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Mucopolysaccharidosis Type VI, an Updated Overview of the Disease.

ABSTRACT: Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10-15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.

SUBMITTER: D'Avanzo F

PROVIDER: S-EPMC8707598 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 microg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.

Project description: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.

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Mucopolysaccharidosis Type VI, an Updated Overview of the Disease.

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