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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.

orphanet journal of rare diseases

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