The online version of this article (doi:10.1007/s00415-016-8051-1) contains supplementary material, which is available to authorized users.
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.
Supplementary material 1 (DOCX 30 kb)415_2016_8051_MOESM1_ESM.docx
Actelion (2014) Miglustat (Zavesca ®) summary of product characteristics. EMA (EudraPharm) http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000435/human_med_001171.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125. Accessed 9 Nov 2015
Fecarotta S, Amitrano M, Romano A, Della Casa R, Bruschini D, Astarita L, Parenti G, Andria G (2011) The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann–Pick disease type C after therapy with miglustat. Am J Med Genet A 155A:540–547 CrossRefPubMed
Fecarotta S, Romano A, Della Casa R, Del Giudice E, Bruschini D, Mansi G, Bembi B, Dardis A, Fiumara A, Di Rocco M, Uziel G, Ardissone A, Roccatello D, Alpa M, Bertini E, D’Amico A, Dionisi-Vici C, Deodato F, Caviglia S, Federico A, Palmeri S, Gabrielli O, Santoro L, Filla A, Russo C, Parenti G, Andria G (2015) Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann–Pick disease type C. Orphanet J Rare Dis 10:22 CrossRefPubMedPubMedCentral
Gropman AL (2005) Expanding the diagnostic and research toolbox for inborn errors of metabolism: the role of magnetic resonance spectroscopy. Mol Genet Metab 86:2–9 PubMed
Heron B, Valayannopoulos V, Baruteau J, Chabrol B, Ogier H, Latour P, Dobbelaere D, Eyer D, Labarthe F, Maurey H, Cuisset JM, de Villemeur TB, Sedel F, Vanier MT (2012) Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C. Orphanet J Rare Dis 7:36 CrossRefPubMedPubMedCentral
Patterson MC, Mengel E, Vanier MT, Schwierin B, Muller A, Cornelisse P, Pineda M, Investigators NPCR (2015) Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann–Pick disease type C: an observational cohort study. Orphanet J Rare Dis 10:65 CrossRefPubMedPubMedCentral
Pineda M, Perez-Poyato MS, O’Callaghan M, Vilaseca MA, Pocovi M, Domingo R, Portal LR, Perez AV, Temudo T, Gaspar A, Penas JJ, Roldan S, Fumero LM, de la Barca OB, Silva MT, Macias-Vidal J, Coll MJ (2010) Clinical experience with miglustat therapy in pediatric patients with Niemann–Pick disease type C: a case series. Mol Genet Metab 99:358–366 CrossRefPubMed
Pineda M, Wraith JE, Mengel E, Sedel F, Hwu WL, Rohrbach M, Bembi B, Walterfang M, Korenke GC, Marquardt T, Luzy C, Giorgino R, Patterson MC (2009) Miglustat in patients with Niemann–Pick disease type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab 98:243–249 CrossRefPubMed
Wassif CA, Cross JL, Iben J, Sanchez-Pulido L, Cougnoux A, Platt FM, Ory DS, Ponting CP, Bailey-Wilson JE, Biesecker LG, Porter FD (2015) High incidence of unrecognized visceral/neurological late-onset Niemann–Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med. doi: 10.1038/gim.2015.25(epub before print)PubMed
- Normalisation of brain spectroscopy findings in Niemann–Pick disease type C patients treated with miglustat
Marie T. Vanier
- Springer Berlin Heidelberg