Xuntian Jiang1, Rohini Sidhu1, Joseph J Orsini2, Nicole Y Farhat3, Forbes D Porter3, Elizabeth Berry-Kravis4, Jean E Schaffer1, Daniel S Ory5. 1. Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA. 2. New York State Dept. of Health, Wadsworth Center, Albany, NY 12201, USA. 3. Section on Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, Bethesda, MD 20892, USA. 4. Rush University Medical Center, Chicago, IL 60612, USA. 5. Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: dory@wustl.edu.
Abstract
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.
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 NPC1patients, 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 NPC1patients 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 NPC1patients, 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.
Authors: L Kuchar; J Sikora; M E Gulinello; H Poupetova; A Lugowska; V Malinova; H Jahnova; B Asfaw; J Ledvinova Journal: Anal Biochem Date: 2017-03-01 Impact factor: 3.365
Authors: J Reunert; A S Lotz-Havla; G Polo; F Kannenberg; M Fobker; M Griese; E Mengel; A C Muntau; P Schnabel; O Sommerburg; I Borggraefe; A Dardis; A P Burlina; M A Mall; G Ciana; B Bembi; A B Burlina; T Marquardt Journal: JIMD Rep Date: 2015-03-13
Authors: Xuntian Jiang; Rohini Sidhu; Laurel Mydock-McGrane; Fong-Fu Hsu; Douglas F Covey; David E Scherrer; Brian Earley; Sarah E Gale; Nicole Y Farhat; Forbes D Porter; Dennis J Dietzen; Joseph J Orsini; Elizabeth Berry-Kravis; Xiaokui Zhang; Janice Reunert; Thorsten Marquardt; Heiko Runz; Roberto Giugliani; Jean E Schaffer; Daniel S Ory Journal: Sci Transl Med Date: 2016-05-04 Impact factor: 17.956
Authors: Marc C Patterson; Eugen Mengel; Marie T Vanier; Barbara Schwierin; Audrey Muller; Peter Cornelisse; Mercè Pineda Journal: Orphanet J Rare Dis Date: 2015-05-28 Impact factor: 4.123
Authors: Christopher A Wassif; Joanna L Cross; James Iben; Luis Sanchez-Pulido; Antony Cougnoux; Frances M Platt; Daniel S Ory; Chris P Ponting; Joan E Bailey-Wilson; Leslie G Biesecker; Forbes D Porter Journal: Genet Med Date: 2015-03-12 Impact factor: 8.822
Authors: Rohini Sidhu; Pamela Kell; Dennis J Dietzen; Nicole Y Farhat; An Ngoc Dang Do; Forbes D Porter; Elizabeth Berry-Kravis; Janine Reunert; Thorsten Marquardt; Roberto Giugliani; Charles M Lourenço; Raymond Y Wang; Nina Movsesyan; Ellen Plummer; Jean E Schaffer; Daniel S Ory; Xuntian Jiang Journal: Mol Genet Metab Date: 2020-11-18 Impact factor: 4.797