TY - JOUR
T1 - Development of a bile acid-based newborn screen for Niemann-Pick disease type C
AU - Jiang, Xuntian
AU - Sidhu, Rohini
AU - Mydock-McGrane, Laurel
AU - Hsu, Fong Fu
AU - Covey, Douglas F.
AU - Scherrer, David E.
AU - Earley, Brian
AU - Gale, Sarah E.
AU - Farhat, Nicole Y.
AU - Porter, Forbes D.
AU - Dietzen, Dennis J.
AU - Orsini, Joseph J.
AU - Berry-Kravis, Elizabeth
AU - Zhang, Xiaokui
AU - Reunert, Janice
AU - Marquardt, Thorsten
AU - Runz, Heiko
AU - Giugliani, Roberto
AU - Schaffer, Jean E.
AU - Ory, Daniel S.
N1 - Funding Information:
This work was supported by grants from the National Niemann-Pick Disease Foundation (X.J.), Dana's Angels Research Trust (D.S.O. and N.Y.F.), Ara Parseghian Medical Research Foundation (D.S.O. and N.Y.F.), Support of Accelerated Research for NPC Disease (D.S.O.), and NIH (T32 HL07275 to L.M.-M. and R01 NS081985 to D.S.O. and J.E.S.). This study was also supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.) and a Bench to Bedside award from the Office of Rare Diseases (F.D.P. and D.S.O.). This work was performed in the Metabolomics Facility at Washington University (NIH, P30 DK020579).
PY - 2016/5/4
Y1 - 2016/5/4
N2 - 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, 5aα, 6β trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β, 5aα, 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.
AB - 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, 5aα, 6β trihydroxycholanic acid and its glycine conjugate, which were shown to be metabolites of cholestane-3β, 5aα, 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.
UR - http://www.scopus.com/inward/record.url?scp=84969983713&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaf2326
DO - 10.1126/scitranslmed.aaf2326
M3 - Article
C2 - 27147587
AN - SCOPUS:84969983713
SN - 1946-6234
VL - 8
JO - Science translational medicine
JF - Science translational medicine
IS - 337
ER -