Molecular, Biochemical and Cellular Basis

The mucopolysaccharidoses are a family of metabolic disorders caused by the deficiency of lysosomal enzymes needed to degrade glycosaminoglycans (or “mucopolysaccharides,” an older name). In these disorders, undegraded or partially degraded glycosaminoglycans accumulate in lysosomes. In MPS I, the missing or deficient enzyme is α-L-iduronidase, a lysosomal enzyme that cleaves terminal iduronidase residues from dermatan sulfate and heparan sulfate^[1]. In virtually all tissues where there is widespread distribution of dermatan sulfate and heparan sulfate, manifestations of the disease eventually arise as a result of deficiency of α-L-iduronidase.

Dermatan sulfate and heparan sulfate are found in large quantities in connective tissues and essentially all tissues to some degree. With the exception of hyaluronic acid, which is not covalently bound to protein, all glycosaminoglycans, including dermatan sulfate and heparan sulfate, occur as proteoglycans (polysaccharides bound to a core protein) to form a major component of the extracellular matrix. Proteoglycans create hydrated spaces around and between the cells and form gels of varying size and charge density. This in turn is important for the diffusion of gases and nutrients to and from cells and to control cell migration. Proteoglycans can also be integral parts of cells, in which they are embedded in the plasma membrane. As integral membrane components, they control cell-cell communication as well as cell division and differentiation in part by binding to, and modulating the actions of, growth factors^[2,3]. Another important function of glycosaminoglycans is as constituents of the connective tissues and fluid associated with joints, where they help sustain forces of compression and aid in lubrication^[4,5].

Given the widespread distribution of heparan sulfate and dermatan sulfate in tissues and the general importance of proteoglycans in cell-cell signaling and differentiation, it is not surprising that MPS I is associated with pathology in most tissue types and that the disease exhibits a chronic and progressive course. Manifestations of the disease within the central nervous system (CNS) and skeleton lead to mental retardation and dysostosis multiplex, respectively, and reflect how a defect in glycosaminoglycan metabolism is particularly disruptive during stages of rapid growth and development. It is during this time when nervous and growth plate tissues undergo extensive re-modeling. The undegraded or partially degraded glycosaminoglycans accumulate in lysosomes, a process which ultimately results in cell, tissue and organ dysfunction. As the disease progresses, accumulation of dermatan sulfate and heparan sulfate becomes prominent in the lysosomes of hepatocytes and virtually all other tissue cells of the individual (e.g. fibroblasts).

References

1.Neufeld, E.F., and Muenzer, J. (2001) The mucopolysaccharidoses. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D., Childs, B., Kinzler, K.W., and Vogelstein, B. (eds.). 8th edition, Vol. III. McGraw-Hill, Medical Publishing Division, pp. 3421.

2. Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J.D. (1989) Molecular Biology of the Cell. 2nd ed., Garland Publishing, New York.

3. Bernfield, M., Gotte, M., Park, P.W., Reizes, O., Fitzgerald, M.L., Lincecum, J., and Zako, M. (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68: 729

4. Moremen, K., and Malm, D. (1977) Human Genetic Disease: A Layman’s Approach Last update July 22, 1997.

5. Clarke, L.A. (1997) Clinical diagnosis of lysosomal storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth, D.A., Dimmick, J.E., and Hall, J.G. (eds.). Chapman and Hall Medical, London, pp. 37