Heparan sulfate derived disaccharides in plasma and total urinary excretion of glycosaminoglycans correlate with disease
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ORIGINAL ARTICLE
Heparan sulfate derived disaccharides in plasma and total urinary excretion of glycosaminoglycans correlate with disease severity in Sanfilippo disease J. de Ruijter & L. IJlst & W. Kulik & H. van Lenthe & T. Wagemans & N. van Vlies & F. A. Wijburg
Received: 31 May 2012 / Revised: 7 August 2012 / Accepted: 13 August 2012 / Published online: 12 September 2012 # SSIEM and Springer 2012
Abstract Background Sanfilippo disease (Mucopolysaccharidosis III) is a neurodegenerative lysosomal disorder characterized by accumulation of the glycosaminoglycan heparan sulfate (HS). MPS III has a large phenotypic variability and early assessment of disease severity is difficult. We investigated the correlation between disease severity and the plasma concentration of HS (pHS, defined by the sum of the heparan sulfate derived disaccharides obtained after enzymatic digestion) and urinary total GAGs level (uGAGs, measured by the dimethylene blue test) in a cross-sectional cohort of 44 MPS III patients. Methods Disease severity was established on the basis of the age of complete loss of independent walking and of full loss of speech in all patients. Hazard ratios (HR) were obtained with cox-regression analysis. In order to allow prediction of a severe phenotype based on a cut-off value for pHS, patients were divided in two groups (severely affected and less severely affected) based on predictive
Communicated by: Ed Wraith J. de Ruijter : T. Wagemans : N. van Vlies : F. A. Wijburg Department of Pediatrics and Amsterdam Lysosome Centre ‘Sphinx’, University of Amsterdam, Amsterdam, The Netherlands L. IJlst : W. Kulik : H. van Lenthe : T. Wagemans : N. van Vlies Lab. Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands F. A. Wijburg (*) Department of Pediatrics, Division of Metabolic Diseases (H7270), Academic Medical Centre (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands e-mail: [email protected]
mutations or on the age of full loss of speech. Receiver operator characteristics (ROC) were obtained for pHS. Results pHS and uGAGs were independently and linearly associated with an increased risk of speech loss with a HR of 1.8 (95 % CI 1.3–2.7) per 500 ng/ml increase of HS in plasma (p00.002), and a HR of 2.7 (95 % CI 1.6–4.4) per 10 mg/mmol creatinine increase of uGAGs (p10 years: 8 mg/ mmol creatinine) and subsequently categorized in quartiles. Patient characteristics (age, gender and MPS subtype) were summarized across these quartiles: median and ranges for continuous non-normal variables, and frequencies and percentages for categorical variables. Differences among patient characteristics across pHS and uGAGs quartiles were evaluated using the Kruskal-Wallis test for continuous non normal variables (age), and χ2 test for gender and MPS subtype (Tables 1 and 2). Survival analysis of full loss of speech and full loss of walking were assessed across the quartiles of pHS and uGAGs by Kaplan–Meier curves and log-ra
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