Miglustat in Niemann-Pick disease type C patients: a review

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Abstract

Objective

Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive, neurodegenerative disease associated with a wide variety of progressive neurological manifestations. Miglustat is indicated for the treatment of progressive neurological manifestations in both adults and children. Since approval in 2009 there has been a vast growth in clinical experience with miglustat. The effectiveness of miglustat has been assessed using a range of measures.

Methods

Comprehensive review of published data from studies of cellular neuropathological markers and structural neurological indices in the brain, clinical impairment/disability, specific clinical neurological manifestations, and patient survival.

Results

Cranial diffusion tensor imaging and magnetic resonance spectroscopy studies have shown reduced levels of choline (a neurodegeneration marker), and choline/N-acetyl aspartate ratio (indicating increased neuronal viability) in the brain during up to 5 years of miglustat therapy, as well as a slowing of reductions in fractional anisotropy (an axonal/myelin integrity marker). A 2-year immunoassay study showed significant reductions in CSF-calbindin during treatment, indicating reduced cerebellar Purkinje cell loss. Magnetic resonance imaging studies have demonstrated a protective effect of miglustat on cerebellar and subcortical structure that correlated with clinical symptom severity. Numerous cohort studies assessing core neurological manifestations (impaired ambulation, manipulation, speech, swallowing, other) using NP-C disability scales indicate neurological stabilization over 2–8 years, with a trend for greater benefits in patients with older (non-infantile) age at neurological onset. A randomized controlled trial and several cohort studies have reported improvements or stabilization of saccadic eye movements during 1–5 years of therapy. Swallowing was also shown to improve/remain stable during the randomized trial (up to 2 years), as well as in long-term observational cohorts (up to 6 years). A meta-analysis of dysphagia – a potent risk factor for aspiration pneumonia and premature death in NP-C – demonstrated a survival benefit with miglustat due to improved/stabilized swallowing function.

Conclusions

The effects of miglustat on neurological NP-C manifestations has been assessed using a range of approaches, with benefits ranging from cellular changes in the brain through to visible clinical improvements and improved survival.

Electronic supplementary material

The online version of this article (10.1186/s13023-018-0844-0) contains supplementary material, which is available to authorized users.

Related collections

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Author and article information

Contributors

Mercè Pineda: +34 932 033 959 , pineda@sjdhospitalbarcelona.org

Mark Walterfang: Mark.Walterfang@mh.org.au

Marc C. Patterson: Patterson.Marc@mayo.edu

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 15 August 2018

Publication date PMC-release: 15 August 2018

Publication date Collection: 2018

Volume: 13

Electronic Location Identifier: 140

Affiliations

[1 ]ISNI 0000 0001 0663 8628, GRID grid.411160.3, Fundacio Hospital Sant Joan de Déu, ; Barcelona, Spain

[2 ]Florey Institute of Neuroscience and Mental Health, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia

[3 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Mayo Clinic, ; Rochester, MN USA

[4 ]ISNI 0000 0001 0663 8628, GRID grid.411160.3, Hospital Sant Joan de Déu, ; Passeig de Sant Joan de Déu No. 2, Esplugues, 8950 Barcelona, Spain

Article

Publisher ID: 844

DOI: 10.1186/s13023-018-0844-0

PMC ID: 6094874

PubMed ID: 30111334

SO-VID: 06c68bd2-84d7-4c95-bafd-34e9e1c5fb6a

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.