title: Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat.
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.
authors.affiliation: Department of Neurology, AP-HP, Federation of Nervous System Diseases, Salpêtrière Hospital, 47 Boulevard de l'Hôpital, 75651, Paris Cedex 13, France. frederic.sedel@medday-pharma.com.|Neuro-Metabolic Unit and Reference Center for Lysosomal Diseases, GRC13UPMC, Pierre and Marie Curie University, AP-HP, Salpêtrière Hospital, Paris, France. frederic.sedel@medday-pharma.com.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sedel
authors.affiliation: Department of Pediatrics, La Timone Hospital, CHU of Marseille, Marseille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.affiliation: Department of Neurology, Division of Clinical Neuroscience, Aix-Marseille University, CNRS, CRMBM UMR 7339, AP-HM, Timone Hospital, Marseille, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Audoin
authors.affiliation: Department of Neurology, Division of Clinical Neuroscience, CHU Timone, AP-HM, Marseille, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Kaphan
authors.affiliation: Department of Neurology, CHU Hautepierre and FMTS, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: International Drug Development Institute (IDDI), Louvain-la-Neuve and Hasselt University, Hasselt, Belgium.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Burzykowski
authors.affiliation: Department of Neurology, Central University Hospital, Faculté de Médecine de Reims URCA and EA 2027, Université Paris VIII, Sant-Denis, France.
authors.forename: Ayman
authors.initials: A
authors.lastname: Tourbah
authors.affiliation: INSERM Unit 820, Lyon, France.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.affiliation: Department of Neuroradiology, Pierre and Marie Curie University, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Galanaud
mesh_terms: D017485:1-Deoxynojirimycin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects* / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D004185:Disability Evaluation; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010352:Patient Dropouts; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; D001224:Aspartic Acid; C000179:N-acetylaspartate; C059896:miglustat; D002794:Choline
keywords: Magnetic resonance spectroscopy; Miglustat; Niemann–Pick disease type C; Substrate reduction therapy