Gaucher Disease

Dominique P Germain, Université de Versailles–St Quentin en Yvelines, Garches, France

Published online: September 2009

DOI: 10.1002/9780470015902.a0021432

Gaucher disease (GD) is a lysosomal storage disorder due to deficiency in acid -glucosidase. Partial enzyme deficiency is associated with parenchymal disease of the liver, spleen and bone marrow in non-neuronopathic, type 1 GD, while complete deficiency, caused by severe mutations in the GBA gene, is additionally associated with neurological manifestations in type 2 and type 3 GD. Specific therapy is available for GD: enzyme replacement therapy has proven safe and effective and is the current standard of care for type 1 GD but cannot reverse the neurological deficits in type 2 or type 3. New recombinant enzymes are currently in clinical trials. Small-molecule inhibitors of glucosylceramide synthase are both available and being developed for substrate reduction therapy. Active-site-specific pharmacological chaperones and gene therapy are being explored as other potential therapeutic options.

Key concepts:

  • Gaucher disease (GD) is an autosomal recessive inborn error of sphingolipid metabolism due to the deficient activity of the lysosomal enzyme acid -glucosidase.
  • Three phenotypes of GD are conventionally distinguished on the basis of the absence (type 1) or presence and severity (types 2 and 3) of central nervous system involvement.
  • Patients with type 1 GD may present with splenomegaly, hepatomegaly, radiologic bone disease, thrombocytopaenia, anaemia and bone pain.
  • A higher incidence of multiple myeloma in GD has been reported and patients should have their immunoglobulin profile determined at diagnosis and monitored every 2 years.
  • The natural course of GD varies widely, with some subjects remaining asymptomatic up to the age of 70 or 80 years, in contrast to the sometimes fatal progression in childhood. This emphasizes the need for a regular follow-up to enable timely initiation of enzyme therapy.
  • The demonstration of a deficient activity of acid -glucosidase activity in leukocytes is the reference laboratory method which should be used to confirm the clinical diagnosis of GD.
  • Enzyme replacement therapy (ERT) with imiglucerase is central to modern management of GD. The aim of ERT is to achieve reversal of the symptomatic clinical manifestations and prevent irreversible lesions of the various organs.
  • Over 3500 patients are receiving treatment worldwide, with a maximum follow-up of 15 years. The therapeutic results have been the subject of several analyses. The response to ERT is generally excellent, although marked inter-individual variability exists. ERT is safe and well tolerated.
  • Substrate reduction therapy (miglustat) reduces tissue glycosphingolipid storage by limiting the amount of the precursor synthesized to a level that can be cleared by the mutant enzyme with residual hydrolytic activity.
  • Since the neurological forms of GD do not respond to ERT, further research on other therapeutic strategies including gene therapy, substrate reduction therapy and chaperone therapy is warranted.

Keywords: Gaucher disease; lyosome; enzyme replacement therapy; substrate reduction therapy; active-site chaperone therapy

Figure 1. Spleen echography in an untreated 40-year-old woman with severe Gaucher disease showing heterogeneous multinodular splenomegaly with long axis measured at 21.8 cm.
Figure 2. Liver ultrasound showing hepatomegaly (long axis=21.6 cm) in the same 40-year-old female patient.
Figure 3. Bilateral hip replacement after avascular necrosis of femoral heads in a 45-year-old man with type 1 Gaucher disease.
Figure 4. MRI showing femoral bone infarcts in a 37-year-old male with Gaucher disease prior to enzyme replacement therapy with imiglucerase.
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 Further Reading
    book Beutler E and Grabowski GA (2001) "Gaucher disease". In: Scriver CR, Sly WS and Childs B et al. (eds) The Metabolic and Molecular Bases of Inherited Disease, pp. 3635–3668. New York: McGraw-Hill, Inc.
    book Erikson A, Bembi B and Schiffmann R (1997) "Neurologic forms of Gaucher disease". In: Zimran A (ed.) Gaucher's Disease, pp. 711–723. London, UK: Bailliere Tindall.
    book Germain DP (2007) "The liver in intracellular and extracellular lipidosis". In: Rodes J, Benhamou J-P, Blei A, Reichen J and Rizzetto M (eds) The Textbook of Hepatology: From Basic Science to Clinical Practice. Oxford, UK: Blackwell.
    ePath Online Mendelian Inheritance in Man (OMIM). An internet version of the catalogue of genetic disorders assembled by Victor Mc Kusick. http://www.ncbi.nlm.nih.gov/Omim.

Related Sub-Topics:

Cell Compartments and Cellular Organelles | Specific Genetic Disorders | Enzymes: Structure and Action Mechanism | Lipids: Structure, Function, Metabolism
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Article Title: Gaucher Disease
 
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Germain, Dominique P(Sep 2009) Gaucher Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021432]