Lysosomal glycogen degradation (acid alpha-glucosidase) — Pompe disease (GSD II)

Lysosomal glycogen degradation is the acid-hydrolase route for breaking down the glycogen that is delivered to lysosomes by autophagy (glycophagy), complementing the cytosolic glycogenolysis pathway (phosphorylase/debranching). Its single enzyme is lysosomal acid alpha-glucosidase (GAA, acid maltase), a glycoside-hydrolase-family-31 enzyme that works at the acidic pH of the lysosomal lumen to completely hydrolyse glycogen to free glucose, cleaving the alpha-1,4-glucosidic bonds (and, more slowly, the alpha-1,6 branch linkages). GAA is synthesised as a precursor, N-glycosylated and mannose-6-phosphate-tagged for delivery to the lysosome, and proteolytically matured to its active forms. Because this route continuously clears autophagocytosed glycogen, its loss is not compensated by cytosolic glycogenolysis: inherited GAA deficiency causes Pompe disease (glycogen storage disease type II) — lysosomal glycogen accumulation producing hypertrophic cardiomyopathy and profound hypotonia in the infantile-onset form, and a progressive limb-girdle and respiratory myopathy in late-onset disease. It is one of the few glycogenoses treatable by enzyme replacement therapy (recombinant human GAA, e.g. alglucosidase/avalglucosidase alfa).