title: Development of a bile acid-based newborn screen for Niemann-Pick disease type C.
abstract: Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, it is imperative to improve diagnostics and facilitate early intervention. We used metabolomic profiling to identify potential markers and discovered three unknown bile acids that were increased in plasma from NPC but not control subjects. The bile acids most elevated in the NPC subjects were identified as 3β,5α,6β-trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β,5α,6β-triol, an oxysterol elevated in NPC. A high-throughput mass spectrometry-based method was developed and validated to measure the glycine-conjugated bile acid in dried blood spots. Analysis of dried blood spots from 4992 controls, 134 NPC carriers, and 44 NPC subjects provided 100% sensitivity and specificity in the study samples. Quantification of the bile acid in dried blood spots, therefore, provides the basis for a newborn screen for NPC that is ready for piloting in newborn screening programs.
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xuntian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Laurel
authors.initials: L
authors.lastname: Mydock-McGrane
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Scherrer
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Earley
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gale
authors.affiliation: Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Nicole Y
authors.initials: NY
authors.lastname: Farhat
authors.affiliation: Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Dietzen
authors.affiliation: New York State Department of Health, Wadsworth Center, Albany, NY 12201, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Orsini
authors.affiliation: Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Berry-Kravis
authors.affiliation: Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany.
authors.forename: Janice
authors.initials: J
authors.lastname: Reunert
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Department of Genetics and Pharmacogenomics, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul 90035-003, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA. dory@wustl.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
mesh_terms: D001647:Bile Acids and Salts / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D059788:Dried Blood Spot Testing; D006801:Humans; D007231:Infant, Newborn; D052556:Niemann-Pick Disease, Type C / Q000097:blood* / Q000175:diagnosis*; D012680:Sensitivity and Specificity
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers