Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study
Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study
复制标题
DOI：
10.1016/s1474-4422(20)30235-0
复制
发表时间：
2020-09-01
期刊：
影响因子：
48
通讯作者：
Klockgether, Thomas
中科院分区：
文献类型：
--
作者：
Jacobi, Heike;du Montcel, Sophie Tezenas;Klockgether, Thomas
背景脊髓小脑共济失调（Spinocerebellar ataxias，SCA）是一种常染色体显性遗传的神经退行性疾病。我们的目的是研究与最常见SCA相关的突变的表面健康携带者向明显共济失调的转化（SCA 1，SCA 2，SCA 3，和SCA 6），以及临床和功能测量的敏感性，以检测这些individuals.Methods在这个前瞻性的，纵向的，观察性队列研究中，基于14个转诊中心在7个欧洲国家，我们招募了SCA 1、SCA 2、SCA 3或SCA 6患者的子女或兄弟姐妹。符合条件的个体为无共济失调的个体，定义为共济失调评估和评级量表（SARA）评分小于3分; SCA 1、SCA 2或SCA 3患者的儿童或兄弟姐妹的参与者年龄必须为18-50岁，SCA 6患者的儿童或兄弟姐妹的参与者年龄必须为35-70岁。研究访视在招募时以及2年、4年和6年（± 3个月）后进行。我们做了基因检测来识别突变携带者，结果对参与者和临床研究者保密。我们用临床量表、患者报告结果测量问卷、检查者对共济失调存在的信心评级和基于表现的协调测试对患者进行评估。转换为共济失调定义为SARA评分为3或更高。我们分析了基线因素与转换为共济失调的相关性，以及在突变状态和转换状态的背景下，时间尺度上结果参数的演变（从入选的时间和到共济失调发作时预测年龄的时间）。该研究在ClinicalTrials.gov注册，NCT 01037777。结果在2008年9月13日至2015年10月28日期间，招募了302名参与者。我们分析了至少有一次随访的252名参与者的数据。83名（33%）参与者来自受SCA 1影响的家庭，99名（39%）来自SCA 2，46名（18%）来自SCA 3，24名（10%）来自SCA 6。在携带SCA突变的参与者中，50名SCA 1携带者中有26名（52%），37名SCA 2携带者中有22名（59%），26名SCA 3携带者中有11名（42%），15名SCA 6携带者中有2名（13%）转化为共济失调。33名SCA 1非携带者中有1名（3%）和62名SCA 2非携带者中有1名（2%）转化为共济失调。由于符合我们共济失调标准的人数很少，因此无法在SCA 6突变携带者中进行后续分析。与转换相关的基线因素为年龄（风险比1. 13 [95% CI 1. 13]）。03-1. 24]; p=0.011），CAG重复长度（1.25 [1- 11-1. 41]; p=0 . 0002）和共济失调置信度评分（1.72 [1.23-2.41]; p=0 . 0015）对于SCA 1;年龄（1.08 [1.02-1-14]; p=0.0077）和CAG重复长度（1.65 [1.27-2.13]; p=0.0001）对于SCA 2;和年龄（1.27 [1.09-1.50]; p=0.0031）、置信度（2.60 [1.23-5.47]; p=0.012）和复视（14.83 [245-102.44]; p=0 . 0063）。SCA 1、SCA 2和SCA 3突变携带者的SARA评分从诱导时开始增加，而非携带者的SARA评分保持稳定。在由共济失调发作的预测时间定义的时间尺度上，SCA 1，SCA 2和SCA 3突变携带者中的SARA进展是非线性的，共济失调发作前的边缘进展和共济失调发作后的进展增加。解释我们的研究提供了非共济失调SCA 1，SCA 2和SCA 3突变携带者转化为表现共济失调的定量数据。我们的数据可以证明是有用的预防性试验的设计，旨在通过帮助样本量计算和分层的研究参与者，以延迟共济失调的发病。版权所有（C）2020爱思唯尔有限公司保留所有权利。
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 dinical 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 [245-102.44]; p=0 . 0063) for SCA3. From the time of indusion, 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. Copyright (C) 2020 Elsevier Ltd. All rights reserved.