Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C.
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.
Lachmann
Robin H
RH
Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK. rhl20@cam.ac.uk
te Vruchte
Danielle
D
Lloyd-Evans
Emyr
E
Reinkensmeier
Gabriele
G
Sillence
Daniel J
DJ
Fernandez-Guillen
Luisa
L
Dwek
Raymond A
RA
Butters
Terry D
TD
Cox
Timothy M
TM
Platt
Frances M
FM
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*
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D005456:Fluorescent Dyes; D006017:Glycolipids; D005962:Glucosylceramidase; C090568:imiglucerase