Bethlem Myopathy

At a glance

A slowly progressive and inherited congenital myopathy with muscle weakness and contractures.

Synonyms

Bethlem Myopathy Type I; Benign Congenital Muscular Dystrophy.

Incidence

Bethlem Myopathy (BM) is estimated to affect about 0.77 per 100,000 individuals in the general population of Northern England. Since the original report of the condition (28 patients in 3 families) in 1976 by the two Dutch scientists Jaap Bethlem and George K. van Wijngaarden, the myopathy has been described in several different pedigrees from various geographical locations. The largest pedigree with the disorder is of French-Canadian ancestry in which the disease could be traced back through seven generations. Both sexes are equally affected.

Genetic inheritance

In general, inheritance is autosomal dominant, although a few cases with autosomal recessive transmission have been reported. Several sporadic cases have also been described. The mutations affect the COL6A1 (Collagen type VI alpha 1 chain), COL6A2 and COL6A3 genes, which have been mapped to chromosome 21q22.3 (COL6A1 and 2) and chromosome 2q37 (COL6A3).

Pathophysiology

BM is caused by mutations in the genes encoding for the three constituent α-chain subunits of type VI collagen. Collagen VI is a microfibrillar component in several extracellular matrices, including in muscles, tendons, joints, and skin. Collagen VI in the extracellular matrix of skeletal muscles is synthetized by muscle interstitial fibroblasts. This matrix forms a complex interstitial microfilamentous network and provides support for structural stability and growth of the muscle cells. Microfibrillar type VI collagen is believed to play a key role in bridging the extracellular matrix with skeletal muscle cells and thus in maintaining their structural and functional integrity. Mutations in the collagen VI genes result in an abnormal collagen VI matrix with loss of the tight connections between collagen VI and the skeletal muscle cell basement membranes.

Diagnosis

Based on the clinical features consistent with the condition and family history. Electromyography demonstrates a myopathic pattern. Muscle biopsy reveals nonspecific features of a myopathy. Nerve conduction velocity is normal, and creatinine phosphokinase serum levels are either normal or mildly-to-moderately elevated. Immunofluorescence labeling of collagen VI in skin fibroblast cultures is highly predictive of a COL6A mutations and can be used to guide molecular genetic testing, the gold standard diagnostic technique for BM. Scanning with CT or MRI offers a highly specific pattern of muscle involvement on of the lower extremity with a reported sensitivity of up to 90% (MRI).

Clinical aspects

The somatic presentation is highly variable with marked inter- and intrafamilial variability. These patients are of normal intelligence. This (so-called) benign limb-girdle myopathy is typically associated with symmetrical, mild-to-moderate weakness, muscle atrophy, and contractures. Most children present with weakness and contractures (which are initially dynamic) and delayed ...