Objective: To perform a multimodal comparison of AT, AOA1 and AOA2 focusing on video-oculography.

Background: Autosomal recessive cerebellar ataxias (ARCAs) are heterogeneous disabling inherited neurodegenerative disorders. Their diagnostic workup remains a challenge. Identifying phenotypic supportive clues is necessary to improve diagnosis delay and accuracy.

Methods: We compared 40 patients with AT, AOA1 and AOA2, referred between 2008 and 2015 at two French tertiary adult movement disorders centers to 17 healthy subjects. Clinical examination, functional scores, video-oculography, nerve conduction studies, brain MRI, and biomarkers were studied.

Results: Video-oculography revealed complex oculomotor disorders in patients relative to controls. Constant impairments were cerebellar signs (p<0.0001) (either downbeat (p<0.01) or gaze-evoked (p<0.0001) nystagmus or hypermetric horizontal saccades (p<0.0001)), altered fixation (p<0.0001), impaired pursuit, hypometric saccades (p<0.0001) and abnormal antisaccades (p<0.001). Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in 27.5 to 40% of the patients. A higher intra- and intersubject variability of saccade latencies (p<0.05) was observed in patients. Discriminating AFP thresholds with good specificities and predictive values were determined: 7-15µg/L for AOA1, 15-65µg/L for AOA2 and > 65µg/L for AT patients. Other shared features were early ages at onset, severe walking disability, various movement disorders, sensori-motor neuropathy, cerebellar atrophy.

Conclusions: We show AOA1, AOA2 and AT share close, complex, highly variable oculomotor phenotypes. Video-oculography is not able by itself to differentiate between them and is not mandatory in the diagnosis workup of patients with ARCA, but an appropriate oculomotor examination remains crucial. In ARCAs’ diagnosis workup, AOA1, AOA2 and AT should be considered as a peculiar group characterized by ataxia with complex oculomotor disturbances and elevated AFP. Increased AFP serum level seems to be more relevant than video-oculography in distinguishing them, which finally relies on genetic analysis. Our findings will allow reliable reverse-phenotyping, which will be mandatory to interpret the numerous variants of unknown significance provided by premature next-generation sequencing.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/how-do-ataxias-with-oculomotor-apraxia-look-and-look-like-a-comparative-controlled-multimodal-study-of-at-aoa1-and-aoa2-focusing-on-video-oculography/