Late-onset GM2 gangliosidosis: magnetic resonance imaging, diffusion tensor imaging, and correlational fiber tractography differentiate Tay-Sachs and Sandhoff diseases.

GM2 gangliosidosis is lysosomal storage disorder caused by deficiency of the heterodimeric enzyme β-hexosaminidase A. Tay-Sachs disease is caused by variants in HEXA encoding the α-subunit and Sandhoff disease is caused by variants in HEXB encoding the β-subunit. Due to shared clinical and biochemical findings, the two have been considered indistinguishable. We applied T1-weighted volumetric analysis, diffusion tensor imaging (DTI), and correlational fiber tractography to assess phenotypic differences in these two diseases. 51 T1-weighted and 40 DTI scans from 19 Late-Onset GM2 patients with either late-onset Sandhoff disease (LOSD), or late-onset Tay-Sachs (LOTS) were included and compared to 1033 neurotypical control volumetric MRI scans. LOTS patients had significantly smaller cerebellum volume compared to neurotypical controls (p < 0.0001) and LOSD patients (p < 0.0001). There was no statistical difference for the volume of any structure between LOSD and neurotypical controls. DTI analysis showed LOTS patients had higher mean diffusivity (MD) in the left cerebellum (p = 0.003703), right cerebellum (p = 0.003435), superior cerebellar peduncle (p = 0.007332), and vermis (p = 0.01007) compared to LOSD. LOTS patients had lower fractional anisotropy (FA) in the left cerebellum (p = 0.005537), right cerebellum (p = 0.01905), SCP (p = 0.02844), and vermis (p = 0.02469) when compared to LOSD. Correlational fiber tractography identified fiber tracts in cerebellar pathways with higher FA and lower MD in LOSD patients compared to LOTS patients. Our study shows neurobiologic differences between these two related disorders. To our knowledge, this is the first study using correlational tractography in a lysosomal storage disorder. This result indicates a greater burden of cerebellar pathology in LOTS patients compared with LOSD patients.