Progression of Clinical and Eye Movement Markers in Preataxic Carriers of Machado‐Joseph Disease.

Background: Little is known about preclinical stages of Machado‐Joseph disease, a polyglutamine disorder characterized by progressive adult‐onset ataxia. Objective: We aimed to describe the longitudinal progression of clinical and oculomotor variables in the preataxic phase of disease. Methods: Carriers and noncarriers were assessed at three visits. Preataxic carriers (Scale for Assessment and Rating of Ataxia score < 3) expected to start ataxia in ≤4 years were considered near onset (PAN). Progressions of ataxic and preataxic carriers, considering status at the end of the study, were described according to the start (or its prediction) of gait ataxia (TimeToAfterOnset) and according to the study time. Results: A total of 35 ataxics, 38 preataxics, and 22 noncarriers were included. The "TimeToAfterOnset" timeline showed that Neurological Examination Scale for Spinocerebellar Ataxias (NESSCA; effect size, 0.09), Inventory of Non‐Ataxia Symptoms (INAS0.07), and the vestibulo‐ocular reflex gain (0.12) progressed in preataxic carriers, and that most slopes accelerate in PAN, turning similar to those of ataxics. In the study time, NESSCA (1.36) and vertical pursuit gain (1.17) significantly worsened in PAN, and 6 of 11 PANs converted to ataxia. For a clinical trial with 80% power and 2‐year duration, 57 PANs are needed in each study arm to detect a 50% reduction in the conversion rate. Conclusions: NESSCA, INAS, vestibulo‐ocular reflex, and vertical pursuit gains significantly worsened in the preataxic phase. The "TimeToAfterOnset" timeline unveiled that slopes of most variables are small in preataxics but increase and reach the ataxic slopes from 4 years before the onset of ataxia. For future trials in preataxic carriers, we recommend recruiting PANs and using the conversion rate as the primary outcome. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

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