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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].
Biocatalytic Nanoreactors for Medical Purposes
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Oscar González-Davis, Chauhan Kanchan, Rafael Vazquez-Duhalt
Mucopolysaccharidosis type I (MPS I) is a rare disease in which the body is missing or does not have enough of α-L-iduronidase needed to break down long chains of glycosaminoglycans. There are several other types of MPS, including MPS II or Hunter syndrome originated by the absence of iduronate-2-sulfatase; MPS III or Sanfilippo syndrome derived by low activity of N-acetylglucosaminidase; MPS IV or Morquio syndrome originated by the absence of galactose-6-sulfate sulfatase activity, and MPS VI derived from the absence of N-acetylgalactosamine-4-sulfatase. The ERT has been studied for most of MPS subtypes (Dornelles et al., 2017; Whiteman and Kimura, 2017; Gilkes and Heldermon, 2014; Tomatsu et al., 2015; Vairo et al., 2015).
Expanding the phenotype of mucopolysaccharidosis type II retinopathy
Published in Ophthalmic Genetics, 2021
Tanya Kowalski, Jonathan B Ruddle, Gerard de Jong, Heather G Mack
Mucopolysaccharidosis type II (MPS II, Hunter Syndrome, OMIM #309900) is an X-linked recessive lysosomal storage disorder caused by deficiency of iduronate 2-sulfatase (IDS) affecting 1 in 36,000 Australian male births (1), and very rarely females due to non-random inactivation of the X-chromosome (2). It is the only known X-linked MPS subtype; all others are inherited in an autosomal recessive pattern. IDS is a lysosomal enzyme required for the degradation of glycosaminoglycans (GAG) heparan sulfate and dermatan sulfate. IDS deficiency leads to lysosomal accumulation of these GAG and subsequent structural and biochemical dysfunction within many organ systems including respiratory, cardiac, gastrointestinal, musculoskeletal, central nervous system (CNS) and ocular (3). Up to two-thirds of patients present with CNS involvement with seizures and cognitive impairment (3,4). A continuum of clinical severity ranges between attenuated to severe forms (3) and life expectancy varies with death occurring between the second to fifth decades, usually from cardiac or pulmonary disease.
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
Idursulfase (I2S, IDS, Elaprase®, α-L-iduronate sulfate sulfatase, EC: 3.1.6.13), as a recombinant form of human iduronate-2-sulfatase, has received FDA approval in 2006 for the treatment of MPS II. This enzyme is produced using genetic engineering in a continuous human cell line and is being intravenously injected at a dose of 0.5 mg/kg per week [11]. The idursulfase is a glycoprotein composed of 525 amino acids, containing eight N-linked glycosylation sites that are occupied by 2 bis-M6P containing oligosaccharide chains. All members of the sulfatase family undergo PTMs in the endoplasmic reticulum (ER). Cα-formylglycine (Cα-FGly) is a catalytic residue in the active site of the sulfatase enzymes and plays an essential role in their catalytic activity. In eukaryotes, it is generated in the rough ER of a conserved cysteine residue by a formylglycine-generating enzyme (FGE). Idursulfase as a member of the sulfatase family catalyzes the removal of the sulfate group from the 2-position of L-iduronic acid in DS and HS in the lysosomes [75]. Idursulfase beta is another approved ERT for Hunter syndrome, which is produced in the CHO cell line. Based on the biochemical and physicochemical comparison of two recombinant enzymes, idursulfase beta has a higher content of formylglycine and exhibits significantly greater specific enzymatic activity compared to the idursulfase. However, further clinical evaluations should be conducted to demonstrate the long-term efficacy and differentiation between these enzymes [76].
Gene therapy for neurological disorders: challenges and recent advancements
Published in Journal of Drug Targeting, 2020
Stefanie A. Pena, Rahul Iyengar, Rebecca S. Eshraghi, Nicole Bencie, Jeenu Mittal, Abdulrahman Aljohani, Rahul Mittal, Adrien A. Eshraghi
A few notable clinical trials have validated the future applications of in vivo gene therapy. As a part of the CHAMPIONS Phase 1 and 2 trials, a patient with an inherited metabolic disorder called mucopolysaccharidosis (MPS) type II, or Hunter syndrome, underwent the first in vivo gene editing to replace the dysfunctional iduronate-2-sulfatase (IDS) enzyme [114]. Without this enzyme, people with MPS II are significantly debilitated due to buildup of toxic carbohydrate metabolites throughout their body. Current enzyme-replacement therapy (ERT) is effective; however, ERT imposes a substantial burden of lifelong infusions since blood levels of IDS become nearly undetectable within a day of receiving ERT. The trial is investigating the use of ZFN editing coupled with an AAV vector to deliver therapeutic DNA to the liver via a single intravenous infusion. Specific targeting allows only liver cells to activate DNA instructions, upon which ZFNs cut out and replace a specific portion within the albumin gene, enabling permanent and precise integration of the functional IDS gene [115].