Recent advances in the biochemistry and genetics of sphingolipidoses.

Sphingolipidoses are a subgroup of lysosomal storage diseases. They are defined as disorders caused by a genetic defect in catabolism of sphingosine-containing lipids. Catabolism of these lipids involves enzymes and activator proteins. After the discovery of lysosomes by de Duve and the demonstration of the first defective lysosomal enzyme by Hers in 1963, the first enzyme deficiency for sphingolipidoses was characterized in 1965 and all the defective enzymes were demonstrated in the last three decades. In 1984, the first activator protein was found and it expanded the concept of sphingolipidoses. In the following years, many researches have been undertaken to understand the molecular basis of these diseases, the mechanism of pathogenesis, the mechanism of lysosomal digestion of glycosphingolipids (GSLs) and the functional domains of lysosomal enzymes. New hypotheses and theories have been put forward for the mechanism of lysosomal digestion and pathogenesis. However, although much has been done, the pathogenesis of sphingolipidoses has not been fully elucidated. Mouse models of these diseases have facilitated the elucidation of pathogenesis and the development of therapeutic strategies for these diseases, which are not treatable at present except for Fabry and type 1 Gaucher disease. The purpose of this review is to collect information on the recent researches related to sphingolipidoses. The review includes the hydrolysis of GSLs in lysosome, mechanism of hydrolysis, pathogenesis and genetics of sphingolipidoses, a brief mouse model and therapeutic strategies of these diseases.