Collagen VI-related myopathy

Disease summary: First described by Ullrich in 1930 and Bethlem in 1976, respectively [1]. Caused by mutations in any of the 3 genes which code for collagen type VI synthesis, COL6A1, COL6A2 and COL6A3 [2]. Collagen VI is a major contributor to the stability of the extracellular matrix. The remaining function of collagen VI determines the clinical severity of the disorder [3,4]. Considered different entities in the past, Bethlem and Ullrich myopathy are now considered extremes in the spectrum of collagen VI myopathy. Both inheritance (mostly autosomal recessive) and de-novo mutations (mostly autosomal dominant) are possible, the latter is more common. Combined prevalence is estimated at approximately 1 in 100,000 births (varying data for subtypes). Diagnosis relies on muscle biopsy and molecular genetic testing. There exists no causative treatment. In Bethlem myopathy, patients will experience moderate muscle weakness, peripheral joint laxity and proximal joint contractures. Onset of symptoms will take place in late childhood or adolescence. Mobility will diminish over the years but usually still be present in advanced years. No valid data on life expectancy. Overall benign course. In Ullrich myopathy, muscle weakness and muscular contractures are noticed at birth or in early infancy. Neonates may present with congenital hip dislocation and general hypotonia, whereas infants may present with difficulty climbing stairs. Even where independent ambulation is achieved in childhood, most will be wheelchair-bound from early adolescence onward. Affection of respiratory muscles is frequent and ventilation support may be necessary, intermittently (nocturnal) or permanently. The clinical course may be complicated by recurrent pulmonary infections. The phenotype will be characterised by hypermobility of peripheral joints and contractures of proximal joints as well as scoliosis and kyphosis. Affected individuals may present with a round facies with long thin limbs and muscular wasting. Muscular weakness may also prevent adequate mastication and may lead to underweight. Impaired collagen VI function can also lead to follicular hyperkeratosis resulting in impaired wound healing and keloid scar formation.