Alpha-galactosidase A (GLA) (GLA)

Alpha-galactosidase A (GLA) is a critical lysosomal enzyme responsible for the catabolism of glycosphingolipids, specifically by cleaving terminal alpha-galactosyl residues from substrates such as globotriaosylceramide (Gb3) [UniProt P06280]. Mutations in the GLA gene lead to Fabry disease, a progressive X-linked lysosomal storage disorder characterized by the systemic accumulation of Gb3 in the vascular endothelium, renal podocytes, and cardiomyocytes [NIH MedlinePlus]. This biochemical defect results in multi-organ dysfunction, including chronic kidney disease, hypertrophic cardiomyopathy, and an increased risk of premature stroke [StatPearls]. As a therapeutic target, GLA is primarily addressed through enzyme replacement therapy (ERT), which utilizes recombinant versions of the enzyme (e.g., agalsidase alfa and beta) to clear accumulated substrates [FDA Fabrazyme Label]. Additionally, the pharmacological chaperone migalastat is used to stabilize certain amenable mutant forms of GLA, enhancing their trafficking to the lysosome and restoring enzymatic function [FDA Galafold Label]. Emerging therapies also include pegylated enzyme variants designed for improved stability and reduced immunogenicity [EMA Elfabrio Summary].

Other names

Alpha-D-galactosidase AAlpha-D-galactoside galactohydrolaseMelibiaseAgalsidase

Enzyme replacement therapy (ERT) provides exogenous recombinant Alpha-galactosidase A to substitute for the deficient endogenous enzyme, facilitating the breakdown of accumulated glycosphingolipids [FDA Fabrazyme Label]. Pharmacological chaperones, such as migalastat, bind to and stabilize specific amenable mutant forms of the enzyme in the endoplasmic reticulum, promoting proper folding and trafficking to the lysosome where enzymatic activity is restored [FDA Galafold Label].