Characterization of disease-specific chondroitin sulfate nonreducing end accumulation in mucopolysaccharidosis IVA

Roger Lawrence, Heather Prill, Preejith P. Vachali, Evan G. Adintori, Greg de Hart, Raymond Y. Wang, Barbara K. Burton, Marzia Pasquali, Brett E. Crawford

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Morquio syndrome type A, also known as MPS IVA, is a rare autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, a lysosomal hydrolase critical in the degradation of keratan sulfate (KS) and chondroitin sulfate (CS). The CS that accumulates in MPS IVA patients has a disease-specific nonreducing end (NRE) terminating with N-acetyl-Dgalactosamine 6-sulfate, which can be specifically quantified after enzymatic depolymerization of CS polysaccharide chains. The abundance of N-acetyl-D-galactosamine 6-sulfate over other possible NRE structures is diagnostic for MPS IVA. Here, we describe an assay for the liberation and measurement of N-acetyl-D-galactosamine 6-sulfate and explore its application to MPS IVA patient samples in pilot studies examining disease detection, effects of age and treatment with enzyme-replacement therapy. This assay complements the existing urinary KS assay by quantifying CS-derived substrates, which represent a distinct biochemical aspect of MPS IVA. A more complete understanding of the disease could help to more definitively detect disease across age ranges and more completely measure the pharmacodynamic efficacy of therapies. Larger studies will be needed to clarify the potential value of this CS-derived substrate to manage disease in MPS IVA patients.

Original languageEnglish (US)
Pages (from-to)433-445
Number of pages13
JournalGlycobiology
Volume30
Issue number7
DOIs
StatePublished - 2021

Funding

R.L., G.d.H. and B.E.C. are employees of and have interest in BioMarin Pharmaceutical Inc. H.P. and E.G.A. are former employees. R.Y.W. and B.K.B. have collaborated with BioMarin Pharmaceutical Inc. during and outside of the conduct of this study. B.K.B. has received consulting fees and honoraria from BioMarin Pharmaceutical Inc. and has conducted clinical trials funded by BioMarin. P.P.V. and M.P. collaborated with BioMarin Pharmaceutical Inc. in study design, data generation and interpretation, and provided contractual services for clinical assay validation during the conduct of the study.

Keywords

  • Biomarker
  • Chondroitin sulfate
  • Mucopolysaccharidosis IVA
  • N-acetylgalactosamine-6-sulfatase

ASJC Scopus subject areas

  • Biochemistry

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