A major part of the inherited disorders in metabolism is caused by inherited defects in lysosomal glycosidases. Most prominent are Gaucher disease (lysosomal β-glycosidase deficiency involving the GBA gene and degradation of the lipid glucosylceramide), Pompe disease (lysosomal α-glucosidase deficiency involving the GAA gene and degradation of glycogen) and Fabry disease (lysosomal α-galactosidase A deficiency involving the GLA gene and degradation of globotriaosylceramide).
A frontrunner in developing advanced diagnostics and effective therapies has been, and still is, Gaucher disease. There exists no strict relationship between GBA genotype and phenotypic manifestation of Gaucher disease. In particular, homozygotes for common milder mutations, like N370S GBA, may express variable disease severity from severe organomegalies and hematological symptoms to a virtual asymptomatic course. This has prompted a search for biomarkers. In Gaucher disease, glucosylceramide laden macrophages (Gaucher cells) are a hallmark of disease. Identified have been as biomarkers specific proteins secreted by these storage cells: chitotriosidase, CCL18 and gp-NMB. These proteins are markedly elevated in plasma of symptomatic patients, assisting confirmation of diagnosis and monitoring of disease. More recently, de-acylated glucosylceramide, named glucosylsphingosine, has been found to be about 200-fold elevated in plasma of Gaucher patients. With sensitive assays, employing 13c-encoded internal standard, glucosylsphingosine can be determined and used to monitor disease status. Several treatments have been developed and are presently registered, including enzyme supplementation and substrate reduction therapy. In development are gene therapy, small compound chaperone and activator therapies. The design and development of activity-based probes specifically labelling glucocerebrosidase is assisting further diagnosis and optimization of therapeutic interventions. Similar approaches are presently copied for other lysosomal glycosidase deficiencies such as Pompe and Fabry disease.