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Treatment with miglustat reverses the lipid-trafficking defect in Niemann–Pick disease type C

Lachmann, Robin H., te Vruchte, Danielle, Lloyd-Evans, Emyr ORCID:, Reinkensmeier, Gabriele, Sillence, Daniel J., Fernandez-Guillen, Luisa, Dwek, Raymond A., Butters, Terry D., Cox, Timothy M. and Platt, Frances M. 2004. Treatment with miglustat reverses the lipid-trafficking defect in Niemann–Pick disease type C. Neurobiology of Disease 16 (3) , pp. 654-658. 10.1016/j.nbd.2004.05.002

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Niemann–Pick disease type C (NP-C) is a hereditary neurovisceral lipid storage disorder. Although traditionally considered a primary cholesterol storage disorder, a variety of glycolipids accumulate in NP-C cells, which resemble those from glycosphingolipidosis patients. Substrate reduction therapy (SRT) with miglustat, an inhibitor of glycosphingolipid biosynthesis, is a novel therapy for the glycosphingolipidoses. We report the use of SRT in a patient with NP-C. We show that depletion of glycosphingolipids by miglustat treatment reduces pathological lipid storage, improves endosomal uptake and normalises lipid trafficking in peripheral blood B lymphocytes. The demonstration that treatment with miglustat, which has no direct effect on cholesterol metabolism, corrects the abnormal lipid trafficking seen in B lymphocytes in NP-C indicates that glycosphingolipid accumulation is the primary pathogenetic event in NP-C. These observations support the use of SRT in patients with this devastating neurodegenerative disease.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0969-9961
Last Modified: 27 Oct 2022 08:48

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