We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (α subunit) or Hexb (β subunit) genes, respectively, encoding lysosomal β-hexosaminidase A (structure, α) and B (structure, ββ). Both mutant mice accumulate G_M2 ganglioside in brain, much more so in Hexb −/− mice, and the latter also accumulate glycolipid G_A2. Hexa −/− mice suffer no obvious behavioral or neurological deficit, while Hexb −/− mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb −/− but not the Hexa −/− mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of G_M2. We propose that Hexa −/− mice escape disease through partial catabolism of accumulated G_M2 via G_A2 (asialo-G_M2) through the combined action of sialidase and β-hexosaminidase B.