Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD
- Conditions
- Spinocerebellar Ataxia Type 3Machado-Joseph Disease
- Interventions
- Diagnostic Test: Video-oculographyDiagnostic Test: Clinical ScalesDiagnostic Test: Genotyping
- Registration Number
- NCT04229823
- Lead Sponsor
- Hospital de Clinicas de Porto Alegre
- Brief Summary
The study will consist of a prospective observation of subjects in a natural history design. Disease progression will be monitored through clinical scales and video-oculography. Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls). The following clinical scales will be applied in all subjects at baseline and at months 12 and 24: SARA, SCAFI, CCFS, NESSCA, INAS and ICARS. Oculomotor function will be registered using video-oculography (EyeSeeCam, InterAcoustics) at the same time points. Progression rates, effect sizes and responsiveness to change will be established for all parameters and results will be compared between candidate biomarkers.
- Detailed Description
Spinocerebellar ataxia type 3, also called Machado-Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder caused by a CAG expansion (CAGexp) on ATXN3. Over 20 years after the identification of the causal mutation, no form of prevention or treatment for this incapacitating condition was discovered. Similarly to other polyglutamine (polyQ) diseases, SCA3/MJD has a slow progression. Changes detected by clinical scales are small and, therefore, long intervals are needed to document disease progression. Clinical trials using clinical scales as primary outcomes should be very long, what makes them hardly feasible. In this context, the discovery of disease biomarkers is of utmost importance. Biomarkers associated with disease progression and/or with therapeutic intervention might be more easily verified than the changes measured by clinical scales. Seminal studies have demonstrated that oculomotor alterations and vestibulo-ocular reflex (VOR) impairment may be present even during presymptomatic periods. Our primary hypothesis is eye movement parameters including VOR, saccades, smooth pursuit and fixation measured by video-oculography could be biomarkers of SCA3/MJD disease progression. Besides that, the investigators aim to test if the candidate biomarkers present changes before disease-onset and if their responsiveness will be better than those of clinical scales, with more noticeable variations during a shorter period of time. The study will consist of a prospective observation of subjects in a natural history design. The investigators will monitor disease progression of the CAGexp carriers through clinical scales and video-oculography. At least 75 adult subjects from Rio Grande do Sul will be invited to participate in the study, and at least 50 of the participants will be asymptomatic subjects, at 50% risk of carrying the mutation. The study design will allow the subjects who wanted and the evaluators to stay blinded to subjects' genotypes. Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls). Genotypes will be recorded separately to guarantee double blindness. For every pre-ataxic carrier, time until the disease-onset will be estimated by an equation previously built, in which individual age and CAGexp are the determinants. The following clinical scales will be applied in all subjects at baseline and at months 12 and 24: SARA, SCAFI, CCFS, NESSCA, INAS and ICARS. Oculomotor function will be registered in video and analyzed using the EyeSeeCam device. Progression rates of all variables will be estimated by mixed models, including as covariates age, groups and their interactions. Progression rates, effect sizes and responsiveness to change will be established for all parameters and results will be compared between candidate biomarkers.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 95
- Individuals with molecular diagnosis of SCA3/MJD
- Individuals at 50% risk of inheriting SCA3/MJD mutation without any clinical manifestation
- Other diagnosed neurological or vestibular condition
- Dyschromatopsia
- Refusal to sign informed consent
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Related controls Video-oculography Subjects without a CAG repeat expansion on ATXN3, but with a first degree relative affected by the disease. Pre-ataxic carriers Clinical Scales Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of less than 3 points. Related controls Genotyping Subjects without a CAG repeat expansion on ATXN3, but with a first degree relative affected by the disease. Ataxic carriers Video-oculography Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of 3 points or more. Ataxic carriers Clinical Scales Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of 3 points or more. Related controls Clinical Scales Subjects without a CAG repeat expansion on ATXN3, but with a first degree relative affected by the disease. Pre-ataxic carriers Video-oculography Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of less than 3 points. Pre-ataxic carriers Genotyping Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of less than 3 points.
- Primary Outcome Measures
Name Time Method Change in vestibulo-ocular reflex gain regression slope (VORr) 24 months Gain (Eye velocity/Head velocity)
Change in vertical smooth pursuit gain 24 months Regression slope of eye velocity versus target velocity during vertical smooth pursuit task
Change in slow-phase velocity of gaze evoked nystagmus (SPV-GE) 24 months Degrees/second
Change in the slope of peak duration versus amplitude of volitional vertical saccades 24 months egression slope between peak duration and saccade amplitude during volitional vertical saccades
Change in slow-phase velocity of central nystagmus (SPV-C) 24 months Degrees/second
Change in the slope of peak duration versus amplitude of reflexive vertical saccades 24 months Regression slope between peak duration and saccade amplitude during reflexive vertical saccades
Change in Neurological Examination Score for Spinocerebellar Ataxia (NESSCA) 24 months Neurological examination score, varying between 0 and 40. Score increases with disease severity.
Change in SCA Functional Index (SCAFI) 24 months Composite score. Score decreases with disease severity.
Change in Composite Cerebellar Functional Severity Score (CCFS) 24 months Composite score. Score increases with disease severity.
Change in International Cooperative Ataxia Rating Scale (ICARS) 24 months Absolute score, varying between 0 and 100. Score increases with disease severity.
Change in Inventory of Non-Ataxia Symptoms (INAS) count 24 months Scale varying between 0 and 16. Score increases with disease severity.
- Secondary Outcome Measures
Name Time Method Change in horizontal smooth pursuit gain 24 months Gain (Eye velocity/Target velocity)
Change in reflexive vertical saccade velocity (RVSV) 24 months Degrees/second
Change in volitional vertical saccade velocity (VVSV) 24 months Degrees/second
Trial Locations
- Locations (1)
Universidade Federal do Rio Grande do Sul
🇧🇷Porto Alegre, Brazil