24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: Follow up using brain spectroscopy

https://doi.org/10.1016/j.ymgme.2008.10.002Get rights and content

Abstract

Niemann-Pick C (NPC) is a fatal progressive neurolipidosis. Miglustat, an inhibitor of glycosphingolipid synthesis, has been proposed to treat patients but questions remain regarding its efficacy. A major problem has been the lack of suitable objective efficacy endpoints. Three adults with NPC were treated with miglustat for 24 months. Efficacy of treatment was assessed clinically and using brain magnetic resonance spectroscopy. All patients reported mild clinical improvement or stabilization. Furthermore, a sustained decrease in the choline/creatine ratio was observed in all three patients over time. Although these preliminary results require confirmation on a larger cohort of patients, they suggest that miglustat has some beneficial effect on brain dysfunction in NPC and that MRS could be used routinely as a non invasive surrogate marker of treatment efficacy.

Introduction

Niemann-Pick disease type C (NPC) is a progressive neurological lysosomal storage disease of autosomal recessive inheritance. NPC arises from mutations in two genes, NPC1 (95% of patients) and NPC2, that play a role in intracellular cholesterol and glycolipid trafficking [1]. While large amounts of free cholesterol accumulate in peripheral organs, the most conspicuous storage in brain concerns glycosphingolipids, essentially GM2 and GM3 gangliosides. Mechanisms by which gangliosides accumulate are probably multiple and the relationship between glycolipid storage and abnormalities in cholesterol transport are still controversial. Neurological signs of NPC arise both from neuronal loss and neuronal dysfunction [2]. While symptoms related to cell loss are less likely to be improved by treatments, restoring cellular homeostasis by any therapeutic approach could potentially reverse cellular dysfunction and then provide clinical stabilization or improvement.

Adult forms of NPC are characterized by psychiatric disorders, vertical supranuclear gaze palsy, cerebellar ataxia, cognitive deficits, movement disorders, gelastic cataplexy and hepatosplenomegaly [3]. Death occurs on average 12 years after the onset of psychiatric or neurological signs. N-butyl-deoxynojirimycin (NB-DNJ, OGT 918, miglustat) is an inhibitor of glucosylceramide synthetase, currently approved for the treatment of Gaucher type I disease [4]. It also inhibits the biosynthesis of all glycolipids derived from the glucosylceramide precursor, among which most gangliosides. Consequently, this compound has been tested in animal models of NPC: treatment with miglustat delayed onset of neurological symptoms, prolonged survival and improved brain neuropathology [5]. However, in humans, results are equivocal. Several case reports described some stabilization or improvement in adult patients but not in children [6], [7], [8]: as in Gaucher disease type II, early onset forms of NPC are usually more severe, rapidly progress and are therefore less accessible to treatments. A recent open-randomized controlled trial in patients with a late onset disease, reported stabilization or improvement of horizontal saccade velocity, swallowing and ambulatory index, however, statistical difference was weak [9].

A major problem in previous trials with miglustat in NPC has been the lack of quantifiable objective markers that could be predictive of clinical efficacy. Neurological examination can be quantified through clinical scales but these are not fully appropriate to NPC: given the slow mechanism of action of miglustat, as observed in Gaucher disease [10] and given the probable irreversible neuronal damage, a rapid clinical improvement is not expected.

Here we report the follow up with MRS of three patients treated with miglustat for 24 months. Interestingly, we observed a decrease of the choline/creatine ratio in all three patients.

Section snippets

Methods

From March 2006 to December 2008, nine patients with NPC were treated with miglustat off license in France. Patients who accessed to treatment had relative late-onset-diseases (juvenile or adult forms) and were relatively autonomous i.e., without gastric tube, dementia or severe psychiatric problems. Follow up with serial brain MRS was obtained in three patients followed at the Pitié-Salpêtrière Hospital (Paris). Only these three patients are reported here. All patients were treated initially

Clinical data

The clinical, biological and genetic characteristics of the three patients have been previously reported [3]. Patients 1–3 in the present study correspond to cases 11, 13 and 7, respectively, in Sevin et al. [3]. Main clinical characteristics, genotypes, and clinical evolution under treatment with miglustat are summarized in Table 1. Clinical evolution under treatment with miglustat is summarized in Table 2. In brief, after 24 months of treatment, all three patients exhibited mild improvement

Discussion

We observed a sustained decrease in the Cho/Cr ratio in three NPC patients treated with miglustat for up to 24 months. This ratio decreased after 18 months of treatment and was observed whatever the dose of miglustat (600 mg vs 300 mg/day). Since Cho/Cr is considered as a marker of brain dysfunction, it is suggested that miglustat has a beneficial effect over time. Interestingly, the same effect was observed in patient 3 who had 22 years of symptomatic disease versus 4 years in patients 1 and 2

References (15)

There are more references available in the full text version of this article.

Cited by (64)

  • Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

    2014, Journal of Lipid Research
    Citation Excerpt :

    Similarly, in Npc1−/− mice, miglustat reduced ganglioside storage in LEs/Ls. In addition, miglustat modestly extended life span of (87) and produced some neurological improvements in NPC patients (152–156). However, the mechanism underlying these clinical improvements is not clear because reduction of gangliosides in LEs/Ls of NPC-deficient mice does not appear to be beneficial (93–95).

  • Use of MRS in Inborn Errors of Metabolism. Canavan's Disease and MRS in Differential Diagnosis.

    2013, Magnetic Resonance Spectroscopy: Tools for Neuroscience Research and Emerging Clinical Applications
  • Extracellular matrix components: An intricate network of possible biomarkers for lysosomal storage disorders?

    2013, FEBS Letters
    Citation Excerpt :

    In addition, in the case of LSDs with neurological involvement, the setting in the discovery of analytes specifically related to central nervous system (CNS) is even more obscure. These disorders often require more imaginative approaches and represent an area of intense investigation in BM discovery, since there are very few available analytical tools which could potentially demonstrate CNS involvement [60–62]. The composition and spatial orientation of ECM varies significantly, both quantitatively and qualitatively, from organ to organ and is carefully regulated.

View all citing articles on Scopus
View full text