THE BETA-HEXOSAMINIDASE DEFICIENCY DISORDERS - DEVELOPMENT OF A CLINICAL PARADIGM IN THE MOUSE

Tay-Sachs disease and Sandhoff disease are severe neurodegenerative di sorders caused by a deficiency of beta-hexosaminidase A and resultant accumulation of its substrate, G(M2) ganglioside, in neuronal lysosome s. The three clinical forms of the disorders (infantile, juvenile and adult) are of varying severity and onset, and have been correlated wit h the amount of residual G(M2) ganglioside-degrading activity present in patients' cells. Through targeted disruption of the murine beta-hex osaminidase genes in embryonic stem cells, we have developed a set of mice that vary in their G(M2) ganglioside-degrading capacity and exhib it many of the clinical features of the human diseases, These mice are valuable for the study of pathogenic mechanisms and for devising nove l therapeutic strategies in these disorders.