Gaucher's disease (GD) is one of the most prevalent lysosomal storage disorders (LSDs) and a rare
genetic disease for which specific
therapy is now available. GD is an autosomal, recessive, inborn error of
glycosphingolipid metabolism, due to a deficiency in the
enzyme acid beta-glucosidase. Partial deficiency of
acid beta-glucosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomitant
anemia and
thrombocytopenia in non-neuronopathic, type 1 GD. Severe deficiency of
glucocerebrosidase caused by severe mutations is additionally associated with
neurological manifestations in the less common type 2 and type 3 GD subtypes. Outside of the Ashkenazi Jewish community, a high molecular diversity is observed. Clarification of genotype/phenotype relationship and the identification of modifier loci that impact on GD phenotypes remains a critical area for research.
Enzyme replacement therapy (ERT) is proven to be safe and effective in the treatment of type 1 GD, establishing
imiglucerase as the current standard of care. Amelioration of hepatosplenomegaly and of hematological manifestations is usually apparent within 6-12 months, whereas the
bone disease responds more slowly. ERT cannot reverse the neurological deficits in type 2 or type 3 GD. Small molecule inhibitors of
glucosylceramide synthase are being developed for substrate reduction
therapy. Other potential therapeutic options such as chaperon-mediated
enzyme enhancement
therapy and gene therapy are being explored.