Abstract | BACKGROUND: 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.
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Authors | Marion M Brands, Marianne Hoogeveen-Westerveld, Marian A Kroos, Willemieke Nobel, George J Ruijter, Lale Özkan, Iris Plug, Daniel Grinberg, Lluïsa Vilageliu, Dicky J Halley, Ans T van der Ploeg, Arnold J Reuser |
Journal | Orphanet journal of rare diseases
(Orphanet J Rare Dis)
Vol. 8
Pg. 51
(Apr 04 2013)
ISSN: 1750-1172 [Electronic] England |
PMID | 23557332
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Recombinant Proteins
- N-Acetylgalactosamine-4-Sulfatase
- galsulfase
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Topics |
- Adolescent
- Antibody Formation
(immunology)
- Child
- Child, Preschool
- Enzyme-Linked Immunosorbent Assay
- Female
- Genotype
- Humans
- Immunoprecipitation
- Infant
- Male
- Mucopolysaccharidosis VI
(genetics, immunology, pathology)
- Mutagenesis, Site-Directed
- N-Acetylgalactosamine-4-Sulfatase
(immunology)
- Phenotype
- Recombinant Proteins
(immunology)
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