Glycosaminoglycan accumulation

Byers S, Rozaklis T, Brumfield LK, Ranieri E, Hopwood JJ (1998) Glycosaminoglycan accumulation and excretion in the mucopolysaccharidoses characterization and basis of a diagnostic test for MPS. Mol Genet Metab 65 282-290... 

Explain why lysosomal enzyme deficiencies and glycosaminoglycan accumulation result in clinical signs/symptoms. 

Interestingly, fibroblasts derived from retroocular connective tissue and skin in thyroid eye disease exhibited different hormonal regulation. Specifically, skin fibroblasts responded to T3 (100 nmol/liter) and dexamethasone (100 nmol/liter) with 27% and 55% inhibition of glycosaminoglycan accumulation, respectively, whereas retroocular fibroblasts responded to the two hormones with 12% and 8% inhibition, respectively (82). 

Smith TJ, Bahn RS, Gorman CA, Cheavens M. Stimulation of glycosaminoglycan accumulation by interferon gamma in cultured human retroocular fibroblasts. J Clin Endocrinol Metab 1991 72 1169-1171. 

In the Sanfilippo syndrome, glycosaminoglycan accumulates in ocular material (J14), and heparan sulfate is by far the predominant glycosaminoglycan accumulated in the liver (G9), and here the glycosaminoglycan is known to be polydisperse. Heparan sulfate also accumulates... 

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. 

There are numerous inherited disorders of lysosomal metabolism in humans. These disorders result from the lack of a specific acid hydrolase and have several clinical manifestations. A variety of substances may accumulate that interfere with normal cell functions, as is the case with the lipidoses (Chapter 9) or mucopolysaccharides (glycosaminoglycans) in the Hurler s disease (gargoylism). 

Blood coagulation can be altered by suramin, which causes accumulation of glycosaminoglycans, which have heparin-like properties (24). In patients who had received suramin intravenously for 2 weeks there was inhibition of factors V, VIII, IX, X, XI, and XII, while thrombin, prothrombin, and factor VII were unaffected (25). The inhibition of factor V was virtually irreversible, although the effect of suramin on the other factors is readily reversed by dilution. 

It is well known that the activities of various lysosomal hydrolases are strongly inhibited by heparan sulfate and other glycosaminoglycans (Avila and Convit, 1976). A possibility therefore exists that the primary defect in multiple sulfohydrolase deficiency is a mutation of hydrolase acting on heparan sulfate. An accumulation of this glycosaminoglycan may then inhibit other sulfohydrolases (Farooqui and Horrocks, 1984b). This possibility has not been tested. 

Mucopolysaccharidoses This group of disorders is characterized by tissue accumulation of glycosaminoglycans such as heparin sulphate and dermatan sulphate. This results in skeletal deformities, mental retardation and premature death... 

In the clinical disorder known as the mucopolysaccharidoses (caused by accumulation of partially degraded glycosaminoglycans), deformities of the skeleton may occur (Table 49.4). Mental retardation often accompanies these skeletal changes. 

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