title: 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.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Pediatrics, Amsterdam Lysosome Centre Sphinx, Academic Medical Center, University Hospital of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Minke H
authors.initials: MH
authors.lastname: de Ru
authors.forename: Linda
authors.initials: L
authors.lastname: van der Tol
authors.forename: Naomi
authors.initials: N
authors.lastname: van Vlies
authors.forename: Brian W
authors.initials: BW
authors.lastname: Bigger
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.forename: Wim
authors.initials: W
authors.lastname: Kulik
authors.forename: Henk
authors.initials: H
authors.lastname: van Lenthe
authors.forename: Muhammad A
authors.initials: MA
authors.lastname: Saif
authors.forename: Tom
authors.initials: T
authors.lastname: Wagemans
authors.forename: Willem M
authors.initials: WM
authors.lastname: van der Wal
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002648:Child; D002675:Child, Preschool; D003871:Dermatan Sulfate / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004187:Disaccharides / Q000097:blood / Q000378:metabolism* / Q000652:urine; D056947:Enzyme Replacement Therapy; D005260:Female; D006025:Glycosaminoglycans / Q000652:urine*; D006497:Heparan Sulfate / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008059:Mucopolysaccharidosis I / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003871:Dermatan Sulfate; D004187:Disaccharides; D006025:Glycosaminoglycans; D006497:Heparan Sulfate