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Sci Transl Med. 2016 May 4;8(337):337ra63. doi: 10.1126/scitranslmed.aaf2326.

Development of a bile acid-based newborn screen for Niemann-Pick disease type C.

Author information

1
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
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.
5
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
New York State Department of Health, Wadsworth Center, Albany, NY 12201, USA.
7
Rush University Medical Center, Chicago, IL 60612, USA.
8
Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
9
Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany.
10
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.
11
Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, Rio Grande do Sul 90035-003, Brazil.
12
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA. dory@wustl.edu.

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.

PMID:
27147587
PMCID:
PMC5316294
DOI:
10.1126/scitranslmed.aaf2326
[Indexed for MEDLINE]
Free PMC Article

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