Gaucher's disease: a paradigm for interventional genetics

• Published in: Clinical genetics Vol. 65; no. 2; pp. 77 - 86
• Main Author: Germain, DP
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden , USA Munksgaard International Publishers 01.02.2004; Blackwell
• Subjects: Biological and medical sciences; enzyme replacement therapy; Errors of metabolism; Gaucher Disease - classification; Gaucher Disease - diagnosis; Gaucher Disease - genetics; Gaucher Disease - therapy; Gaucher's disease; Genetic Therapy; Genotype; Humans; interventional genetics; Lipids (lysosomal enzyme disorders, storage diseases); lysosome; Medical sciences; Metabolic diseases; Phenotype; substrate reduction therapy; Nervous system diseases; Replacement therapy; Paradigm; enzyme replacement therapy; Enzyme; Lysosome; Metabolic diseases; Lipids; Enzymopathy; Cerebral disorder; Genetic disease; interventional genetics; Reduction; Gaucher disease; Central nervous system disease; Genetics; substrate reduction therapy; Lipoidosis; Gaucher's disease
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.0009-9163.2004.00217.x

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 β‐glucosidase. Partial deficiency of acid β‐glucosidase is associated with parenchymal disease of the liver, spleen, and bone marrow with concomittant 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.