The spectrum of neuromuscular diseases with tubular aggregates

Tubular aggregates are granular inclusions of unclear function postulated to be massive proliferations from lateral sacs of the sarcoplasmic reticulum. However, immunohistochemical studies suggest a more complex origin. They usually accumulate in type 2 fibers and do not react to the mitochondrial oxidative enzymes. Tubular aggregates are present in diverse acquired and inherited clinical conditions. Myopathies in which the predominant pathological hallmark is tubular aggregates usually manifest in one of three major phenotypes: 1) slowly progressive, proximal predominant weakness; 2) myalgia with or without stiffness and cramps; 3) limb-girdle myasthenic syndrome. Muscle biopsy may play an indispensable role in diagnosing these conditions. Mutations in STIM1 and ORAI1 proteins cause tubular aggregate myopathies (TAM) and Stormorken syndrome (STRMK). These proteins are the main players in store-operated Ca²⁺ entry (SOCE) mechanism, a major regulator of Ca²⁺ homeostasis. Other regulators of SOCE include calsequestrin, ALG2, ALG14, DPAGT1, and GFPT1. Their dysfunction impacts Ca²⁺ homeostasis and causes conditions overlapping with TAM/STRMK at the clinical and histological level.