TY - JOUR
T1 - Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms
T2 - Findings from the ZOOM study
AU - Bauer, Peter
AU - Balding, David J.
AU - Klünemann, Hans H.
AU - Linden, David E.J.
AU - Ory, Daniel S.
AU - Pineda, Mercè
AU - Priller, Josef
AU - Sedel, Frederic
AU - Muller, Audrey
AU - Chadha-Boreham, Harbajan
AU - Welford, Richard W.D.
AU - Strasser, Daniel S.
AU - Patterson, Marc C.
N1 - Funding Information:
Conflict of Interest statement. P.B., H.H.K., J.P., D.S.O., M.P. and F.S. have each received travel expenses, carried out paid consultancy work and received presentation honoraria from Actelion Pharmaceuticals Ltd. D.E.J.L. has received honoraria from Actelion Pharmaceuticals Ltd. D.J.B. and D.E.J.L. have received travel expenses from, and carried out paid consultancy work for, Actelion Pharmaceuticals Ltd. A.M., H.C.-B., R.W.D.W. and D.S.S. are full-time employees of Actelion Pharmaceuticals Ltd. M.C.P. has received a research grant, travel expenses and consulting honoraria (directed to the Mayo Clinic) from Actelion Pharmaceuticals Ltd; travel expenses and consulting honoraria (directed to the Mayo Clinic) from Shire Human Genetic Therapies, consulting honoraria from Amicus Therapeutics and Orphazyme, an honorarium for acting as the Chair of a Data Monitoring Committee from Stem Cells Inc., and royalties as an editor of Up-To-Date. He receives research funding from the National Institutes of Health, and has received travel expenses from the Institute of Medicine for service on the Committee to Review Adverse Effects of Vaccines.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddt284
DO - 10.1093/hmg/ddt284
M3 - Article
C2 - 23773996
AN - SCOPUS:84885830296
SN - 0964-6906
VL - 22
SP - 4349
EP - 4356
JO - Human molecular genetics
JF - Human molecular genetics
IS - 21
ER -