Glycogen Storage Disease Type II

Glycogen Storage Disease Type II results from mutations in the GAA gene encoding acid alpha-glucosidase, the sole enzyme responsible for degrading glycogen within lysosomes. GAA deficiency leads to massive glycogen accumulation, particularly in cardiac myocytes, skeletal muscle fibers, and anterior horn cells. The pathophysiology involves lysosomal dysfunction, autophagic impairment, cellular stress, and ultimately muscle fiber death. The infantile form, with complete or near-complete GAA deficiency, manifests with rapid glycogen accumulation primarily in cardiac tissue, leading to severe cardiomyopathy. Infantile-onset GSD II presents before age 1 year with hypotonia, poor feeding, failure to thrive, and cardiomegaly. Cardiac dysfunction is life-limiting, with most untreated patients dying from cardiac failure by age 2 years. Respiratory muscles are progressively affected. Late-onset GSD II begins in childhood with progressive proximal muscle weakness, preserving cardiac function initially. Adult-onset form is even more indolent, with slow progressive myopathy predominantly affecting lower extremities and trunk, presenting years or decades after birth. Respiratory insufficiency develops insidiously, often becoming apparent initially during sleep. CK levels are markedly elevated. Muscle biopsy shows characteristic glycogen-filled vacuoles. Enzyme replacement therapy with alglucosidase alfa has dramatically improved outcomes, particularly in infantile-onset disease, converting what was a uniformly fatal condition to a manageable chronic disease.