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Morquio syndrome/mucopolysaccharidosis type IV/keratan sulfaturia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
In Morquio type A, the defective enzyme catalyzes the removal of 6-sulfate moieties from galactose, and from the N-acetylgalactosamine residues of chondroitin sulfate. This latter property gave the enzyme its name. N-acetylgalactosamine-6-sulfatase has been purified from human placenta, and the defective enzyme has been demonstrated in cultured fibroblasts and in brain [3, 5, 8]. Deficiency of the type A enzyme has been demonstrated in patients not excreting keratan sulfate [53]. In five patients studied immunochemically, no cross-reacting material was demonstrated [54], but cross-reactive material has been demonstrated immunochemically in both Morquio type B and type A [55]. The full length of cDNA has been cloned and sequenced for human N-acetylgalactosamine-6-sulfatase [13], and transfection into deficient fibroblasts led to activity. The type A gene has 14 exons, and the sequence of 522 amino acids of the enzyme has considerable homology with other sulfatases, such as iduronate-2-sulfatase. At least 16 polymorphisms have been identified in the GALNS gene [56]. Polymorphic haplotypes may be employed for carrier detection and prenatal diagnosis in informative families [56], and this may be useful when mutations have not been identified. A considerable number and variety of mutations have been found in the Morquio type A gene [57].
Enzyme replacement combinational therapy: effective treatments for mucopolysaccharidoses
Published in Expert Opinion on Biological Therapy, 2021
Azam Safary, Hakimeh Moghaddas-Sani, Mostafa Akbarzadeh-Khiavi, Alireza Khabbazzi, Mohammad A. Rafi, Yadollah Omidi
Elosulfase alfa (GALNS, Vimzim®, N-acetylgalactosamine-6-sulfatase, chondroitinsulfatase, EC:3.1.6.4) produced in CHO cells was approved by the FDA for the treatment of MPS IVA in 2014. The elosulfase alfa is a 120 kDa homodimer encompassing 522 amino acids with monomers of 60 kDa. Like other lysosomal enzymes, elosulfase has a signal peptide including 26 residues that lead the nascent protein to the ER and Golgi apparatus system, where the protein is modified through N-glycosylation and proteolytic processing [86]. The deficiency of this enzyme leads to the accumulation of the GAGs, KS, and chondroitin-6-sulfate (C6S) in the lysosome. The most important PTMs, like other sulfatases, are the triggering of the active site through the conversion of cysteine 79 to FGly, in a process mediated by the FGE [87]. Based on clinical trial data, the recommended dose of elosulfase alfa in children and adults is IV administration of 2 mg/kg per week, which significantly reduces the urinary level of KS, which might be considered as a pharmacodynamic marker for the MPS IVA progression. Of note, MPS IV manifests with different severities of the prototypical skeletal and musculoskeletal abnormalities, including KS level [88]. The detection of KS in MPS II, IVA, and IVB has highlighted the importance of this biomarker [89], the presence of which in the urine is an age-related phenomenon [90].