POMT2-related limb-girdle muscular dystrophy R14

POMT2-related limb-girdle muscular dystrophy R14 (LGMDR14), formerly known as LGMD2N, is a rare autosomal recessive muscular dystrophy caused by biallelic pathogenic variants in the POMT2 gene. POMT2 encodes protein O-mannosyltransferase 2, an enzyme essential for the proper glycosylation of alpha-dystroglycan, a key protein that links the muscle cell cytoskeleton to the extracellular matrix. Defective glycosylation of alpha-dystroglycan leads to a group of conditions collectively known as dystroglycanopathies. LGMDR14 represents the milder end of the POMT2-related disease spectrum, with the more severe end including Walker-Warburg syndrome and muscle-eye-brain disease. Patients with LGMDR14 typically present in childhood or adolescence with progressive proximal muscle weakness predominantly affecting the limb-girdle muscles — the muscles around the hips and shoulders. This leads to difficulty climbing stairs, rising from the floor, running, and lifting the arms overhead. Elevated serum creatine kinase (CK) levels are a hallmark laboratory finding. Cognitive impairment of variable severity, including intellectual disability, may be present in some patients, reflecting the role of alpha-dystroglycan in brain development. Muscle biopsy typically shows dystrophic changes with reduced immunostaining for glycosylated alpha-dystroglycan. There is currently no cure or disease-specific treatment for LGMDR14. Management is supportive and multidisciplinary, including physical therapy to maintain mobility and prevent contractures, orthopedic interventions as needed, respiratory monitoring, cardiac surveillance, and neurodevelopmental support when cognitive involvement is present. Genetic counseling is recommended for affected families. Research into therapies targeting the dystroglycanopathy pathway, including gene therapy and pharmacological approaches to enhance glycosylation, is ongoing but remains in early stages.

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