GM2 gangliosidoses are a group of rare lysosomal storage disorders (LSDs) characterized by lysosomal accumulation of GM2 ganglioside in the nervous system, resulting in a range of neurodegenerative disorders. These disorders result from mutations in the genes encoding the 𝛼- or 𝛽-subunits of the enzyme 𝛽-hexosaminidase A (HexA), or more rarely the GM2-activator protein. Loss-of-function mutations in HEXA, encoding the 𝛼-subunit, cause Tay-Sachs disease (TSD) whereas mutations in HEXB, encoding the 𝛽-subunit, cause Sandhoff disease (SD). Successful therapies are available for many lysosomal storage disorders, however none of these are available for treatment of GM2 gangliosidosis. While mice models of SD with juvenile onset have been available for many years, attempts to create similar TSD models have failed due to a sialidase bypass that degrades GM2 in mice. Juvenile-onset TSD mice have since been created by knocking out both Neu3 and Hexa genes. Late-onset GM2 gangliosidosis models in mice have yet to be successfully created. In this study we attempted to create a late-onset GM2 gangliosidosis model using the most common adult onset HEXA mutation in humans, c.805 G>A p. G269S combined with Neu3-/- . The resulting HexA G269S/G269S knock-in, Neu3-/- animals, referred to as the knock-in knock-out model (KIKO) were compared with a previously reported juvenile-onset Hexa-/- Neu3-/- double KO model (dKO) and controls. Monitoring of disease onset, signs of illness and changes to behaviour or neurological phenotype using a variety of methods were undertaken to assess if differences could be detected between these models. dKO and KIKO mice did not display any significant differences in phenotype when compared to each other but did model juvenile GM2 gangliosidoses compared to controls. Motor deterioration, tremors, gait disturbances and behavioural changes were observed in both models. Enzyme activity of HexA in both models was reduced, and no increase in residual activity was observed in KIKO animals. Histological and gross anatomical investigations confirmed widespread accumulation of GM2 throughout the brains of both dKO and KIKO animals. Decreased survival of KIKO and dKO compared to controls was consistent with previously reported dKO models.