Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study

Summary

Background

Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals.

Methods

In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18–50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35–70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and clinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov, NCT01037777.

Findings

Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1·13 [95% CI 1·03–1·24]; p=0·011), CAG repeat length (1·25 [1·11–1·41]; p=0·0002), and ataxia confidence rating (1·72 [1·23–2·41]; p=0·0015) for SCA1; age (1·08 [1·02–1·14]; p=0·0077) and CAG repeat length (1·65 [1·27–2·13]; p=0·0001) for SCA2; and age (1·27 [1·09–1·50]; p=0·0031), confidence rating (2·60 [1·23–5·47]; p=0·012), and double vision (14·83 [2·15–102·44]; p=0·0063) for SCA3. From the time of inclusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset.

Interpretation

Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants.

Funding

European Research Area Network for Research Programmes on Rare Diseases, Polish Ministry of Science and Higher Education, Italian Ministry of Health, European Community's Seventh Framework Programme.

Introduction

The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal, dominantly inherited diseases. The clinical hallmark of SCAs is progressive ataxia. The most common SCAs—SCA1, SCA2, SCA3, and SCA6—are caused by translated unstable CAG repeat expansion mutations in the ataxin-1, ataxin-2, ataxin-3, and calcium voltage-gated channel subunit alpha1 A genes, respectively. Ataxia onset usually occurs at age 30–40 years in SCA1, SCA2, and SCA3, and age 50–60 years in SCA6.1, 2 Individuals with longer CAG repeats have an earlier onset of ataxia, but the repeat length explains only 44–75% of the variability in age at onset.³

Research in context

Evidence before this study

We searched Medline and ISI Web of Science for reports published before Nov 22, 2019, with the search terms [“spinocerebellar ataxia” AND “prodromal” OR “at risk” OR “premotor” OR “presymptomatic“ OR “preclinical“ OR “prediagnostic“ OR “premanifest“ AND “prospective“ OR “follow-up“ OR “longitudinal“]. Only peer-reviewed, English-language reports of human cohort studies with at least five participants were considered. Apart from our baseline study of the present cohort, we identified two cohort studies that longitudinally assessed presymptomatic SCA mutation carriers. One study reported abnormal body sway in nine presymptomatic SCA1 mutation carriers. The other cohort comes from a Cuban SCA2 founder population. In premanifest mutation carriers of this cohort, non-ataxia signs and measures of central and peripheral nerve conduction worsened over time.

Added value of this study

In this European, multicentre, longitudinal study (RISCA), we prospectively investigated a large cohort of individuals at risk for SCA1, SCA2, SCA3, and SCA6. We determined the age at conversion to manifest ataxia in mutation carriers of these SCA subtypes and highlighted the effect of factors other than age and CAG repeat length on conversion. This study is, to the best of our knowledge, the first to define the temporal evolution and sensitivity to change of clinical, patient-reported, and MRI outcome measures in these individuals. Our data should allow the calculation of sample sizes required for preventive trials.

Implications of all the available evidence

The available data provide quantitative information on the conversion of premanifest SCA1, SCA2, SCA3, and SCA6 mutation carriers to manifest ataxia, and allow identification of predictors for conversion. Knowledge of the conversion rates and evolution of outcome markers in these individuals can help researchers to design trials of interventions aimed at delaying the onset of ataxia. owing to the size of this study, the short study duration, and absence of confirmation in an independent cohort, all conclusions should be interpreted with caution.

In SCA1, SCA2, SCA3, and SCA6, ataxia onset can be preceded by mild clinical manifestations, electrophysiological abnormalities, and cerebellar and brainstem volume loss.4, 5, 6, 7, 8, 9, 10 This stage is of particular interest as it could provide a period for preventive intervention before ataxia starts. Current knowledge of the pre-ataxia stage is mainly based on cross-sectional studies. A previous cohort study reported abnormal body sway in nine presymptomatic SCA1 mutation carriers.⁹ In another cohort study, of Cuban families with a history of SCA2, premanifest mutation carriers showed worsening of non-ataxia signs and measures of central and peripheral nerve conduction over time.6, 7, 10 The Ataxia Study Group has undertaken a longitudinal study of individuals at risk for SCA1, SCA2, SCA3, and SCA6 (RISCA) that was designed to study prospectively the conversion of mutation carriers to manifest ataxia, and to determine the sensitivity of clinical, functional, and MRI measures to detect changes in these individuals. We reported the baseline data of 276 children and siblings of patients with SCA1, SCA2, SCA3, or SCA6, enrolled until Dec 1, 2011, in a previous Article.⁵ Here, we report longitudinal data from the RISCA cohort.