Abstract
Introduction
Mucopolysaccharidosis type I (MPS I) results in a defective breakdown of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, which leads to a progressive disease. Enzyme replacement therapy (ERT) results in clearance of these GAGs from a range of tissues and can significantly ameliorate several symptoms. The biochemical efficacy of ERT is generally assessed by the determination of the total urinary excretion of GAGs. However, this has limitations. We studied the concentrations of heparan sulfate and dermatan sulfate derived disaccharides (HS and DS, respectively) in the plasma and urine of seven patients and compared these levels with total urinary GAGs (uGAGs) levels.
Methods
Plasma and urine samples were collected at different time points relative to the weekly ERT for three non-consecutive weeks in seven MPS I patients who had been treated with ERT for at least 2.5 years. Heparan and dermatan sulfate in plasma and urine were enzymatically digested into disaccharides, and HS and DS levels were determined by HPLC-MS/MS analysis. uGAGs were measured by the DMB test.
Results
The levels of HS and DS were markedly decreased compared with the levels before the initiation of ERT. However, the concentrations of DS in plasma and of both HS and DS in urine remained significantly elevated in all studied patients, while in six patients the level of total uGAGs had normalized. The concentrations of plasma and urinary HS during the weekly ERT followed a U-shaped curve. However, the effect size is small. The concentrations of plasma and urinary DS and uGAGs appeared to be in a steady state.
Conclusions
HS and DS are sensitive biomarkers for monitoring the biochemical treatment efficacy of ERT and remain elevated despite long-term treatment. This finding may be related to the labeled dose or antibody status of the patient. The timing of the sample collection is not relevant, at least at the current dose of 100 IU/kg/weekly.
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Competing interests
FAW and CEMH received research and travel grants and the reimbursement of expenses and honoraria for lectures on lysosomal storage diseases from Genzyme Corp., USA. CEMH donated all honoraria to the Gaucher Stichting, a national foundation that supports research in the field of lysosomal storage disorders. MHdR received a travel grant from Genzyme Corp., USA. All other authors have no competing interests.
Funding
The study was partially funded by Genzyme Corp., USA. The funding source played no role in the writing of this article or in the decision to submit it for publication.
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Communicated by: Robin Lachmann
Minke H. de Ru and Linda van der Tol contributed equally to this study
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Fig. 3
a–g. Plasma and urinary HS and DS levels and total uGAGs relative to the day of infusion of laronidase (day 1) in different patients. HSp = HS plasma*, DSp = DS plasma**, uHS = urinary HS***, uDS = urinary DS**. Total uGAGs = total urinary GAGs as measured by the DMB test, * = represented by the disaccharide D0A0, ** = represented by the sum of the disaccharides D0a4 and D0a10, *** = represented by the sum of the disaccharides D0A0, D0A6 + D2A0, D2S0 and D0S6 + D2S0. (JPEG 533 kb)
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de Ru, M.H., van der Tol, L., van Vlies, N. et al. Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement therapy (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans. J Inherit Metab Dis 36, 247–255 (2013). https://doi.org/10.1007/s10545-012-9538-2
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DOI: https://doi.org/10.1007/s10545-012-9538-2