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We determined the cardiologic features of children with MPS I, II and VI, and evaluated the effect of enzyme-replacement therapy (ERT) on cardiac disease. Twenty-four children aged 1-18 years with MPS I, II or VI were prospectively evaluated with echocardiogram and electrocardiogram from the start of enzyme-replacement therapy up to 6 years of treatment. At start of therapy, 66% had abnormal cardiac geometric features. Left-ventricular mass index (LVMI) was increased in half of the patients, due mainly to concentric hypertrophy in MPS I and II and to eccentric hypertrophy in MPS VI. Regurgitation was most severe in a subgroup of young MPS VI patients (<5 years) at the mitral valve. At baseline, all patients had abnormal valves. The ECG showed no clear rhythm or conduction abnormalities; neither, in most patients, did it reflect the hypertrophy. After ERT, the LVMI Z-score normalized in 70% of the patients who had a Z-score > 2. LVMI Z-scores decreased significantly in patients with MPS I and MPS II (p = 0.04 and p = 0.032). Despite ERT, valve regurgitation increased in 60% of the patients. We conclude that all our MPS patients have cardiac abnormalities. The most severe cardiac disease was observed in a subgroup of young MPS VI patients. While ERT had an effect on LVMI and IVSd, it apparently had little or none on valve regurgitation.

Before the discovery of the lysosome, already three out of the seven currently known mucopolysaccharidoses (MPSs) were described in medical literature. In 1917, Hunter syndrome was the first to be described in two brothers (“they are as alike as two peas”) by Charles Hunter. Gertrud Hurler published her two case reports about MPS I in 1919, and MPS IV was outlined in 1929 by the Uruguayan dr. Morquio. All described young children with or without mental impairment, with profound bone abnormalities. In 1955, the Belgian scientist Christian de Duve discovered a new intra-cellular organelle that he named the lysosome. Eventually, this brought light to more than 50 inherited diseases all concerning a defect in the lysosomal system. The group of mucopolysaccharidoses belonged to these lysosomal disorders and all types proved to be characterized by the deficiency of a lysosomal enzyme. New types of MPSs were discovered since then. In 1963 two French physicians described a new form of dysostosis mupltiplex, MPS VI, and the syndrome was named after them: Maroteaux-Lamy’s syndrome 4. In the same year dr. Sanfilippo described for the first time a MPS III patient with mental impairment and excretion of heparan sulphate. Later, Sanfillippo disease was subdivided in type A, B, C, and D because between 1972 and 1980 different enzyme deficiencies were discovered in each of the four subtypes. Finally, in 1973, MPS VII was described by the American dr. Sly . MPS V and MPS VIII, first thought to be novel diseases, later turned out to be already known types of MPS and are not separate entities anymore. In 1996 Natowicz et al reported the first patient with MPS IX . Till now, only one other family has been reported with this disease.

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 potent