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

被引:124
作者
Lachmann, RH
Vruchte, DT
Lloyd-Evans, E
Reinkensmeier, G
Sillence, DJ
Fernandez-Guillen, L
Dwek, RA
Butters, TD
Cox, TM
Platt, FM
机构
[1] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England
[2] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England
关键词
Niemann-Pick disease type C; substrate reduction therapy; miglustat; glycosphingolipidoses; lipid trafficking;
D O I
10.1016/j.nbd.2004.05.002
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:654 / 658
页数:5
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