Dysferlinopathies

Dysferlinopathies are a group of inherited muscular dystrophies caused by pathogenic variants in the DYSF gene, which encodes the membrane-associated protein dysferlin. Dysferlin is involved in resealing the sarcolemma after muscle fiber injury, and its deficiency leads to progressive muscle weakness and degeneration. Inheritance is autosomal recessive.

The clinical spectrum includes two main phenotypes. Miyoshi myopathy is a distal myopathy characterized by early weakness of the calf muscles and foot drop, often followed by proximal involvement. Limb-girdle muscular dystrophy type 2B (LGMD2B) presents with proximal weakness of the pelvic and shoulder girdles, with possible later distal weakness. Onset typically occurs in adolescence or young adulthood, but presentation can vary. Creatine kinase levels are usually markedly elevated. Cardiac and respiratory involvement are less common but may occur in advanced disease.

Pathophysiology and pathology: Loss of dysferlin impairs repair of the injured sarcolemma, contributing to ongoing muscle damage and degeneration. Muscle biopsies often show dystrophic changes, with reduced or absent dysferlin on immunohistochemistry. Inflammatory infiltrates can be present, but inflammation is not the primary driver of disease.

Diagnosis involves clinical evaluation, elevated serum CK, and confirmation by genetic testing for DYSF mutations. Muscle biopsy with immunostaining for dysferlin supports the diagnosis, but genetic testing is essential for definitive confirmation.

Management is supportive and multidisciplinary. There is no cure or disease-modifying therapy. Physical and occupational therapy aim to maintain strength and mobility, prevent contractures, and preserve ambulation; bracing or mobility aids may be needed. Regular monitoring of pulmonary function and orthopedic issues is important. Genetic counseling is recommended due to autosomal recessive inheritance. Prognosis varies with phenotype and degree of muscle involvement.