MOUSE MODELS OF TAY-SACHS AND SANDHOFF DISEASES DIFFER IN NEUROLOGIC PHENOTYPE AND GANGLIOSIDE METABOLISM

Tay-Sachs and Sandhoff diseases are clinically similar neurodegenerati ve disorders. These two sphingolipidoses are characterized by a herita ble absence of beta-hexosaminidase A resulting in defective G(M2) gang lioside degradation. Through disruption of the Hexa and Herb genes in embryonic stem cells, we have established mouse models corresponding t o each disease, Unlike the two human disorders, the two mouse models s how very different neurologic phenotypes. Although exhibiting biochemi cal and pathologic features of the disease, the Tay-Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was se verely affected. The phenotypic difference between the two mouse model s is the result of differences in the ganglioside degradation pathway between mice and humans.