A-L-Iduronidase deficiency

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... 

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). 

The receptor-binding of high-uptake forms of lysosomal enzymes to human diploid skin fibroblasts has been demonstrated directly by using a sensitive assay for the bound enzyme. a-L-Iduronidase-deficient cells were incubated with human urinary a-L-iduronidase and the cell-associated enzyme was assayed with 4-methylumbelliferyl a-L-idopyranosiduronic acid. D-Mannose 6-phosphate greatly accelerated the dissociation of the bound enzyme, and during uptake of a-L-iduronidase the receptors were regenerated every few minutes, even in the absence of protein synthesis. 

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. 

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. 

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. 

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. 

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. ... 

Hurler s syndrome (252800) is caused by a deficiency of L-iduronidase, an enzyme normally expressed in most human cell types. It was demonstrated by Neufeld that exogenous L-iduronidase could be taken up by deficient cells via a targeting signal that directed the enzyme to its normal lysosomal location. Which of the therapeutic strategies below would be the most realistic and efficient mode of therapy ... 

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