Objective: To assess whether quantitative eye movement measures correlate with disease severity in late-onset GM2 gangliosidosis, and to perform exploratory assessments of novel cognitive/neuropsychiatric measures and a first study of sleep quality.

Background: The late-onset GM2 gangliosidoses, Late-Onset Tay-Sachs (LOTS) and Sandhoff disease are rare, inherited, neurodegenerative lysosomal storage disorders due to deficiency in β-hexosaminidase A (LOTS) and A and B (Sandhoff) and are felt to be clinically indistinguishable. Symptoms include progressive ataxia, anterior horn cell disease and prominent psychiatric symptoms and cognitive dysfunction, hypothesized to represent the cerebellar cognitive affective syndrome (CCAS). Eye movements are an abnormal and discriminating feature in LOTS and quantitative oculomotor analysis has been suggested as a potential clinical biomarker.

Methods: We enrolled 10 subjects with LOTS/Sandhoff. Each subject underwent video oculography including measurements of the anglular vestibulo-ocular reflex (VOR) compared to age and sex-matched controls. We utilized candidate clinical rating scales including the Brief Ataxia Rating Scale, Scale for the Assessment and Rating of Ataxia, Friedreich’s Ataxia Rating Scale and LOTS Severity Scale. Cognitive/Neuropsychiatric features were assessed by the CCAS-Scale (Hoche, Brain 2018) and sleep quality was evaluated.

Results: Oculomotor abnormalities were found in all patients, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) more than horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10) and impaired VOR cancellation (2/10). Compared to controls, there were significant differences in VOR gain, OKN, visually enhanced vestibulo-ocular reflex, SVAR and a reduction in saccadic accuracy. Severity of saccadic dysmetria and OKN impairment correlated with ataxia scales (p<0.05). 9/10 had evidence of the CCAS (4/10 definite, 5/10 probable). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality.

Conclusions: There are significant oculomotor abnormalities in LOTS/Sandhoff, which worsen with increasing disease severity, suggesting its potential utility as a biomarker. We found evidence of the CCAS, as well as widespread subjective poor sleep quality and increased daytime sleepiness.

References: 1. Hoche F, Guell X, Vangel MG, Sherman JC, Schmahmann JD. The cerebellar cognitive affective/Schmahmann syndrome scale. Brain. 2018;141(1):248-270.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/quantitative-oculomotor-assessment-and-non-motor-biomarkers-in-late-onset-gm2-gangliosidosis/