title: 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.
abstract: BACKGROUND
  Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat.
  
  
  METHODS
  The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if <3 scores were lower/unchanged between enrolment and last follow-up visit.
  
  
  RESULTS
  In total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early-infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (≥15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data.
  
  
  CONCLUSIONS
  Disability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years.
authors.affiliation: Department of Neurology, Mayo Clinic, 200 first Street SW, Rochester, MN, 55905, USA. patterson.marc@mayo.edu.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Patterson
authors.affiliation: Villa Metabolica, University of Mainz, Mainz, Germany. eugen.mengel@unimedizin-mainz.de.
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.affiliation: INSERM Unit 820, Lyon, France. marie-t.vanier@inserm.fr.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. Barbara.Schwierin@actelion.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schwierin
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. audrey.muller@actelion.com.
authors.forename: Audrey
authors.initials: A
authors.lastname: Muller
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. peter.cornelisse@ext.actelion.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Cornelisse
authors.affiliation: Fundació Hospital Sant Joan de Déu, CIBERER, Barcelona, Spain. pineda@hsjdbcn.org.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pineda
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000473:pathology; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat