominant limb-girdle myopathy with contractures) is a hereditary myopathy with slowly progressive muscular atrophy and weakness, and contractures of multiple joints. ^[1,2] Onset of weakness is usually either in the neonatal period, presenting with hypotonia, or in early childhood. ^[3] There is generalized, slight atrophy of the musculature and diffuse, mild weakness, proximal more severe than distal. Involvement of the facial muscles is absent. Nearly all patients have flexion contractures of the interphalangeal joints of the last four fingers, elbows, and ankles. ^[2,4] Contractures of the metacarpophalangeal joints, wrists, knees, hips, and shoulders are less common. In contrast with X-linked Emery-Dreifuss muscular dystrophy, contractures of the neck and spine are rarely present. ^[2] The contractures, present from onset of weakness onwards, ^[2,4] give little or no functional impairment in most patients. ^[2]

In spite of slowly ongoing deterioration of muscle power, ability to work is preserved until old age. ^[2] Many patients remain ambulant, often with the help of a cane, whereas others become wheelchair-dependent for outdoor transportation (manuscript in preparation). There is no cardiac involvement ^[2,5] and life expectancy is unaffected. ^[1] Ancillary investigations such as electrophysiologic studies and muscle biopsy indicate a myopathic origin of the disease. ^[2]

Bethlem myopathy has an autosomal dominant mode of inheritance with complete penetrance. A previous linkage effort failed to detect genetic linkage. ^[6] In the current study we carried out a genomewide search with highly polymorphic microsatellite markers in six Dutch families.

Methods.