Tubular aggregate myopathy

Tubular aggregate myopathy (TAM) is a rare inherited muscle disorder characterized by the accumulation of tubular aggregates within skeletal muscle fibers, visible on muscle biopsy. Tubular aggregates are abnormal structures derived from the sarcoplasmic reticulum, the calcium-storing compartment of muscle cells. The disease primarily affects skeletal muscles, leading to progressive muscle weakness and fatigue. Symptoms typically include proximal muscle weakness (affecting muscles closer to the trunk, such as those in the hips and shoulders), exercise intolerance, muscle stiffness, and myalgia (muscle pain). Some patients may also experience facial weakness, ophthalmoplegia (difficulty moving the eyes), or muscle cramps. The severity and progression of the disease can vary considerably among affected individuals. Tubular aggregate myopathy is caused by mutations in genes involved in calcium homeostasis within muscle cells, most notably STIM1, ORAI1, and CASQ1. Mutations in STIM1 and ORAI1 lead to dysregulation of store-operated calcium entry (SOCE), a critical pathway for maintaining calcium levels in muscle cells. The condition is predominantly inherited in an autosomal dominant pattern, though autosomal recessive inheritance has also been reported in some families. Notably, STIM1 and ORAI1 mutations can also be associated with additional features beyond myopathy, including thrombocytopenia, immunodeficiency, or Stormorken syndrome, reflecting the broader role of these genes in multiple cell types. There is currently no cure or disease-specific treatment for tubular aggregate myopathy. Management is supportive and symptomatic, focusing on physical therapy, occupational therapy, and monitoring for complications such as respiratory muscle weakness. Pain management and avoidance of overexertion may help alleviate symptoms. Genetic counseling is recommended for affected families. Research into calcium channel modulators and targeted therapies is ongoing but has not yet yielded approved treatments.

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