title: Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study.
abstract: Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. 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 = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.
authors.affiliation: Institute of Medical Genetics and Applied Genomics, Tübingen University, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: David J
authors.initials: DJ
authors.lastname: Balding
authors.forename: Hans H
authors.initials: HH
authors.lastname: Klünemann
authors.forename: David E J
authors.initials: DE
authors.lastname: Linden
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Mercè
authors.initials: M
authors.lastname: Pineda
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Frederic
authors.initials: F
authors.lastname: Sedel
authors.forename: Audrey
authors.initials: A
authors.lastname: Muller
authors.forename: Harbajan
authors.initials: H
authors.lastname: Chadha-Boreham
authors.forename: Richard W D
authors.initials: RW
authors.lastname: Welford
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Strasser
authors.forename: Marc C
authors.initials: MC
authors.lastname: Patterson
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D010641:Phenotype; D017422:Sequence Analysis, DNA; 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