Lysosomal acid alpha-glucosidase (GAA) (GAA)

Lysosomal acid alpha-glucosidase (GAA) is an essential enzyme located within the lysosome that catalyzes the breakdown of glycogen into glucose by cleaving alpha-1,4 and alpha-1,6 glycosidic linkages [1]. It is synthesized as a 110 kDa precursor that undergoes complex glycosylation and proteolytic processing to reach its mature, active forms [1, 2]. A deficiency in GAA activity leads to Pompe disease (Glycogen Storage Disease Type II), a progressive metabolic disorder characterized by the accumulation of glycogen in various tissues, most notably cardiac and skeletal muscle [4]. This accumulation causes cellular dysfunction, leading to muscle weakness, respiratory insufficiency, and potentially fatal cardiomyopathy in infants [4]. Therapeutic strategies focus on enzyme replacement therapy (ERT), which provides recombinant human GAA to restore lysosomal glycogen degradation [3]. Modern treatments like cipaglucosidase alfa (Pombiliti) are often paired with chaperones like miglustat to enhance enzyme stability and uptake into target tissues [3]. Monitoring of the disease and treatment efficacy typically involves measuring muscle function and biochemical markers such as urinary glucose tetrasaccharides [4].

Other names

Acid maltaseAlpha-1,4-glucosidaseGlucosidase alpha acidAcid alpha-glucosidaseGAA

Enzyme replacement therapy (ERT) restores lysosomal glycogen hydrolysis by providing exogenous recombinant human GAA, which is targeted to lysosomes via mannose-6-phosphate receptors [1, 3]. Pharmacological chaperones like miglustat may be used to stabilize the recombinant enzyme, improving its pharmacokinetic profile and lysosomal delivery [3].