title: Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase.
abstract: BACKGROUND
  Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B).
  
  
  METHODS
  We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the in vitro inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome.
  
  
  RESULTS
  Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase in vitro.
  
  
  CONCLUSIONS
  The clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy.
authors.forename: Marion M
authors.initials: MM
authors.lastname: Brands
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.forename: Marian A
authors.initials: MA
authors.lastname: Kroos
authors.forename: Willemieke
authors.initials: W
authors.lastname: Nobel
authors.forename: George J
authors.initials: GJ
authors.lastname: Ruijter
authors.forename: Lale
authors.initials: L
authors.lastname: Özkan
authors.forename: Iris
authors.initials: I
authors.lastname: Plug
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.forename: Lluïsa
authors.initials: L
authors.lastname: Vilageliu
authors.forename: Dicky J
authors.initials: DJ
authors.lastname: Halley
authors.forename: Ans T
authors.initials: AT
authors.lastname: van der Ploeg
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Reuser
mesh_terms: D000293:Adolescent; D000917:Antibody Formation / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D008297:Male; D009087:Mucopolysaccharidosis VI / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D016297:Mutagenesis, Site-Directed; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000276:immunology*; D010641:Phenotype; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D011994:Recombinant Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase; C508864:galsulfase
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