Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase

Abstract

BackgroundMucopolysaccharidosis 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).MethodsWe 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.ResultsFive 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.ConclusionsThe 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.

Clinical Evolution After Enzyme Replacement Therapy in Twins with the Severe Form of Maroteaux–Lamy Syndrome

“…In our study, both twins showed negative results, despite higher levels of total antibodies in Twin 1, probably associated with the increased basal levels of the endogenous enzyme. In other lysosomal diseases, the antibody levels in the blood can affect the efficacy of the ERT by inhibiting the uptake of the enzyme by the target tissues (Brands et al 2013). Our results show no galsulfase antibodies in MPS VI patients, so the marked signs and symptoms might be only associated with the rapid, progressive form of the disease.…”

“…In particular, the left ventricular hypertrophy and functional abnormalities of the mitral and aortic valves are progressive in individuals who are not treated (Braunlin et al 2013). These abnormalities are stabilized by galsulfase treatment (Brands et al 2013;Giugliani et al 2014). We found mild mitral insufficiency in both twins, although mitral valve regurgitation is described in most MPS VI pediatric reports (Azevedo et al 2004;Scarpa et al 2009;Fesslova et al 2009;Lael et al 2010).…”

Molecular Analysis of Turkish Maroteaux-Lamy Patients and Identification of One Novel Mutation in the Arylsulfatase B (ARSB) Gene

“…Among these, Emre and colleagues characterized biochemically and genetically a group of MPS patients including three MPS VI cases . Recently, Brands described four MPS VI patients of Turkish ethnogeographic origin (Brands et al 2013). Hence this is the first study reporting the molecular characterization of the ARSB mutations in a quite large group of Maroteaux-Lamy cases from Turkey.…”

“…Through the in vitro expression of the mutated protein they evidenced a slightly reduced amount of the 66 kDa ARSB precursor, while they did not detect the 46 kDa mature form of the enzyme (Brands et al 2013).…”

“…Although several studies on lysosomal storage disorders in the Turkish population are reported in literature, only few of them describe MPS cases, including one study reporting 3 MPS VI patients (Elcioglu et al 2009;Emre et al 2000;Terzioglu et al 2002) and, recently, a paper on MPS VI that described, among others, four Maroteaux-Lamy subjects (among which two siblings) of Turkish ethnicity (Brands et al 2013). However, no studies specifically targeted to the analysis of the MPS VI Turkish patients have been so far conducted.…”