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Substrate reduction therapy of glycosphingolipid storage disorders

  • SSIEM SYMPOSIUM 2005
  • Published:
Journal of Inherited Metabolic Disease

Summary

In the last 15 years enormous progress has been made regarding therapy of type I Gaucher disease, a severely disabling disorder characterized by intralysosomal storage of glucosylceramide in tissue macrophages. Effective enzyme replacement therapy of type I Gaucher disease, based on chronic intravenous administration of mannose-terminated recombinant human glucocerebrosidase, has been available since 1990 and has been applied in several thousand patients without serious adverse effects. An alternative therapeutic approach, so-called substrate reduction therapy, is based on partial reduction of the synthesis of glucosylceramide and hence of subsequent metabolites. Oral administration of an inhibitor of glucosylceramide synthesis (N-butyldeoxynojirimycin, registered in Europe since 2002 as miglustat (Zavesca)), is effective in reversing clinical symptoms in type I Gaucher patients with mild to moderate disease manifestations. The growing long-term experience with substrate reduction therapy indicates that this treatment is also without major adverse effects. Substrate reduction therapy, in conjunction with enzyme replacement therapy, may play an important role in the future clinical management of patients suffering from type I Gaucher disease. Clinical trials are under way that should reveal the value of substrate reduction for maintenance therapy of type I Gaucher disease and for treatment of neuronopathic variants of Gaucher disease, Niemann–Pick disease type C, late-onset Tay–Sachs disease and Sandhoff disease.

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Authors and Affiliations

  1. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands

    Johannes M. F. G. Aerts, Rolf G. Boot & Johanna E. M. Groener

  2. Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Carla E. M. Hollak

  3. Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Mario Maas

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  1. Johannes M. F. G. Aerts
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  2. Carla E. M. Hollak
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  3. Rolf G. Boot
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  4. Johanna E. M. Groener
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  5. Mario Maas
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Correspondence to Johannes M. F. G. Aerts.

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Communicating editor: Jean-Marie Saudubray

Competing interests: None declared

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Aerts, J.M.F.G., Hollak, C.E.M., Boot, R.G. et al. Substrate reduction therapy of glycosphingolipid storage disorders. J Inherit Metab Dis 29, 449–456 (2006). https://doi.org/10.1007/s10545-006-0272-5

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