Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat.

Frédéric Sedel,Ayman Tourbah,Elsa Kaphan,Christine Tranchant,Brigitte Chabrol,Damien Galanaud,Bertrand Audoin,Tomasz Burzykowski,Marie T Vanier

doi:10.1007/s00415-016-8051-1

Abstract

Niemann–Pick disease type C (NP-C) is a fatal progressive neurolipidosis involving neuronal storage of cholesterol and gangliosides. Miglustat, an inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NP-C. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale. Overall, 16 patients were included and received miglustat for a mean period of 30.6 months: 12 continued on miglustat throughout follow up, and 4 discontinued miglustat because of adverse effects (n = 2) or perceived lack of efficacy (n = 2). In the ‘continued’ subgroup, the mean (SD) annual progression of CFD scores decreased from 0.75 (0.94) before treatment to 0.29 (1.29) during the period between miglustat initiation and last follow-up. In the discontinued subgroup, CFD progression increased from 0.48 (0.44) pre-treatment to 1.49 (1.31) at last follow up (off treatment). Mean (SD) Cho/NAA ratio [normal level 0.48 (0.076)] decreased during miglustat treatment in the continued subgroup: 0.64 (0.12) at baseline (miglustat initiation), 0.59 (0.17) at 12-month follow up, and 0.48 (0.09) at 24-month follow up. Cho/NAA ratio remained relatively stable in the discontinued subgroup: 0.57 (0.15), 0.53 (0.04) and 0.55 (0.09), respectively. In conclusion, H-MRS Cho/NAA ratio might serve as an objective, quantitative neurological marker of brain dysfunction in NP-C, allowing longitudinal analysis of the therapeutic effect of miglustat.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-016-8051-1) contains supplementary material, which is available to authorized users.

Highlights

Niemann–Pick disease type C (NP-C) is a rare lysosomal storage disorder of autosomal recessive inheritance that is characterised by progressive neurological deterioration and premature death
An inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NPC. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale
In a previous publication we reported that treatment with miglustat could enable attainment of a normal Cho peak based on a follow-up study of three patients with NP-C treated for 24 months [8]

Summary

Introduction

Niemann–Pick disease type C (NP-C) is a rare lysosomal storage disorder of autosomal recessive inheritance that is characterised by progressive neurological deterioration and premature death. NP-C arises from mutations in either of two genes, NPC1 (in 95 % of patients) and NPC2, which code for proteins that play roles in intracellular cholesterol and glycolipid trafficking [29]. Deficiencies in NPC1 or NPC2 protein products leads to the accumulation of large amounts of free cholesterol and sphingomyelin in various peripheral organs and glycosphingolipids (primarily GM2 and GM3 gangliosides) in the brain. The mechanisms through which brain gangliosides accumulate are probably multiple, and the relationship between glycolipid storage and abnormalities in cholesterol transport are still controversial [29]. Death occurs approximately 12 years after the onset of psychiatric or neurological signs [26]

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