Similarities and differences in the late-onset GM2 gangliosidoses: Tay-Sachs and Sandhoff diseases

Due to shared ß-hexosamindase A deficiencies and significant clinical overlap, the predominating subtypes of late-onset GM2 gangliosidosis, late-onset Tay-Sachs (LOTS) and late-onset Sandhoff disease (LOSD) have been considered essentially indistinguishable. However, growing evidence supports several distinctions between the two entities. We highlight these distinctions through the cross-sectional evaluation of 27 (21 LOTS and 6 LOSD) late-onset GM2 gangliosidosis participants. Study protocol included physical examinations, assessments of gait, balance, muscle strength, ataxia, and nerve conduction velocities, and brain magnetic resonance imaging. Lower limb weakness and later development of upper limb weakness was highly prevalent in both diseases. Accompanying gait disturbances, balance issues, and dysmetria were also prevalent in both cohorts. Strength evaluations showed weakness in both the LOTS and LOSD cohorts compared to controls primarily impacting extensor muscles. In contrast, BARS scores for dysarthria and oculomotor dysfunction were present and heterogenous in LOTS participants and absent in LOSD participants. Twenty-four percent of LOTS participants and none of the LOSD participants had a history of neuropsychiatric symptoms. Cerebellar volume including lobules V and VI were lower in LOTS compared to LOSD and normative data. However, severe length-dependent sensory neuropathy was present in all LOSD participants but not in LOTS participants. The finding of lower cerebellar volume in LOTS suggests the distinctive features of the LOTS phenotype are related to cerebellar dysfunction. However, the cause of the phenotypic differences between LOTS and LOSD remains a mystery, and the molecular and biochemical basis for the dichotomy requires further investigation.