Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method
Background: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective treatment is available. We previously described a liqui...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426916300076 |
| _version_ | 1818881156262658048 |
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| author | Lisa Bleyle Hidde H. Huidekoper Frederic M. Vaz Renu Singh Robert D. Steiner Andrea E. DeBarber |
| author_facet | Lisa Bleyle Hidde H. Huidekoper Frederic M. Vaz Renu Singh Robert D. Steiner Andrea E. DeBarber |
| author_sort | Lisa Bleyle |
| collection | DOAJ |
| description | Background: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective treatment is available. We previously described a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) test with potential to screen newborn dried bloodspots (DBS) for CTX. We report here modifications to the methodology and application of the modified test to analysis of DBS from a CTX-affected and unaffected newborns.
Methods: The testing methodology utilizes keto derivatization to enable sensitive LC-ESI-MS/MS measurement of elevated 7α,12α-dihydroxy-4-cholesten-3-one (7α12αC4) in CTX newborn DBS. We report here method modifications, including use of a DBS extraction procedure used in newborn screening laboratories and a reduced analysis time of 2 min per sample.
Results: Rapid isotope-dilution LC-ESI/MS/MS quantification of the ketosterol bile acid precursor 7α12αC4 provides a test that could readily discriminate a CTX positive newborn DBS sample (with a concentration of 104.4 ng/ml) from unaffected newborn samples (with a mean concentration of 4.1 ± 3.4 ng/ml; range 0.2–15.6 ng/ml, n = 39) analyzed in a blinded manner.
Conclusions: We provide additional evidence suggesting 7α12αC4 may be a promising test marker to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefit those affected with CTX, preventing morbidity and mortality. |
| first_indexed | 2024-12-19T14:57:23Z |
| format | Article |
| id | doaj.art-35491396e8964353bf0845f9b2bc6c19 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-19T14:57:23Z |
| publishDate | 2016-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-35491396e8964353bf0845f9b2bc6c192022-12-21T20:16:41ZengElsevierMolecular Genetics and Metabolism Reports2214-42692016-06-017C111510.1016/j.ymgmr.2016.02.002Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry methodLisa Bleyle0Hidde H. Huidekoper1Frederic M. Vaz2Renu Singh3Robert D. Steiner4Andrea E. DeBarber5BioAnalytical Shared Resource Facility, Department of Physiology & Pharmacology, Oregon Health & Science University (OHSU), Portland, OR, United StatesDepartment of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The NetherlandsLaboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The NetherlandsBioAnalytical Shared Resource Facility, Department of Physiology & Pharmacology, Oregon Health & Science University (OHSU), Portland, OR, United StatesUniversity of Wisconsin, Madison, WI, United StatesBioAnalytical Shared Resource Facility, Department of Physiology & Pharmacology, Oregon Health & Science University (OHSU), Portland, OR, United StatesBackground: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective treatment is available. We previously described a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) test with potential to screen newborn dried bloodspots (DBS) for CTX. We report here modifications to the methodology and application of the modified test to analysis of DBS from a CTX-affected and unaffected newborns. Methods: The testing methodology utilizes keto derivatization to enable sensitive LC-ESI-MS/MS measurement of elevated 7α,12α-dihydroxy-4-cholesten-3-one (7α12αC4) in CTX newborn DBS. We report here method modifications, including use of a DBS extraction procedure used in newborn screening laboratories and a reduced analysis time of 2 min per sample. Results: Rapid isotope-dilution LC-ESI/MS/MS quantification of the ketosterol bile acid precursor 7α12αC4 provides a test that could readily discriminate a CTX positive newborn DBS sample (with a concentration of 104.4 ng/ml) from unaffected newborn samples (with a mean concentration of 4.1 ± 3.4 ng/ml; range 0.2–15.6 ng/ml, n = 39) analyzed in a blinded manner. Conclusions: We provide additional evidence suggesting 7α12αC4 may be a promising test marker to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefit those affected with CTX, preventing morbidity and mortality.http://www.sciencedirect.com/science/article/pii/S2214426916300076LeukodystrophyCYP27A1Bile acid synthesisKetosterolsNewborn screeningLC-ESI-MS/MS |
| spellingShingle | Lisa Bleyle Hidde H. Huidekoper Frederic M. Vaz Renu Singh Robert D. Steiner Andrea E. DeBarber Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method Molecular Genetics and Metabolism Reports Leukodystrophy CYP27A1 Bile acid synthesis Ketosterols Newborn screening LC-ESI-MS/MS |
| title | Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method |
| title_full | Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method |
| title_fullStr | Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method |
| title_full_unstemmed | Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method |
| title_short | Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method |
| title_sort | update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis an available high throughput liquid chromatography tandem mass spectrometry method |
| topic | Leukodystrophy CYP27A1 Bile acid synthesis Ketosterols Newborn screening LC-ESI-MS/MS |
| url | http://www.sciencedirect.com/science/article/pii/S2214426916300076 |
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