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Hurler disease/mucopolysaccharidosis type IH (MPSIH)/α-L-iduronidase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The molecular defect in Hurler disease is in the activity of α-L-iduronidase (see Figure 76.1) [3, 4, 5]. This enzyme catalyzes the hydrolysis terminal iduronic acid residues of dermatan sulfate and heparin sulfate. The enzyme has been purified from the human liver, kidney, and lung [29–31]. The cDNA codes a protein of 653 amino acids [32]. The protein exists as a monomer of 70 kDa minus the signal sequence [33]. There are six potential sites for N-glycosylation. It acquires mannose-6-phosphate, which permits targeting to lysosomes [33]. The deficient activity of enzyme is readily demonstrated in cultured fibroblasts and in leukocytes [34–37]. Residual activity of the enzyme has not been useful in distinguishing variants with phenotypes of greater or lesser severity, including the Scheie syndrome. Also, immunochemical studies have not been helpful with these distinctions.
Animal Models Of Connective Tissue Diseases
Published in Marcos Rojkind, Connective Tissue in Health and Disease, 2017
Gerald Α. Hegreberg, Lynetta J. Freeman
Several clinical forms of type 1 mucopolysaccharidosis have been identified, including a severe form (Hurler's disease), a least severe form (the Scheie syndrome), and a form which has characteristics of both forms (the Hurler-Scheie syndrome). Hurler's disease is clinically accompanied by progressive clouding of the cornea; skeletal abnormalities resulting in dwarf stature and an altered shape of the head and vertebrae; joint stiffness; mental deterioration; an accumulation of the polysaccharide material in viscera and connective tissue, including the cardiovascular system; and early death. In the Scheie syndrome, corneas are severely clouded, deformities are observed in the hands, and cardiac abnormalities include aortic stenosis or regurgitation. Disorders of stature and intelligence are not severe clinical manifestations of the disease as seen in the Hurler's syndrome. These forms of type I mucopolysaccharidosis are inherited as autosomal recessive traits.
Enzyme therapy: a forerunner in catalyzing a healthy society?
Published in Expert Opinion on Biological Therapy, 2020
Saptashwa Datta, K Narayanan Rajnish, C George Priya Doss, S. Melvin Samuel, E. Selvarajan, Hatem Zayed
Enzyme replacement therapy was the first publicized use of enzymes for therapeutic purposes. The possibility of using enzymes for the therapy of lysosomal storage diseases was proposed in 1964 by Dr. Christian de Duve [3]. Since its provenance, enzyme replacement therapy has made large strides and is currently used for the treatment of multiple enzyme deficiency disorders, including Gaucher disease [4], Fabry disease [5], Pompe disease [6], Hunter syndrome [7], Hurler–Scheie syndrome [8], Sly syndrome [9], Morquio A syndrome [10], Tay–Sachs disease [11], Wolman disease [12], adenosine deaminase-severe combined immune deficiency [13], hypophosphatasia [14], metachromatic leukodystrophy [15], Sphingomyelinase deficiency [16], homocystinuria [17], Maroteaux–Lamy syndrome [18], alpha-mannosidosis [19] and ceroid lipofuscinosis type 2 [20]. Pancreatic enzyme replacement therapy is a specialized category of replacement therapy using enzymes used for the therapy of exocrine pancreatic insufficiency, which can occur in various diseases, such as cystic fibrosis, chronic pancreatitis, and celiac disease [21]. Moreover, in the modern era, the therapeutic use of enzymes has been further applied for cancer treatment [22], wound healing [23], improving the life of patients suffering from irritable bowel syndrome [24], fighting antibiotic-resistant microbial infections [25] and gene therapy [26]. In this article, we review the properties of various enzymes, along with their efficacy in the treatment of various disorders. The enzymes have been grouped into sections based on the various diseases they are used to treat. This article also provides an update on recent developments in enzyme research and their application as therapeutics.
The potential of gene therapy for mucopolysaccharidosis type I
Published in Expert Opinion on Orphan Drugs, 2020
Luisa Natalia Pimentel Vera, Guilherme Baldo
Patients with MPS I can present different phenotypes. The severe form (called Hurler syndrome) has an early manifestation, starting between the first and third year of life, with a profound and progressive systemic and neurologic impairment. The intermediary phenotype, described as Hurler-Scheie may not display an aggressive cognitive decline at early stage, but learning disabilities can be present. There is also a more attenuated (or less severe) form, where the patients present a residual enzyme activity, called Scheie syndrome. These patients are cognitive normal, but still develop several other abnormalities seen in the most severe forms [6,7].