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 TomatsuEmail author
Original Article



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.


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.


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.


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.


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.



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


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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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
    Email author
  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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