title: Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database.
abstract: BACKGROUND
  Niemann-Pick disease type C (NP-C) is a rare neurovisceral lipid storage disorder characterised by progressive, disabling neurological symptoms and premature death in most patients. During the last decade, national cohort studies have accrued a great deal of data on the symptomatology and natural history of NP-C.
  
  
  METHODS
  In an observational cohort study, we present a substantial update based on the clinical presentation and follow-up of all known UK-based patients with a confirmed diagnosis of NP-C who have been tracked on an electronic database at the Department of Genetic Medicine, University of Manchester, UK. Patients were stratified according to accepted age-at-neurological-onset categories. Data on patients' clinical signs and symptoms, medical history and genetic studies are summarised using descriptive methods.
  
  
  RESULTS
  A total of 146 patients with NP-C were included, representing the full known UK NP-C cohort, as observed from database information between 1999 and the end of 2011: 72 patients (49 %) were alive at the end of the observation period. Among a total of 116 patients (79 %) who possessed at least one identified, disease-causing NP-C gene mutation, 114 (98 %) had NPC1 and two (2 %) had NPC2 mutations. Overall, 53/194 (27 %) identified mutations were novel. Six patients (4 %) had an early, non-neurological neonatal onset form of NP-C. The numbers (%) of patients with accepted age-at-neurological onset forms were: 8 (5 %) early-infantile onset, 51 (35 %) late-infantile onset, 42 (29 %) juvenile onset, and 25 (17 %) adolescent/adult onset. Fourteen patients diagnosed based on visceral symptoms and/or sibling history, confirmed in most cases by genetic analysis, did not have any neurological manifestations at last follow up (11 patients with mean [SD] age at last follow up 2.5 [1.8] years: 3 with mean [SD] age at death 20.8 [15.9] years). A total of 51 patients (35 %) received miglustat therapy. The mean (SD) overall treatment duration up to the end of the observation period was 2.6 (2.3) years.
  
  
  CONCLUSIONS
  This UK cohort is the largest national NP-C cohort reported to date, and confirms the wide phenotypic variability of the disease, as reported in other countries. Further analyses are required to assess the impact of miglustat therapy on neurological disease progression.
authors.affiliation: NPUK, Vermont House, Concord, Washington, Tyne and Wear, NE37 2SQ, UK. jackie@niemann-pick.org.uk.
authors.forename: Jackie
authors.initials: J
authors.lastname: Imrie
authors.affiliation: Department of Genetic Medicine, University of Manchester, Manchester, UK. lesley.heptinstall@cmft.nhs.uk.
authors.forename: Lesley
authors.initials: L
authors.lastname: Heptinstall
authors.affiliation: Department of Genetic Medicine, University of Manchester, Manchester, UK. Stephen.Knight@thermofisher.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Knight
authors.affiliation: The Care Forum, Bristol, UK. katestrong@thecareforum.org.uk.
authors.forename: Kate
authors.initials: K
authors.lastname: Strong
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000453:epidemiology* / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D033921:Vesicular Transport Proteins; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins