Gaucher Disease

Abstract

Gaucher disease (GD) is a lysosomal storage disorder due to deficiency in acid β‐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 β‐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 β‐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.

close

References

Altarescu G, Hill S, Wiggs E et al. (2001) The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease. Journal of Pediatrics 138(4): 539–547.

Altarescu G, Schiffmann R, Parker CC et al. (2000) Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease. Blood Cells, Molecules & Diseases 26(4): 285–290.

Andersson HC, Charrow J, Kaplan P et al. (2005) Individualization of long‐term enzyme replacement therapy for Gaucher disease. Genetics in Medicine 7(2): 105–110.

Andersson H, Kaplan P, Kacena K et al. (2008) Eight‐year clinical outcomes of long‐term enzyme replacement therapy for 884 children with Gaucher disease type 1. Pediatrics 122(6): 1182–1190.

Aviezer D, Brill‐Almon E, Shaaltiel Y et al. (2009) A plant‐derived recombinant human glucocerebrosidase enzyme‐a preclinical and phase I investigation. PLoS ONE 4: e4792.

Baldellou A, Andria G, Campbell PE et al. (2004) Paediatric non‐neuronopathic Gaucher disease: recommendations for treatment and monitoring. European Journal of Pediatrics 163(2): 67–75.

Barton NW, Brady RO, Dambrosia JM et al. (1991) Replacement therapy for inherited enzyme deficiency: macrophage‐targeted glucocerebrosidase for Gaucher's disease. New England Journal of Medicine 324: 1464–1470.

Beutler E and Grabowski GA (1995) Gaucher disease. In: Scriver CR, Beaudet A, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Diseases, pp. 2641–2670. New York: McGraw‐Hill.

Biegstraaten M, van Schaik IN, Aerts JM et al. (2008) ‘Non‐neuronopathic’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. Journal of Inherited Metabolic Dissease 31(3): 337–349.

Boot RG, Verhoek M, de Fost M et al. (2004) Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 103(1): 33–39.

Brady RO, Barton NW and Grabowski GA (1993) The role of neurogenetics in Gaucher disease. Archives of Neurology 50: 1212–1224.

Brady RO, Kanfer JN and Shapiro D (1965) Metabolism of glucocerebrosidase II. Evidence of an enzymatic deficiency in Gaucher's disease. Biochemical and Biophysical Research Communications 18: 221–225.

Chamoles NA, Blanco M, Gaggioli D et al. (2002) Gaucher and Niemann–Pick diseases–enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn‐screening cards. Clinica Chimica Acta 317(1–2): 191–197.

Cox TM, Aerts JM, Andria G et al. (2003) The role of the iminosugar N‐butyldeoxynojirimycin (miglustat) in the management of type I (non‐neuronopathic) Gaucher disease: a position statement. Journal of Inherited Metabolic Disease 26: 513–526.

Cox TM, Aerts JM, Belmatoug N et al. (2008) Management of non‐neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring. Journal of Inherited Metabolic Disease 31(3): 319–336.

Cox T, Lachmann R, Hollak C et al. (2000) Novel oral treatment of Gaucher's disease with N‐butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355(9214): 1481–1485.

Deegan PB, Moran MT, McFarlane I et al. (2005) Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease. Blood Cells, Molecules & Diseases 35(2): 259–267.

Diaz‐Font A, Chabas A, Grinberg D et al. (2006) RNAi‐mediated inhibition of the glucosylceramide synthase (GCS) gene: a preliminary study towards a therapeutic strategy for Gaucher disease and other glycosphingolipid storage diseases. Blood Cells, Molecules & Diseases 37(3): 197–203.

Elstein D, Hollak C, Aerts JM et al. (2004) Sustained therapeutic effects of oral miglustat (Zavesca, N‐butyldeoxynojirimycin, OGT 918) in type I Gaucher disease. Journal of Inherited Metabolic Dissease 27(6): 757–766.

Eto Y and Ida H (1999) Clinical and molecular characteristics of Japanese Gaucher disease. Neurochemical Research 24(2): 207–211.

de Fost M, Hollak CE, Groener JE et al. (2006) Superior effects of high‐dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2‐center retrospective analysis. Blood 108: 830–835.

Germain DP (2004) Gaucher's disease: a paradigm for interventional genetics. Clinical Genetics 65(2): 77–86.

Germain DP, Kaneski CR and Brady RO (2001) Mutation analysis of the acid beta‐glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase. Mutation Research 483(1–2) : 89–94.

Germain DP, Puech JP, Caillaud C et al. (1998) Exhaustive screening of the acid beta‐glucosidase gene, by fluorescence‐ assisted mismatch analysis using universal primers: mutation profile and genotype/phenotype correlations in Gaucher disease. American Journal of Human Genetics 63: 415–427.

Goker‐Alpan O, Schiffmann R, LaMarca ME et al. (2004) Parkinsonism among Gaucher disease carriers. Journal of Medical Genetics 41(12): 937–940.

Grabowski GA (2000) Gaucher disease: considerations in prenatal diagnosis. Prenatal Diagnosis 20(1): 60–62.

Grabowski GA, Andria G, Baldellou A et al. (2004) Pediatric non‐neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements. European Journal of Pediatrics 163(2): 58–66.

Grabowski GA, Barton NW, Pastores G et al. (1995) Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose‐terminated glucocerebrosidase from natural and recombinant sources. Annals of Internal Medicine 1: 33–39.

Grabowski GA, Kacena K, Cole JA et al. (2009) Dose‐response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1. Genet Med 11: 92–100.

Hollak CEM, van Weely S, van Oers MHJ et al. (1994) Marked elevation of plasma chitotriosidase activity. a novel hallmark of Gaucher disease. Journal of Clinical Investigation 93: 1288–1292.

Hruska KS, Goker‐Alpan O and Sidransky E (2006) Gaucher disease and the synucleinopathies. Journal of Biomedicine and Biotechnology 2006(3): 78549.

Hruska KS, LaMarca ME, Scott CR et al. (2008) Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Human Mutation 29(5) : 567–583.

Hughes D, Cappellini MD, Berger M et al. (2007) Recommendations for the management of the haematological and onco‐haematological aspects of Gaucher disease. British Journal of Haematology 138(6): 676–686.

Kaplan P, Andersson HC, Kacena KA et al. (2006) The clinical and demographic characteristics of nonneuronopathic Gaucher disease in 887 children at diagnosis. Archives of Pediatrics & Adolescent Medicine 160(6): 603–608.

Lachmann RH, Grant IR, Halsall D et al. (2004) Twin pairs showing discordance of phenotype in adult Gaucher's disease. QJM 97(4): 199–204.

Maas M, van Kuijk C, Stoker J et al. (2003) Quantification of bone involvement in Gaucher disease: MR imaging bone marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging–initial experience. Radiology 229(2): 554–561.

Mistry PK, Sirrs S, Chan A et al. (2002) Pulmonary hypertension in type 1 Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy. Molecular Genetics and Metabolism 77: 91–98.

Petterschmitt J, Lukina E, Watman N et al. (2009) Genz‐112638, an investigational oral treatment for Gaucher disease type 1: Preliminary Phase 2 clinical trial results. Molecular Genetics and Metabolism 96: S34.

Platt FM and Jeyakumar M (2008) Substrate reduction therapy. Acta Paediatrica Supplement 97(457): 88–93.

Rosenbloom BE, Weinreb NJ, Zimran A et al. (2005) Gaucher disease and cancer incidence: a study from the Gaucher Registry. Blood 105: 4569–4572.

Sawkar AR, Cheng WC, Beutler E et al. (2002) Chemical chaperones increase the cellular activity of N370S beta‐glucosidase: a therapeutic strategy for Gaucher disease. Proceedings of the National Academy of Sciences of the USA 99(24): 15428–15433.

Sidransky E, LaMarca ME and Ginns EI (2007) Therapy for Gaucher disease: don't stop thinking about tomorrow. Molecular Genetics and Metabolism 90(2): 122–125.

Sims KB, Pastores GM, Weinreb NJ et al. (2008) Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48‐month longitudinal cohort study. Clinical Genetics 73(5): 430–440.

Stone DL, Carey WF, Christodoulou J et al. (2000) Type 2 Gaucher disease: the collodion baby phenotype revisited. Archives of Disease in Childhood. Fetal and Neonatal Edition 82(2): F163–F166.

Tayebi N, Callahan M, Madike V et al. (2001) Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Molecular Genetics and Metabolism 73(4): 313–321.

Tylki‐Szymanska A, Czartoryska B, Vanier MT et al. (2007) Non‐neuronopathic Gaucher disease due to saposin C deficiency. Clincal Genetics 72(6): 538–542.

Vellodi A, Bembi B, de Villemeur TB et al. (2001) Management of neuronopathic Gaucher disease: a European consensus. Journal of Inherited Metabolic Disease 24(3): 319–327.

Weinreb NJ, Charrow J, Andersson HC et al. (2002) Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. American Journal of Medicine 113(2): 112–119.

Wenstrup RJ, Bailey L, Grabowski GA et al. (2004) Gaucher disease: alendronate disodium improves bone mineral density in adults receiving enzyme therapy. Blood 104(5): 1253–1257.

Wenstrup RJ, Roca‐Espiau M, Weinreb NJ et al. (2002) Skeletal aspects of Gaucher disease: a review. British Journal of Radiology 75(suppl. 1): A2–A12.

Zimran A and Elstein D (2007) No justification for very high‐dose enzyme therapy for patients with type III Gaucher disease. Journal of Inherited Metabolic Disease 30(6): 843–844.

Zimran A, Loveday K, Fratazzi C et al. (2007) A pharmacokinetic analysis of a novel enzyme replacement therapy with gene‐activated human glucocerebrosidase (GA‐GCB) in patients with type 1 Gaucher disease. Blood Cells, Molecules & Diseases 39(1): 115–118.

Further Reading

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.

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.

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.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Germain, Dominique P(Sep 2009) Gaucher Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021432]