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Peer-reviewedCC BY-NC-NDCarbohydrate research

Synthesis of the Endogenous Non-Reducing End Heparan Sulfate Disaccharides for Newborn Screening and Diagnosis of Mucopolysaccharidosis types I and II

  • Gurpreet Singh1
  • Sachin Popat Gholap1
  • Sanghyun Lim2
  • Zackary M. Herbst2
  • Michael H. Gelb1
  1. 1Department of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195 USA.
  2. 2Enfanos, LLC, Seattle, WA 98195
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Abstract

There is ongoing newborn screening (NBS) for mucopolysaccharidoses types I and II (MPS I and MPS II) because initiation of treatment early in life leads to better clinical outcomes. NBS starts with measurement of the relevant enzymatic activities in dried blood spots (DBS) on NBS cards. A second-tier test is carried out to eliminate false positives when enzymatic activity is low. In MPS I and MPS II, heparan sulfate accumulates, and previous studies have shown that the non-reducing end disaccharide fragments found endogenously in patient DBS and urine are elevated in patients but not in false positives. The proposed biomarker for MPS I is l-iduronic acid α(1,4)-linked to N-acetyl-d-glucosamine-6-sulfate, and the proposed biomarker for MPS II is l-iduronic acid(2-sulfate) α(1,4)-linked to N-acetyl-d-glucosamine. We now report the total synthesis of these candidate biomarkers for the first time and show by liquid chromatography-tandem mass spectrometry that they are identical to the analytes that accumulate in urine from MPS I and MPS II patients. The biomarkers were also prepared in heavy isotope labeled form so that they can be added to samples as internal standards. These reagents will allow for the first time the absolute moles of biomarkers to be determined in patient samples.

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Cite

BibTeXRIS
BibTeX
@article{singh2026synthesis,
  title = {{Synthesis of the Endogenous Non-Reducing End Heparan Sulfate Disaccharides for Newborn Screening and Diagnosis of Mucopolysaccharidosis types I and II}},
  author = {Gurpreet Singh and Sachin Popat Gholap and Sanghyun Lim and Zackary M. Herbst and Michael H. Gelb},
  journal = {Carbohydrate research},
  year = {2026},
  month = sep,
  doi = {10.1016/j.carres.2026.110100},
  url = {https://doi.org/10.1016/j.carres.2026.110100},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Synthesis of the Endogenous Non-Reducing End Heparan Sulfate Disaccharides for Newborn Screening and Diagnosis of Mucopolysaccharidosis types I and II
AU  - Gurpreet Singh
AU  - Sachin Popat Gholap
AU  - Sanghyun Lim
AU  - Zackary M. Herbst
AU  - Michael H. Gelb
PY  - 2026
DA  - 2026/09/17
JO  - Carbohydrate research
DO  - 10.1016/j.carres.2026.110100
UR  - https://doi.org/10.1016/j.carres.2026.110100
AB  - There is ongoing newborn screening (NBS) for mucopolysaccharidoses types I and II (MPS I and MPS II) because initiation of treatment early in life leads to better clinical outcomes. NBS starts with measurement of the relevant enzymatic activities in dried blood spots (DBS) on NBS cards. A second-tier test is carried out to eliminate false positives when enzymatic activity is low. In MPS I and MPS II, heparan sulfate accumulates, and previous studies have shown that the non-reducing end disaccharide fragments found endogenously in patient DBS and urine are elevated in patients but not in false positives. The proposed biomarker for MPS I is l-iduronic acid α(1,4)-linked to N-acetyl-d-glucosamine-6-sulfate, and the proposed biomarker for MPS II is l-iduronic acid(2-sulfate) α(1,4)-linked to N-acetyl-d-glucosamine. We now report the total synthesis of these candidate biomarkers for the first time and show by liquid chromatography-tandem mass spectrometry that they are identical to the analytes that accumulate in urine from MPS I and MPS II patients. The biomarkers were also prepared in heavy isotope labeled form so that they can be added to samples as internal standards. These reagents will allow for the first time the absolute moles of biomarkers to be determined in patient samples.
SN  - 0008-6215
SN  - 1873-426X
ER  -