Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment
Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried blood...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-11-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520309214 |
| _version_ | 1818726392535187456 |
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| author | Andrea E. DeBarber Limor Kalfon Ayalla Fedida Vered Fleisher Sheffer Shani Ben Haroush Natalia Chasnyk Efrat Shuster Biton Hanna Mandel Krystal Jeffries Eric S. Shinwell Tzipora C. Falik-Zaccai |
| author_facet | Andrea E. DeBarber Limor Kalfon Ayalla Fedida Vered Fleisher Sheffer Shani Ben Haroush Natalia Chasnyk Efrat Shuster Biton Hanna Mandel Krystal Jeffries Eric S. Shinwell Tzipora C. Falik-Zaccai |
| author_sort | Andrea E. DeBarber |
| collection | DOAJ |
| description | Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried bloodspots (DBSs) or samples collected prospectively from a high-risk Israeli newborn population. All DBS samples were analyzed with flow injection analysis (FIA)-MS/MS, and 5% of samples were analyzed with LC-MS/MS. Consecutively collected samples were analyzed to identify CTX-causing founder genetic variants common among Druze and Moroccan Jewish populations. First-tier analysis with FIA-MS/MS provided 100% sensitivity to detect CTX-positive newborn DBSs, with a low false-positive rate (0.1–0.5%). LC-MS/MS, as a second-tier test, provided 100% sensitivity to detect CTX-positive newborn DBSs with a false-positive rate of 0% (100% specificity). In addition, 5β-cholestane-3α,7α,12α,25-tetrol-3-O-β-D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTX-positive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 gene variant, providing an estimated disease prevalence of 1:3,600 in this population. These data support the feasibility of two-tier DBS screening for CTX in newborns and set the stage for large-scale prospective pilot studies. |
| first_indexed | 2024-12-17T21:57:29Z |
| format | Article |
| id | doaj.art-cf3fdd64f8524465a3914bda3dc8e1c9 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T21:57:29Z |
| publishDate | 2018-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-cf3fdd64f8524465a3914bda3dc8e1c92022-12-21T21:31:04ZengElsevierJournal of Lipid Research0022-22752018-11-01591122142222Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatmentAndrea E. DeBarber0Limor Kalfon1Ayalla Fedida2Vered Fleisher Sheffer3Shani Ben Haroush4Natalia Chasnyk5Efrat Shuster Biton6Hanna Mandel7Krystal Jeffries8Eric S. Shinwell9Tzipora C. Falik-Zaccai10To whom correspondence should be addressed.; Physiology and Pharmacology Department, Oregon Health and Science University (OHSU), Portland, ORInstitute of Human Genetics, Galilee Medical Center, Naharia, IsraelInstitute of Human Genetics, Galilee Medical Center, Naharia, Israel; Azrieli Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel; andInstitute of Human Genetics, Galilee Medical Center, Naharia, IsraelInstitute of Human Genetics, Galilee Medical Center, Naharia, IsraelInstitute of Human Genetics, Galilee Medical Center, Naharia, IsraelInstitute of Human Genetics, Galilee Medical Center, Naharia, IsraelInstitute of Human Genetics, Galilee Medical Center, Naharia, IsraelPhysiology and Pharmacology Department, Oregon Health and Science University (OHSU), Portland, ORAzrieli Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel; and; Department of Neonatology, Ziv Medical Center, Tzfat, IsraelInstitute of Human Genetics, Galilee Medical Center, Naharia, Israel; Azrieli Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel; andCerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried bloodspots (DBSs) or samples collected prospectively from a high-risk Israeli newborn population. All DBS samples were analyzed with flow injection analysis (FIA)-MS/MS, and 5% of samples were analyzed with LC-MS/MS. Consecutively collected samples were analyzed to identify CTX-causing founder genetic variants common among Druze and Moroccan Jewish populations. First-tier analysis with FIA-MS/MS provided 100% sensitivity to detect CTX-positive newborn DBSs, with a low false-positive rate (0.1–0.5%). LC-MS/MS, as a second-tier test, provided 100% sensitivity to detect CTX-positive newborn DBSs with a false-positive rate of 0% (100% specificity). In addition, 5β-cholestane-3α,7α,12α,25-tetrol-3-O-β-D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTX-positive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 gene variant, providing an estimated disease prevalence of 1:3,600 in this population. These data support the feasibility of two-tier DBS screening for CTX in newborns and set the stage for large-scale prospective pilot studies.http://www.sciencedirect.com/science/article/pii/S0022227520309214inborn errors of metabolismstorage diseasesbile acids and saltsdiagnostic toolsmass spectrometry |
| spellingShingle | Andrea E. DeBarber Limor Kalfon Ayalla Fedida Vered Fleisher Sheffer Shani Ben Haroush Natalia Chasnyk Efrat Shuster Biton Hanna Mandel Krystal Jeffries Eric S. Shinwell Tzipora C. Falik-Zaccai Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment Journal of Lipid Research inborn errors of metabolism storage diseases bile acids and salts diagnostic tools mass spectrometry |
| title | Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment |
| title_full | Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment |
| title_fullStr | Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment |
| title_full_unstemmed | Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment |
| title_short | Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment |
| title_sort | newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment |
| topic | inborn errors of metabolism storage diseases bile acids and salts diagnostic tools mass spectrometry |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520309214 |
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