Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

  • Tsutomu Shimada
  • Shunji TomatsuEmail author
  • Robert W. Mason
  • Eriko Yasuda
  • William G. Mackenzie
  • Jobayer Hossain
  • Yuniko Shibata
  • Adriana M. Montaño
  • Francyne Kubaski
  • Roberto Giugliani
  • Seiji Yamaguchi
  • Yasuyuki Suzuki
  • Kenji E. Orii
  • Toshiyuki Fukao
  • Tadao Orii
Research Report
Part of the JIMD Reports book series (JIMD, volume 21)


Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: mono-sulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono- and di-sulfated KS using liquid chromatography–tandem mass spectrometry and measured both KS levels in various specimens.

Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono- and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of mono- and di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.

In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders.


Enzyme Replacement Therapy Skeletal Dysplasia Keratan Sulfate Sulfation Pattern Shark Cartilage 
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.





Dried blood spot


Extracellular matrix






N-acetylgalactosamine-6-sulfate sulfatase




Keratan sulfate


High-performance liquid chromatography– tandem mass spectrometry




Newborn screening





This work was supported by grants from the Austrian MPS Society and International Morquio Organization (Carol Ann Foundation). This work was also supported by Japanese MPS Family Society. 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 number P20GM103464. S.T. and A.M were supported by National Institutes of Health grant 1R01HD065767-02. The content of the article has not been influenced by the sponsors. F.K. was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico from Brazil (CNPq). Editorial assistance to the manuscript was provided by Michelle Stofa at Nemours/Alfred I. duPont Hospital for Children.


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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Tsutomu Shimada
    • 1
  • Shunji Tomatsu
    • 1
    • 7
    Email author
  • Robert W. Mason
    • 1
  • Eriko Yasuda
    • 1
  • William G. Mackenzie
    • 1
  • Jobayer Hossain
    • 1
  • Yuniko Shibata
    • 2
  • Adriana M. Montaño
    • 3
  • Francyne Kubaski
    • 1
  • Roberto Giugliani
    • 4
  • Seiji Yamaguchi
    • 5
  • Yasuyuki Suzuki
    • 6
  • Kenji E. Orii
    • 7
  • Toshiyuki Fukao
    • 7
  • Tadao Orii
    • 7
  1. 1.Nemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  2. 2.Central Research Laboratory, R&D DivisionSeikagaku Co.TokyoJapan
  3. 3.Department of PediatricsSaint Louis UniversitySt. LouisUSA
  4. 4.Medical Genetics Service/HCPA and Department of Genetics/UFRGSPorto AlegreBrazil
  5. 5.Department of PediatricsShimane UniversityIzumoJapan
  6. 6.Medical Education Development CenterGifu UniversityGifuJapan
  7. 7.Department of PediatricsGifu UniversityGifuJapan

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