title: Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Republic: a surprisingly stable diagnostic rate spanning almost 40 years.
abstract: BACKGROUND
  Niemann-Pick disease type C (NPC) is a rare, fatal neurovisceral disorder with autosomal recessive inheritance, and featuring striking clinical variability dependent on the age at onset of neurological symptoms. We report data from a large cohort of 56 Czech patients with NPC diagnosed over a period of 37 years.
  
  
  METHODS
  An observational, retrospective analysis of historic and current clinical and laboratory information was performed among all NPC patients originating from the area of the contemporary Czech Republic and diagnosed between 1975 and 2012. All patients with ≥1 positive diagnostic test and relevant clinical information were included. Data on diagnostic methods (histopathological and/or ultrastructural; biochemical; genetic), clinical status and general information on treatment were collated. Data were examined in accordance with international guidelines for the management of NPC.
  
  
  RESULTS
  Between 1975 and 1985 diagnoses were based exclusively on specific histopathological findings, often at autopsy. Bone marrow smear (BMS) analyses have proved to be a very specific indicator for NPC and have become an important part of our diagnostic algorithm. Filipin staining and cholesterol esterification assays became the definitive diagnostic tests after 1985 and were applied in 24 of our patients. Since 2005, more and more patients have been assessed using NPC1/NPC2 gene sequencing. Twelve patients were diagnosed with neonatal/early-infantile onset NPC, 13 with the late-infantile onset form, 20 with the juvenile onset form, and nine with the adolescent/adult onset form. Two diagnosed patients remained neurologically asymptomatic at study completion. Nineteen patients were siblings. Causal NPC1 mutations were determined in 38 patients; two identical NPC2 mutations were identified in one patient. In total, 30 different mutations were identified, 14 of which have been confirmed as novel. The frequency of individual mutated NPC1 alleles in our cohort differs compared with previous published data: the most frequent mutant NPC1 allele was p.R1186H (n = 13), followed by p.P1007A (n = 8), p.S954L (n = 8) and p.I1061T (n = 4).
  
  
  CONCLUSIONS
  These data demonstrate the evolution of the diagnostic process in NPC over the last four decades. We estimate the contemporary birth prevalence of NPC in the Czech Republic at 0.93 per 100,000.
authors.affiliation: Institute of Inherited Metabolic Disorders, Charles University, First Faculty of Medicine, and General University Hospital in Prague, Prague, Czech Republic. helena.jahnova@vfn.cz.
authors.forename: Helena
authors.initials: H
authors.lastname: Jahnova
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvorakova
authors.forename: Hana
authors.initials: H
authors.lastname: Vlaskova
authors.forename: Helena
authors.initials: H
authors.lastname: Hulkova
authors.forename: Helena
authors.initials: H
authors.lastname: Poupetova
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebicek
authors.forename: Pavel
authors.initials: P
authors.lastname: Jesina
mesh_terms: D018153:Czech Republic / Q000453:epidemiology; D006801:Humans; D052556:Niemann-Pick Disease, Type C / Q000175:diagnosis / Q000453:epidemiology* / Q000503:physiopathology; D012189:Retrospective Studies