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Journal of Inherited Metabolic Disease

, Volume 40, Issue 1, pp 151–158 | Cite as

Newborn screening for mucopolysaccharidoses: a pilot study of measurement of glycosaminoglycans by tandem mass spectrometry

  • Francyne Kubaski
  • Robert W. Mason
  • Akiko Nakatomi
  • Haruo Shintaku
  • Li Xie
  • Naomi N. van Vlies
  • Heather Church
  • Roberto Giugliani
  • Hironori Kobayashi
  • Seiji Yamaguchi
  • Yasuyuki Suzuki
  • Tadao Orii
  • Toshiyuki Fukao
  • Adriana M. Montaño
  • Shunji Tomatsu
Original Article

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.

Keywords

Newborn Screening Dermatan Sulfate Keratan Sulfate Median Absolute Deviation Newborn Screen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by grants from Japanese MPS Society, the Austrian MPS Society, The Bennett Foundation, and International Morquio Organization (Carol Ann Foundation). R.W.M. and S.T. were supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of NIH under grant numbers P20GM103464 and P30GM114736. S.T. and A.M were supported by National Institutes of Health grant 1R01HD065767. F.K. was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico, from Brazil (CNPq). The content of the article has not been influenced by the sponsors. We also appreciate individual patients with MPS, who participated in projects of “Newborn screening and biomarkers for Mucopolysaccharidoses.”

Compliance with ethics guidelines

Conflict of interest

None.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). The study was approved by Nemours IRB (protocol 281495). Informed consent was obtained from all patients for being included in the study.

Supplementary material

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References

  1. Auclair D, Hopwood JJ, Brooks DA et al (2003) Replacement therapy in Mucopolysaccharidosis type VI: advantages of early onset of therapy. Mol Genet Metab 78:163–174CrossRefPubMedGoogle Scholar
  2. Baldo G, Matte U, Artigalas O et al (2011) Placenta analysis of prenatally diagnosed patients reveals early GAG storage in mucopolysaccharidoses II and VI. Mol Genet Metab 103:197–198CrossRefPubMedGoogle Scholar
  3. Baldo G, Mayer FQ, Martinelli BZ et al (2013) Enzyme replacement therapy started at birth improves outcome in difficult-to-treat organs in mucopolysaccharidosis I mice. Mol Genet Metab 109:33–40CrossRefPubMedGoogle Scholar
  4. Beck M, Braun S, Coerdt W et al (1992) Fetal presentation of Morquio disease type A. Prenat Diagn 12:1019–1029CrossRefPubMedGoogle Scholar
  5. Blanchard S, Sadilek M, Scott CR et al (2008) Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis I. Clin Chem 54:2067–2070CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chace DH, Hannon WH (2010) Impact of second-tier testing on the effectiveness of newborn screening. Clin Chem 56:1653–1655CrossRefPubMedGoogle Scholar
  7. de Ruijter J, Minke HR, Wagemans T et al (2012) Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses type I, II and III. Mol Genet Metab 107:705–710CrossRefPubMedGoogle Scholar
  8. Gabrielli O, Clarke LA, Bruni S et al (2010) Enzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow-up. Pediatrics 125:183–187CrossRefGoogle Scholar
  9. Gelb MH, Turecek F, Scott CR et al (2006) Direct multiplex assay of enzymes in dried blood spots by tandem mass spectrometry for the newborn screening of lysosomal storage disorders. J Inherit Metab Dis 29:397–404CrossRefPubMedPubMedCentralGoogle Scholar
  10. Gelb MH, Scott CR, Turecek F (2015) Newborn screening for lysosomal storage diseases. Clin Chem 61:335–346CrossRefPubMedGoogle Scholar
  11. Gucciardi A, Legini E, Di Gangi IM et al (2014) A column-switching HPLC-MS/MS method for mucopolysaccharidosis type I analysis in a multiplex assay for the simultaneous newborn screening of six lysosomal storage disorders. Biomed Chromatogr 28:1131–1139CrossRefPubMedGoogle Scholar
  12. Hennessey PT, Hurst RE, Hemstreet GP et al (1981) Urinary glycosaminoglycan excretion as a biochemical marker in patients with bladder carcinoma. Cancer Res 41:3868–3873PubMedGoogle Scholar
  13. Hopkins PV, Campbell C, Klug T et al (2015) Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri. J Pediatr 166:172–177CrossRefPubMedGoogle Scholar
  14. Komosinska-Vassev K, Olczyk K, Kozma EM et al (2005) Alterations of glycosaminoglycan metabolism in the development of diabetic complications in relation to metabolic control. Clin Chem Lab Med 43:924–929CrossRefPubMedGoogle Scholar
  15. Lawrence R, Brown JR, Al-Mafraji K et al (2012) Disease-specific non-reducing end carbohydrate biomarkers for mucopolysaccharidoses. Nat Chem Biol 8:197–204CrossRefPubMedPubMedCentralGoogle Scholar
  16. Lawrence R, Brown JR, Lorey F et al (2014) Glycan-based biomarkers for mucopolysaccharidoses. Mol Genet Metab 111:73–83CrossRefPubMedGoogle Scholar
  17. Leys C, Ley C, Klein O et al (2013) Detecting outliers: do not use standard deviation around the mean, use absolute deviation around the median. J Exp Soc Psychol 49:764–766CrossRefGoogle Scholar
  18. Liao HC, Chiang CC, Niu DM et al (2014) Detecting multiple lysosomal storage diseases by tandem mass spectrometry—a national newborn screening program in Taiwan. Clin Chem Acta 431:80–86CrossRefGoogle Scholar
  19. Lin SP, Lin HY, Wang TJ et al (2013) A pilot newborn screening program for Mucopolysaccharidosis type I in Taiwan. Orphanet J Rare Dis 22:1–8Google Scholar
  20. Mankin HJ, Lippiello L et al (1971) The glycosaminoglycans of normal and arthritic cartilage. J Clin Invest 50:1712–1719CrossRefPubMedPubMedCentralGoogle Scholar
  21. Martin JJ, Ceuterick C (1983) Prenatal pathology in mucopolysaccharidoses: a comparison with postnatal cases. Clin Neuropathol 2:122–127PubMedGoogle Scholar
  22. McGill JJ, Inwood AC, Coman DJ et al (2010) Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age—a sibling control study. Clin Genet 77:492–498CrossRefPubMedGoogle Scholar
  23. Meikle PJ, Grasby DJ, Dean CJ et al (2006) Newborn screening for lysosomal storage disorders. Mol Genet Metab 88:307–314CrossRefPubMedGoogle Scholar
  24. Muenzer J (2014) Early initiation of enzyme replacement therapy for the mucopolysaccharidoses. Mol Genet Metab 111:63–72CrossRefPubMedGoogle Scholar
  25. Neufeld E, Muenzer J (2001) The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 3421–3452Google Scholar
  26. Oguma T, Tomatsu S, Montaño AM et al (2007) Analytical method for determination of disaccharides derived from keratan, heparan, and dermatan sulfates in human serum and plasma by high-performance liquid chromatography/turbo ionspray ionization tandem mass spectrometry. Anal Biochem 368:79–86CrossRefPubMedGoogle Scholar
  27. Ohashi A, Montaño AM, Colón JE et al (2009) Sacral dimple: incidental findings from newborn evaluation. Mucopolysaccharidosis IVA disease. Acta Paediatr 98:768–769CrossRefPubMedGoogle Scholar
  28. Poe MD, Chagnon SL, Escolar ML (2014) Early treatment is associated with improved cognition in Hurler syndrome. Ann Neurol 76:1–24CrossRefGoogle Scholar
  29. R Core Team (2014) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. (http://www.R-project.org/)
  30. Rowan DJ, Tomatsu S, Grubb JH et al (2013) Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIA, IVA and VII. J Inherit Metab Dis 36:235–246CrossRefPubMedGoogle Scholar
  31. Ruijter GJ, Goudriaan DA, Boer AM et al (2014) Newborn screening for hunter disease: a small-scale feasibility study. J Inherit Metab Dis Rep 14:23–27Google Scholar
  32. Saad OM, Ebel H, Uchimura K et al (2005) Compositional profiling of heparin/heparan sulfate using mass spectrometry: assay for specificity of a novel extracellular human endosulfatase. Glycobiology 15:818–826CrossRefPubMedGoogle Scholar
  33. Schulze-Frenking G, Jones SA, Roberts J et al (2011) Effects of enzyme replacement therapy on growth in patients with mucopolysaccharidosis type II. J Inherit Metab Dis 34:203–208CrossRefPubMedGoogle Scholar
  34. Scott CR, Elliott S, Buroker N et al (2013) Identification of infants at risk for developing Fabry, Pompe, or Mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J Pediatr 163:498–503CrossRefPubMedPubMedCentralGoogle Scholar
  35. Shimada T, Kelly J, LaMarr WA et al (2014a) Novel heparan sulfate assay by using automated high-throughput mass spectrometry: application to monitoring and screening for mucopolysaccharidoses. Mol Genet Metab 113:92–99CrossRefPubMedPubMedCentralGoogle Scholar
  36. Shimada T, Tomatsu S, Yasuda E et al (2014b) Chondroitin 6-sulfate as a novel biomarker for mucopolysaccharidosis type I, IIIA, IVA and VII. J Inherit Metab Dis Rep 16:15–24Google Scholar
  37. Shimada T, Tomatsu S, Mason RW et al (2015) Di-sulfated KS as a novel biomarker for mucopolysaccharidosis II, IVA, and IVB. J Inherit Metab Dis Rep 21:1–13Google Scholar
  38. Spacil Z, Tatipaka H, Barcenas M et al (2013) High-throughput assay of 9 lysosomal enzymes for newborn screening. Clin Chem 59:502–511CrossRefPubMedPubMedCentralGoogle Scholar
  39. Tomatsu S, Orii KO, Vogler C et al (2003) Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A Disease. Hum Mol Genet 12:3349–3358CrossRefPubMedGoogle Scholar
  40. Tomatsu S, Okamura K, Maeda H et al (2005) Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis 28:187–202CrossRefPubMedGoogle Scholar
  41. Tomatsu S, Montaño AM, Oguma T et al (2010) Validation of keratan sulfate level in mucopolysaccharidosis IVA by liquid tandem mass spectrometry method. J Inherit Metab Dis 33:35–42CrossRefGoogle Scholar
  42. Tomatsu S, Fujii T, Fukushi M et al (2013) Newborn screening and diagnosis of mucopolysaccharidoses. Mol Genet Metab 110:42–53CrossRefPubMedPubMedCentralGoogle Scholar
  43. Tomatsu S, Shimada T, Mason RW et al (2014) Establishment of glycosaminoglycan assays for mucopolysaccharidoses. Metabolites 4:655–679CrossRefPubMedPubMedCentralGoogle Scholar
  44. Tomatsu S, Almeciga-Diaz CJ, Montano AM et al (2015) Therapies for the bone in mucopolysaccharidoses. Mol Genet Metab 114:94–109CrossRefPubMedGoogle Scholar
  45. Tomatsu S, Azario I, Sawamoto K et al (2016) Neonatal cellular and gene therapies for mucopolysaccharidoses: the earlier the better? J Inherit Metab Dis 39:189–202CrossRefPubMedGoogle Scholar
  46. Turgeon CT, Magera MJ, Cuthbert CD et al (2010) Determination of total homocysteine, methylmalonic acid, and 2-methylcitric acid in dried blood spots by tandem mass spectrometry. Clin Chem 56:1686–1695CrossRefPubMedGoogle Scholar
  47. U.S. Department of Health and Human Services (2001) Guidance for Industry. Bioanalytical method validation. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Center for Veterinary Medicine (CVM). Available at: http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070107.pdf
  48. Vogler C, Birkenmeier EH, Sly WS et al (1990) A murine model of mucopolysaccharidosis VII. Gross and microscopic findings in beta-glucuronidase-deficient mice. Am J Pathol 136:207–217PubMedPubMedCentralGoogle Scholar
  49. Wei W, Ninñonuevo MR, Sharma A et al (2011) A comprehensive compositional analysis of heparin/heparan sulfate-derived disaccharides from human serum. Anal Chem 83:3703–3708CrossRefPubMedPubMedCentralGoogle Scholar
  50. Wolfe BJ, Blanchard S, Sadilek M et al (2011) Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis II (Hunter syndrome). Anal Chem 83:1152–1156CrossRefPubMedGoogle Scholar
  51. Zhang Y, Conrad AH, Tasheva ES et al (2005) Detection and quantification of sulfated disaccharides from keratin sulfate and chondroitin/dermatan sulfate during chick corneal development by ESI-MS/MS. Invest Ophthalmol Vis Sci 46:1604–1614CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2016

Authors and Affiliations

  • Francyne Kubaski
    • 1
    • 2
  • Robert W. Mason
    • 1
    • 2
  • Akiko Nakatomi
    • 3
  • Haruo Shintaku
    • 4
  • Li Xie
    • 1
  • Naomi N. van Vlies
    • 5
  • Heather Church
    • 6
  • Roberto Giugliani
    • 7
  • Hironori Kobayashi
    • 8
  • Seiji Yamaguchi
    • 8
  • Yasuyuki Suzuki
    • 9
  • Tadao Orii
    • 10
  • Toshiyuki Fukao
    • 10
  • Adriana M. Montaño
    • 11
    • 12
  • Shunji Tomatsu
    • 1
    • 8
    • 10
  1. 1.Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  2. 2.Department of Biological SciencesUniversity of DelawareNewarkUSA
  3. 3.Department of PediatricsNagasaki UniversityNagasakiJapan
  4. 4.Department of PediatricsOsaka City University Graduate School of MedicineOsakaJapan
  5. 5.Laboratory Genetic Metabolic Diseases Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  6. 6.Willink Biochemical Genetics Unit Regional Genetics Laboratory Genetic MedicineSt Mary’s Hospital ManchesterManchesterUK
  7. 7.Medical Genetics Service, HCPA, Dep. Genetics, UFRGS, and INAGEMPPorto AlegreBrazil
  8. 8.Department of PediatricsShimane UniversityIzumoJapan
  9. 9.Medical Education Development CenterGifu UniversityGifuJapan
  10. 10.Department of PediatricsGifu UniversityGifuJapan
  11. 11.Department of PediatricsSaint Louis UniversitySt. LouisUSA
  12. 12.Department of Biochemistry and Molecular BiologySaint Louis UniversitySt. LouisUSA

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