title: Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C.
abstract: 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.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK. rhl20@cam.ac.uk
authors.forename: Robin H
authors.initials: RH
authors.lastname: Lachmann
authors.forename: Danielle
authors.initials: D
authors.lastname: te Vruchte
authors.forename: Emyr
authors.initials: E
authors.lastname: Lloyd-Evans
authors.forename: Gabriele
authors.initials: G
authors.lastname: Reinkensmeier
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sillence
authors.forename: Luisa
authors.initials: L
authors.lastname: Fernandez-Guillen
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D000328:Adult; D001896:Boron Compounds; D002478:Cells, Cultured; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005456:Fluorescent Dyes; D005962:Glucosylceramidase / Q000008:administration & dosage*; D006017:Glycolipids / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D009542:Niemann-Pick Diseases / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D005456:Fluorescent Dyes; D006017:Glycolipids; D005962:Glucosylceramidase; C090568:imiglucerase