Qualitative or quantitative defects of calpain

Qualitative or quantitative defects of calpain (also referred to as calpainopathy or calpain-3 deficiency) represent the molecular basis of limb-girdle muscular dystrophy type 2A (LGMD2A), now reclassified as LGMD R1 calpain 3-related. This condition is caused by mutations in the CAPN3 gene, which encodes the muscle-specific protease calpain-3. Defects can be quantitative (reduced or absent calpain-3 protein on Western blot) or qualitative (normal protein quantity but impaired enzymatic function). Calpain-3 plays a critical role in sarcomere remodeling and muscle maintenance, and its deficiency leads to progressive skeletal muscle degeneration. The disease primarily affects the proximal muscles of the pelvic and shoulder girdles. Patients typically present with progressive weakness and wasting of the hip and shoulder muscles, difficulty climbing stairs, rising from a seated position, and walking. Scapular winging is a common clinical feature. The calves may initially appear hypertrophied but eventually undergo atrophy. Cardiac and respiratory muscles are generally spared until late stages, though respiratory insufficiency can develop in advanced disease. Serum creatine kinase levels are usually elevated, often markedly so. Currently, there is no curative treatment for calpain-3-related muscular dystrophy. Management is supportive and includes physical therapy to maintain mobility and prevent contractures, orthopedic interventions, respiratory monitoring, and assistive devices as the disease progresses. Gene therapy approaches and other molecular strategies are under investigation in preclinical and early clinical studies. Genetic counseling is recommended for affected families.

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