Sphingolipids accumulation

Hein, L. K., Meikle, P. J., Hopwood, J. J., and Fuller, M., Secondary sphingolipid accumulation in a macrophage model of Gaucher disease. Mol Genet Metab 92 (2007) 336-345. 

Hexoseamidase A is the enzyme which is deficient in Tay-Sachs disease. This inherited condition results in an accumulation of GM2 gangliosides (sphingolipids) in the brain. The consequences are mental retardation, paralysis, blindness and death by the age of 3-4 years. 

The polar lipids of membranes undergo constant metabolic turnover, the rate of their synthesis normally counterbalanced by the rate of breakdown. The breakdown of lipids is promoted by hydrolytic enzymes in lysosomes, each enzyme capable of hydrolyzing a specific bond. When sphingolipid degradation is impaired by a defect in one of these enzymes (Fig. 1), partial breakdown products accumulate in the tissues, causing serious disease. 

Sphingolipids were first described in a remarkable treatise on the chemical constitution of the brain by Johann L. W. Thudichum, a physician-scientist in London, who published his findings more than 100 years ago. A major impetus for the study of the chemistry and metabolism of the sphingolipids was the discovery of several rare human diseases that could be attributed to the abnormal accumulation of sphingolipids. This accumulation has been shown to result from a defect in catabolism that normally occurs in lysosomes. It is now known that many different kinds of sphingolipids exist, and more than 300 structures have been reported to occur in nature. 

A deficiency of lysosomal enzymes results in the inability to degrade the carbohydrate portions of proteoglycans or sphingolipids. Partially digested products accumulate in lysosomes. Tissues become engorged with these residual bodies, and their function is impaired. These diseases are often fatal. 

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