Glycosphingolipid storage diseases

Platt, F. M. and Butters, T. D. Inhibition of substrate synthesis a pharmacological approach for glycosphingolipid storage disease therapy. In F. M. Platt and S. U. Walkley (eds), Lysosomal Disorders of the Brain. New York Oxford University Press, 2004, pp. 381 108. 

Fabry s disease An x-linked recessive lipid storage disease with an accumulation of the glycosphingolipid. 

Jeyakumar, M., Butters, T. D., Dwek, R. A., and Platt, F. M., Glycosphingolipid lysosomal storage diseases therapy and pathogenesis, Neuropathol Appl Neurobiol 28 (2002) 343-357. 

Langeveld, M., Ghauharali, K. J., Sauerwein, H. P., Ackermans, M. T., Groener, J. E., Hollak, C. E., Aerts, H. J., and Serlie, M. J., Type I Gaucher disease, a glycosphingolipid storage disorder, is associated with insulin resistance, J Clin Endocrinol Metab (2007) in press. 

Marks, D.L., Pagano, R.E. 2002. Endocytosis and sorting of glycosphingolipids in sphingolipid storage disease. Trends Cell Biol. 12 605-613. 

Platt, F.M. Butters, T.D. New Therapeutic Prospects for the Glycosphingolipid Lysosmal Storage Diseases. Biochem. Pharmacol, 1998, 56, 421-430. 

Several inborn errors of metabolism exist in which the missing enzyme is one that is involved in the breakdown of a specific lipid molecule. Since the biosynthesis of these lipids is not impaired, the result of the enzyme deficiency is the gradual accumulation of lipids in the tissues. Most of the important diseases of this type are ones that involve structural lipids, frequently glycosphingolipids, of the central nervous system and they are summarized in Table 8.8. The diseases are rare and frequently fatal, which serves to indicate how important it is that the amounts and types of lipids in membranes are strictly controlled to preserve biological function. Many of the lipids involved in these disorders are readily synthesized in the body, so that dietary treatment is ineffective. There is one lipid storage disease, Refsum s disease, however, that can be controlled by strict exclusion of a fatty acid from the diet. This disease is due to a failure to break down by a-oxidation, the branched chain fatty acid, phytanic acid (Figure 8.12), which is formed from phytol, a universal constituent of green plants. In patients, there is a characteristic build-up of phytanic acid in the blood where it may represent 30% of the total fatty acids. A condition of ataxic neuropathy develops and the disease is normally fatal. To survive, the patients must have a low phytol diet. 

When certain enzymes involved in the hydrolytic or oxidative breakdown of cellular lipids are absent from tissues, their lipid substrates tend to accumulate, resulting in a lipid storage disease or lipidosis. All are rare but the most important involve the accumulation of glycosphingolipids in the central nervous system. Enzyme replacement therapy is now becoming a practical possibility in some cases. 

---