Alpha-dystroglycan-related limb-girdle muscular dystrophy R16

Alpha-dystroglycan-related limb-girdle muscular dystrophy R16 (LGMD R16), formerly known as LGMD2I, is a rare autosomal recessive muscular dystrophy caused by mutations in the FKRP gene (fukutin-related protein). This gene is essential for the proper glycosylation of alpha-dystroglycan, a protein that plays a critical role in linking the internal cytoskeleton of muscle cells to the extracellular matrix. When alpha-dystroglycan is not properly glycosylated, this connection is disrupted, leading to progressive muscle weakness and degeneration. LGMD R16 is classified among the dystroglycanopathies, a group of disorders sharing defective glycosylation of alpha-dystroglycan. The disease primarily affects the skeletal muscles, particularly the proximal muscles of the hip and shoulder girdles. Patients typically present with progressive difficulty walking, climbing stairs, and raising their arms. Calf hypertrophy (enlarged calf muscles) is a common clinical feature. Cardiac involvement, including dilated cardiomyopathy, is a significant concern and can occur independently of the severity of skeletal muscle weakness. Respiratory insufficiency may also develop over time, requiring monitoring of pulmonary function. Serum creatine kinase (CK) levels are usually markedly elevated, often 10 to 50 times the normal range. The age of onset and disease severity are highly variable, even among individuals carrying the same mutations. Some patients present in childhood with a more severe phenotype, while others may not develop symptoms until adulthood with a milder course. The most common FKRP mutation associated with LGMD R16 is c.826C>A (p.Leu276Ile), particularly prevalent in European populations. There is currently no cure for LGMD R16. Management is supportive and multidisciplinary, including physical therapy to maintain mobility, cardiac surveillance and treatment of cardiomyopathy, respiratory support when needed, and orthopedic interventions. Gene therapy and other molecular approaches are under active investigation in preclinical and early clinical research.

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