L-Iduronidases

Hurler s and Scheie s syndromes can be detected by assay of the levels of a-L-iduronidase in leucocytes.  

Not all preparations of a-L-iduronidase function as a corrective factor for Hurler s syndrome. Corrective and non-corrective forms of the enzyme in urine have been separated by affinity chromatography on heparin immobilized on agarose whereas they have similar catalytic properties, they differ in molecular weight (8.7 x lOS 6.7 x 10 ) and in binding to an immobilized castor-bean lectin. The corrective form was the only one efficiently taken up by Hurler s fibroblasts. 

A simple assay for a-L-iduronidase activity in leucocytes has been reported for the detection of Hurler syndrome and its carriers. The method avoids time-consuming stages and tedious extraction procedures, but is based on phenyl cK-L-idopyranosyluronic acid as substrate. 

As part of a study on the neurochemistry of genetic hyperglycosamino-glycanuria (mucopolysaccharidoses), lysosomal enzymes, including a-L-iduronidase, in normals and four types of patients have been investigated in brain and liver.  

Several differences occur between the interactions of glycosaminoglycans with a particular lysosomal protein leading to inhibition of lysosomal enzymes including a-D-mannosidase. The mitogenic effect of a-D-mannosidase on lymphocytes has been studied.  

Levels of lysosomal a-o-mannosidase have been determined in normal hair roots and in hair roots obtained from a patient with mannosidosis. The significance of the results was discussed in relation to the levels of other glycoside hydrolases present, and to the detection of lysosomal storage diseases. 

A study of the glycoside hydrolases of human lung showed that the level of a-D-mannosidase activity is high. The electrophoretic mobility of the enzyme on polyacrylamide gels indicated that it is different from serum a-D-manno-sidase. The secretory mechanism of the lung enzyme was discussed. 

5-Anhydro-4-0-(a-L-idopyranosyluronic acid)-D-[l- H]mannitol is cleaved by a-L-iduronidase to give, as one of the products, 2,5-anhydro-D-[l- H]mannitol, which can be separated and assayed. This procedure can be used in the diagnosis of mucopolysaccharidosis type I (Hurler s syndrome). 

A deficiency of a-L-iduronidase has been reported in a patient with hyper-glycosaminoglycanuria, whose phenotypic abnormalities did not resemble either the Hurler or Scheie syndrome.  

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Aldurazyme (tradename, also known as laronidase) is a recombinant version of one polymorphic variant of the human enzyme a-L-iduronidase. It was approved for general medical use in the USA in 2003 and is indicated for the treatment of patients with certain forms of the rare inherited disease MPS I. MPS I is caused by a deficiency of a lysosomal a-L-iduronidase, which normally catalyses the hydrolysis of terminal a-L-iduronic acid residues from the glycosaminoglycans dermatan sulfate and heparin sulfate. The deficiency results in accumulation of the glycosaminoglycans throughout the body, causing widespread cell and tissue dysfunction. 

I Hurler Autosomal recessive Ol-L-iduronidase Dermatan sulfate... 

Laronidase (Aldurazyme) is recombinant-L-idu-ronidase. In mucopolysaccharidosis I (Hurler syndrome) there is a deficiency of the lysosomal enzyme a -L-iduronidase. Laronidase is employed for the non-neurological manifestations of Hurler syndrome. After intravenous infusion laronidase is eliminated with a half-life of 1.5-3.6 hours. Infusion related side effects are seen frequently. Hypersensitivity reactions may occur. 

Chamoles NA, Blanco M, Gaggioli D (2001) Diagnosis of a-L-iduronidase deficiency in dried blood spots on filter paper the possibility of newborn diagnosis. Clin Chem 47 780-781... 

Stirling JL, Robinson D, Fensom AH, Benson PF, Baker JE, Button LR (1979) Prenatal diagnosis of two Hurler fetuses using an improved assay for methylumbelliferyl-a-L-iduronidase. Lancet 2 37... 

This "Hurler corrective factor" was identified as an a-L-iduronidase. In the Hunter syndrome (MPS II) dermatan sulfate and heparan sulfate accumulate. 

MPS I (Hurler) a-l-Iduronidase Dermatan sulfate, heparan sulfate Skeletal, organomegaly, cardiovascular, neurological, ocular Cat, dog, mouse Retrovirus Ex-vivo (Zheng et al., 2004) in utero (Meertens et al., 2002) Plasmid IM (Lutzko et al., 1999) AAV Intracranial (Desmaris et al., 2004) IV (Hartung et al., 2004)... 

Hartung, S. D., Frandsen, J. L., Pan, D., Koniar, B. L., Graupman, P., Gunther, R., Low, W. C., Whitley, C. B. and Mclvor, R. S. (2004). Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene. Mol. Ther. 9, 866-875. 

Genetically corrected autologous stem cells engraft, but host immune responses limit their utility in canine alpha-L-iduronidase deficiency. Blood 93, 1895-1905. 

Meertens, L., Zhao, Y., Rosic-Kablar, S., Li, L., Chan, K., Dobson, H., Gartley, C., Lutzko, C., Hopwood, J., Kohn, D., Kruth, S., Hough, M. R. and Dube, I. D. (2002). In utero injection of alpha-L-iduronidase-carrying retrovirus in canine mucopolysaccharidosis type I Infection of multiple tissues and neonatal gene expression. Hum. Gene Ther. 13, 1809-1820. 

Wraith, J. E., Clarke, L. A., Beck, M., Kolodny, E. H., Pastores, G. M., Muenzer, J., Rapoport, D. M., Berger, K. I., Swiedler, S. J., Kakkis, E. D., Braakman, T., Chadbourne, E., Walton-Bowen, K. and Cox, G. F. (2004). Enzyme replacement therapy for mucopolysaccharidosis I A randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J. Pediatr. 144, 581-588. 

Aldurazyme polymorphic variation of human a-L-iduronidase lysosomal hydrolase hydrolysis of terminal a-L-iduronic acid residues of dermatan sulfate and heparin sulfate No genotoxicity studies clinical trials Studies to assess mutagenic and carcinogenic potential have not been conducted No warnings or precautions regarding carcinogenic risk... 

Canine MPS I was discovered in a Plott hound that presented with corneal clouding [10]. Studies by Shull and Neufeld showed that the dogs were deficient in a-l-iduronidase [11], Being null, MPS I dogs are genetically similar to the most severe form of MPS I in humans, but clinically they more closely resemble moderately affected patients. These animals provide a valuable bio-chemical/clinical model for MPS I disease. Since they have no confounding residual enzyme activity, they accumulate GAGs in relevant tissues, and their clinical phenotype closely resembles the human disease. 

MPS I dogs were used to evaluate the biodistribution of rh-iduronidase, pharmacodynamic reduction of tissue GAGs and in vivo efficacy. Pharmacokinetics and the effects of various doses and regimens of rh-iduronidase were also evaluated in this model. Heterozygote dogs from the MPS I colony, referred to as normal carriers, were used to derive normal tissue levels of a-l-iduronidase activity and GAG storage. 

Shull RM, Munger RJ, Spellacy E, Hall CW, Constantopoulos G, Neufeld EF. Canine alpha-L-iduronidase deficiency. A model of mucopolysaccharidosis I. Am J Pathol 1982 109(2) 244-8. 

Spellacy E, Shull RM, Constantopoulos G, Neufeld EF. A canine model of human alpha-l-iduronidase deficiency. Proc Natl Acad Sci USA 1983 80(19) 6091-5. 

Several endeavors are being directed towards identifying biomarkers that can serve as a surrogate indicator of disease severity, in terms of either overall disease burden or involvement of a particular organ/system in patients with an LSD. In mucopolysaccharidosis type I, the analysis of the levels of oligosaccharides derived from GAGs in cultured fibroblasts (as measured by electrospray ionization tandem mass spectrometry) combined with the residual a-L-iduronidase activity have been shown to distinguish patients with and without CNS involvement (Fuller et al.,... 

Mucopolysaccharidosis I (Hurler, Hurler-Scheie and Scheie syndromes) a-L-Iduronidase HS, DS Short stature, skeletal dysplasia, coarse facial features, joint stiffness, visceromegaly, cardiac disease, comeal clouding, CNS involvement... 

Pfaundler-Hurler syndrome (type I-H) This syndrome is caused by an a-L-iduronidase deficiency (M. v. Pfaundler, 1920 G. Hurler, 1920). It is autosomal recessive and panethnic, with an incidence of approx. 1 100,000 live births. A major cause of morbidity and mortality is respiratory insufficiency together with cardiac compromise (valvular dysfunction). 

UlMch-Scheie s syndrome (type V) This is also characterized by an a-L-iduronidase deficiency, but it does not appear before school... 

These forms overlap in symptomatology and cannot be distinguished by enzyme or urinary assays. A new therapy for a-L-iduronidase deficiency using enzyme replacement (= laronidase) as i.v. infusion has proved safe and efficacious (J. Wraith et al., 2004). 

S-Carboxy-3/ ,4/ ,55 -trihydroxy-piperidine from Baphia racemosa (Leguminosae) seeds is an inhibitor of human P-D-glucuronidase and a-L-iduronidase [147]. The all trans-dihydroxyproline, (25, 3/ ,4f )-2-carboxy-3,4-dihydroxypyrrolidine, from Amanita virasa is structurally analogous at C(2), C(3) and C(4) to O-glucuronic acid and it is also a moderate inhibitor of human P-D-glucuronidase [148]. 

Key CTFR, cystic fibrosis transmembrane conductance regulator FACC, factor C IDUA, a-L-iduronidase SCIDS, severe combined immunodeficiency ADA, adenosine deaminase MDR, multidrug resistance PNP, purine nucleoside phosphorylase. 

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