TY - JOUR
T1 - Diagnosis of niemann-pick C1 by measurement of bile acid biomarkers in archived newborn dried blood spots
AU - Jiang, Xuntian
AU - Sidhu, Rohini
AU - Orsini, Joseph J.
AU - Farhat, Nicole Y.
AU - Porter, Forbes D.
AU - Berry-Kravis, Elizabeth
AU - Schaffer, Jean E.
AU - Ory, Daniel S.
N1 - Funding Information:
We are grateful to the National Niemann-Pick Disease Foundation for their assistance in obtaining samples from NPC1 and NPC1 carrier subjects. The authors express their appreciation to the families and patients who participated in this study. This work was supported by grants from the National Niemann-Pick Disease Foundation (X.J.), Dana's Angels Research Trust (D.S.O.), Support Of Accelerated Research for NPC Disease (D.S.O.), by NIH Grant R01NS081985 (D.S.O. and J.E.S.), and by the Intramural Research Program of NICHD, NIH (F.D.P. and N.Y·F). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579 and NIH P30 DK056341). The content of the article has not been influenced by the sponsors.
Funding Information:
We are grateful to the National Niemann-Pick Disease Foundation for their assistance in obtaining samples from NPC1 and NPC1 carrier subjects. The authors express their appreciation to the families and patients who participated in this study. This work was supported by grants from the National Niemann-Pick Disease Foundation (X.J.), Dana's Angels Research Trust (D.S.O.), Support Of Accelerated Research for NPC Disease (D.S.O.), by NIH Grant R01NS081985 (D.S.O. and J.E.S.), and by the Intramural Research Program of NICHD, NIH (F.D.P. and N.Y·F). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579 and NIH P30 DK056341). The content of the article has not been influenced by the sponsors.
Funding Information:
We are grateful to the National Niemann-Pick Disease Foundation for their assistance in obtaining samples from NPC1 and NPC1 carrier subjects. The authors express their appreciation to the families and patients who participated in this study. This work was supported by grants from the National Niemann-Pick Disease Foundation (X.J.), Dana's Angels Research Trust (D.S.O.), Support Of Accelerated Research for NPC Disease (D.S.O.), by NIH Grant R01NS081985 (D.S.O. and J.E.S.), and by the Intramural Research Program of NICHD, NIH (F.D.P. and N.Y?F). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579 and NIH P30 DK056341). The content of the article has not been influenced by the sponsors.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/2
Y1 - 2019/2
N2 - Background: Niemann-Pick disease type C1 (NPC1) is a rare, neurodegenerative cholesterol storage disorder. Diagnostic delay of >5 years is common due to the rarity of the disease and non-specific early symptoms. To improve diagnosis and facilitate early intervention, we previously developed a newborn screening assay based on newly identified plasma bile acid biomarkers. Because the newborn screen had been validated using dried blood spots (DBS) from already diagnosed NPC1 patients, an unanswered question was whether the screen would be able to detect individuals with NPC1 at birth. Methods: To address this critical question, we obtained the newborn DBS for already diagnosed NPC1 subjects (n = 15) and carriers (n = 3) residing in California, New York, and Michigan states that archive residual DBS in biorepositories. For each of the DBS, we obtained two neighbor controls – DBS from patients born on the same day and in the same hospital as the NPC1 patients and carriers. 3β,5α,6β-trihydroxycholanic acid (bile acid A) and trihydroxycholanic acid glycine conjugate (bile acid B) were measured in the DBS using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Results: Bile acid B, the more specific biomarker for which the fully validated DBS assay was developed, was detected in 8/15 NPC1 patients, and elevated above the cut-off in 2/15 patients (the two samples with the shortest storage time). Bile acid B was detected in 2/2, 6/10, and 0/7 NPC1 samples that have been stored for <10.5 years, 13–20 years, and > 20 years, respectively, indicating that the glycine conjugate is detectable in DBS but may have reduced long-term stability compared with bile acid A, the precursor trihydroxycholanic acid, which was elevated in 15/15 NPC1 subjects, but not in carriers and controls. Conclusions: These results demonstrate that newborn screening for NPC1 disease is feasible using bile acid biomarkers.
AB - Background: Niemann-Pick disease type C1 (NPC1) is a rare, neurodegenerative cholesterol storage disorder. Diagnostic delay of >5 years is common due to the rarity of the disease and non-specific early symptoms. To improve diagnosis and facilitate early intervention, we previously developed a newborn screening assay based on newly identified plasma bile acid biomarkers. Because the newborn screen had been validated using dried blood spots (DBS) from already diagnosed NPC1 patients, an unanswered question was whether the screen would be able to detect individuals with NPC1 at birth. Methods: To address this critical question, we obtained the newborn DBS for already diagnosed NPC1 subjects (n = 15) and carriers (n = 3) residing in California, New York, and Michigan states that archive residual DBS in biorepositories. For each of the DBS, we obtained two neighbor controls – DBS from patients born on the same day and in the same hospital as the NPC1 patients and carriers. 3β,5α,6β-trihydroxycholanic acid (bile acid A) and trihydroxycholanic acid glycine conjugate (bile acid B) were measured in the DBS using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Results: Bile acid B, the more specific biomarker for which the fully validated DBS assay was developed, was detected in 8/15 NPC1 patients, and elevated above the cut-off in 2/15 patients (the two samples with the shortest storage time). Bile acid B was detected in 2/2, 6/10, and 0/7 NPC1 samples that have been stored for <10.5 years, 13–20 years, and > 20 years, respectively, indicating that the glycine conjugate is detectable in DBS but may have reduced long-term stability compared with bile acid A, the precursor trihydroxycholanic acid, which was elevated in 15/15 NPC1 subjects, but not in carriers and controls. Conclusions: These results demonstrate that newborn screening for NPC1 disease is feasible using bile acid biomarkers.
KW - Bile acid
KW - Biomarker
KW - Newborn screening
KW - Niemann-pick C disease
UR - http://www.scopus.com/inward/record.url?scp=85054124504&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2018.08.007
DO - 10.1016/j.ymgme.2018.08.007
M3 - Article
C2 - 30172462
AN - SCOPUS:85054124504
VL - 126
SP - 183
EP - 187
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 2
ER -