Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: Findings from the ZOOM study

Peter Bauer, David J. Balding, Hans H. Klünemann, David E.J. Linden, Daniel S. Ory, Mercè Pineda, Josef Priller, Frederic Sedel, Audrey Muller, Harbajan Chadha-Boreham, Richard W.D. Welford, Daniel S. Strasser, Marc C. Patterson

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54 Scopus citations

Abstract

Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either theNPC1gene (in95%of cases) or theNPC2gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3β, 5α, 6β-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18-90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3β, 5α, 6β-triol levels were observed for all NP-C cases (n 5 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there maybe an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.

Original languageEnglish
Pages (from-to)4349-4356
Number of pages8
JournalHuman molecular genetics
Volume22
Issue number21
DOIs
StatePublished - Nov 1 2013

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    Bauer, P., Balding, D. J., Klünemann, H. H., Linden, D. E. J., Ory, D. S., Pineda, M., Priller, J., Sedel, F., Muller, A., Chadha-Boreham, H., Welford, R. W. D., Strasser, D. S., & Patterson, M. C. (2013). Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: Findings from the ZOOM study. Human molecular genetics, 22(21), 4349-4356. https://doi.org/10.1093/hmg/ddt284