Francyne Kubaski1,2, Robert W Mason1,2, Akiko Nakatomi3, Haruo Shintaku4, Li Xie1, Naomi N van Vlies5, Heather Church6, Roberto Giugliani7, Hironori Kobayashi8, Seiji Yamaguchi8, Yasuyuki Suzuki9, Tadao Orii10, Toshiyuki Fukao10, Adriana M Montaño11,12, Shunji Tomatsu13,14,15. 1. Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19899, DE, USA. 2. Department of Biological Sciences, University of Delaware, Newark, DE, USA. 3. Department of Pediatrics, Nagasaki University, Nagasaki, Japan. 4. Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan. 5. Laboratory Genetic Metabolic Diseases Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 6. Willink Biochemical Genetics Unit Regional Genetics Laboratory Genetic Medicine, St Mary's Hospital Manchester, Manchester, UK. 7. Medical Genetics Service, HCPA, Dep. Genetics, UFRGS, and INAGEMP, Porto Alegre, Brazil. 8. Department of Pediatrics, Shimane University, Izumo, Japan. 9. Medical Education Development Center, Gifu University, Gifu, Japan. 10. Department of Pediatrics, Gifu University, Yanagido-1-1, Gifu, 501-1194, Japan. 11. Department of Pediatrics, Saint Louis University, St. Louis, MO, USA. 12. Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, USA. 13. Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19899, DE, USA. stomatsu@nemours.org. 14. Department of Pediatrics, Shimane University, Izumo, Japan. stomatsu@nemours.org. 15. Department of Pediatrics, Gifu University, Yanagido-1-1, Gifu, 501-1194, Japan. stomatsu@nemours.org.
Abstract
BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis. METHODS: This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n = 7; MPS II, n = 2; MPS III, n = 5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Heparan sulfate (0S, NS), dermatan sulfate (DS) and mono- and di-sulfated KS were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Median absolute deviation (MAD) was used to determine cutoffs to distinguish patients from controls. Cutoffs were defined as median + 7× MAD from general newborns. RESULTS: The cutoffs were as follows: HS-0S > 90 ng/mL; HS-NS > 23 ng/mL, DS > 88 ng/mL; mono-sulfated KS > 445 ng/mL; di-sulfated KS > 89 ng/mL and ratio di-KS in total KS > 32 %. All MPS I and II samples were above the cutoffs for HS-0S, HS-NS, and DS, and all MPS III samples were above cutoffs for HS-0S and HS-NS. The rate of false positives for MPS I and II was 0.03 % based on a combination of HS-0S, HS-NS, and DS, and for MPS III was 0.9 % based upon a combination of HS-0S and HS-NS. CONCLUSIONS: Combination of levels of two or more different GAGs improves separation of MPS patients from unaffected controls, indicating that GAG measurements are potentially valuable biomarkers for newborn screening for MPS.
BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis. METHODS: This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n = 7; MPS II, n = 2; MPS III, n = 5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Heparan sulfate (0S, NS), dermatan sulfate (DS) and mono- and di-sulfated KS were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Median absolute deviation (MAD) was used to determine cutoffs to distinguish patients from controls. Cutoffs were defined as median + 7× MAD from general newborns. RESULTS: The cutoffs were as follows: HS-0S > 90 ng/mL; HS-NS > 23 ng/mL, DS > 88 ng/mL; mono-sulfatedKS > 445 ng/mL; di-sulfated KS > 89 ng/mL and ratio di-KS in total KS > 32 %. All MPS I and II samples were above the cutoffs for HS-0S, HS-NS, and DS, and all MPS III samples were above cutoffs for HS-0S and HS-NS. The rate of false positives for MPS I and II was 0.03 % based on a combination of HS-0S, HS-NS, and DS, and for MPS III was 0.9 % based upon a combination of HS-0S and HS-NS. CONCLUSIONS: Combination of levels of two or more different GAGs improves separation of MPSpatients from unaffected controls, indicating that GAG measurements are potentially valuable biomarkers for newborn screening for MPS.
Authors: Brian J Wolfe; Sophie Blanchard; Martin Sadilek; C Ronald Scott; Frantisek Turecek; Michael H Gelb Journal: Anal Chem Date: 2010-12-30 Impact factor: 6.986
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