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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
Engineering of α-iduronidase by fusion to a receptor-binding peptide from apolipoprotein E (apoE) was carried out to bind to LDL receptors on the blood brain barrier [56]. In mice with MPS I this treatment yielded 2–3 percent of normal iduronidase activity in brain and normal levels of glycosaminoglycan in brain.
Biochemical Basis of Cervical Maturation
Published in Gabor Huszar, The Physiology and Biochemistry of the Uterus in Pregnancy and Labor, 2020
Degradation of hyaluronic acid in mammalian tissue begins with the action of hyaluronidase, an endohexosaminidase, which is capable of degrading the polymer to tetrasaccharides, and is completed by the act of β-glucuronidase and an exohexosamin-idase.20 Only a limited number of glucuronic acid residues in dermatan sulfate are susceptible to hyaluronidase cleavage. Continued degradation requires 0-glucuroni-dase, N-acetyl galactosamine 4-sulfatase, β-N-acetylhexosaminidase, iduronate sulfa-tase, and iduronidase. In addition, proteases are required for degradation of the core.
OCT imaging of macular cysts and treatment response with nepafenac in mucopolysaccharidosis type 1
Published in Ophthalmic Genetics, 2023
Aslıhan Yılmaz Çebi, Mustafa Hepokur
A 27-year-old female with mucopolysaccharidosis type I (MPS I) was referred to our clinic. She had blurry vision for one month. She was diagnosed with MPS I (Scheie phenotype) ten years ago and was treated with enzyme replacement therapy (ERT) with alpha-L-iduronidase (Aldurazyme) at a weekly dose of 0.58 mg/kg for ten years. The best-corrected visual acuity in both eyes was 20/25 (refraction was +7.00D–4.00x155 OD and +7.25D–4.25x17 OS). Both cornea were clear, despite the presence of guttata on specular microscopy. There was no trace of cataract formation. Dilated fundus examination revealed bilateral pigmentary retinopathy, and fine radial abnormalities on the superotemporal side of macula (Figure 1). Optical coherence tomography (OCT) showed macular cysts in the inner and outer nuclear layers (INL and ONL) and central external limiting membrane thickening (Figure 2). The perifoveal ellipsoid zone and the IS/OS line have been preserved. Fluorescein angiography (FA) did not show any evidence of vascular dye leakage (Figure 3).
The potential of gene therapy for mucopolysaccharidosis type I
Published in Expert Opinion on Orphan Drugs, 2020
Luisa Natalia Pimentel Vera, Guilherme Baldo
Mucopolysaccharidosis type I (MPS I-H) is an autosomal recessive disease caused by mutations in the IDUA gene localized at 4q16.3. This gene encodes the lysosomal hydrolase alpha-L-iduronidase (IDUA, EC 3.2.1.76), which is responsible for the hydrolysis of alpha-L iduronic acid residues of glycosaminoglycans (GAGs) Dermatan sulfate and Heparan sulfate [1,2]. This process is a fundamental step for the breakdown of these molecules in the lysosome and mutations in IDUA result in a deficient production or function of the enzyme. It causes progressive accumulation of GAGs within lysosomes, impairing its function [3]. As a result, loss of lysosomal function also involves secondary impairment of other pathways as autophagy and activation of inflammation. These alterations trigger a series of severe symptoms in patients, resulting in ocular, skeletal, visceral, and neurological manifestations, causing death at early ages [1,4,5].
Digital microfluidics comes of age: high-throughput screening to bedside diagnostic testing for genetic disorders in newborns
Published in Expert Review of Molecular Diagnostics, 2018
David Millington, Scott Norton, Raj Singh, Rama Sista, Vijay Srinivasan, Vamsee Pamula
Hunter Syndrome is one of the LSDs that has been treated successfully in early infancy [43] and is being considered as a potential target for NBS. The use of 4-methylumbelliferyl-α-L-iduronide-2-sulfate as a fluorescence substrate to measure the activity of IDS requires the sequential action of a second enzyme, α-iduronidase, to convert the product of the sulfatase, 4-methylumbelliferyl-α-L-iduronic acid, into iduronic acid and the fluorescent end-product, 4-methylumbelliferone (4-MU). Previous fluorometric assays for IDS used partially purified iduronidase from rabbit liver or bovine testis and sequentially performed the two reactions over a 24 h incubation period to accommodate the difference in pH optima for the 2 enzymes [44]. An improved homogeneous assay for IDS was accomplished on the DMF platform by combining both the enzymes in a single reaction mix using sulfatase (from the DBS sample) and pure, recombinant iduronidase with a 1 h incubation time [45]. This novel assay was able to completely differentiate DBS samples from known affected patients with Hunter (n = 6) from unaffected controls (n = 105), and represented an important step toward the validation of DMF assays for LSDs [46].