Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation
Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation
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DOI：
10.1093/brain/awu012
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发表时间：
2014-04-01
期刊：
影响因子：
14.5
通讯作者：
Hanna, Michael G.
中科院分区：
文献类型：
--
作者：
Graves, Tracey D.;Cha, Yoon-Hee;Hanna, Michael G.
发作性共济失调1型是一种罕见的常染色体显性遗传疾病，影响小脑和周围神经。在一项横断面前瞻性研究中，Graves等人描述了KCN 1A基因突变和未突变患者的临床特征，并提出了临床试验中可能使用的结果测量方法。发作性共济失调1型被认为是一种罕见的神经元离子通道疾病，其特征是短暂的不稳定和头晕发作伴持续性肌震颤。为了描述自然史，为未来的临床试验制定结果指标，并将基因型与表型相关联，我们进行了一项国际性、前瞻性、横断面研究。入组了39名受试者（51%男性）：中位年龄37岁（范围15-65岁）。我们在KCNA 1中发现了10种不同的致病性点突变，占该队列85%的遗传基础。携带KCNA 1突变的参与者更有可能有阳性家族史。对整个队列的分析显示，除一名患者外，所有患者的共济失调首次发作均发生在20岁之前，平均发病年龄为7.9岁。体力消耗、情绪压力和环境温度是最常见的发作诱因。发作频率从每天到每月不等，即使具有相同的KCNA 1基因型。平均攻击持续时间为几分钟。10名参与者（26%）出现了永久性小脑体征，这与疾病持续时间有关。所有参与者的平均共济失调评估和评级量表（SARA，临床检查小脑功能障碍的标准化测量，评分范围为0-40）平均为3.15（范围为0-14），但孤立性发作性共济失调患者的平均评分仅为2，而除发作性共济失调外，进行性小脑共济失调患者的平均评分为7.7。37名参与者完成了SF-36，这是一项生活质量调查;所有8个领域基于正常的平均评分（平均值= 50）均低于正常水平，其中突变阳性发作性共济失调1型患者的心理健康水平最低（41.3）。SF-36评分与发作频率呈负相关。在研究的39名参与者中，33名携带KCNA 1突变，其余6名未发现突变。发作性共济失调1型表型以前没有被描述，我们报告他们的临床特征，这似乎是不同的KCNA 1突变。这项对遗传学证实的发作性共济失调1型和发作性共济失调1型表型的大型前瞻性研究提供了这些疾病的详细基线特征及其对参与者的影响。我们发现袭击对生活质量有显著影响。与以前的研究不同，我们发现，有相当数量的人与遗传学证实的发作性共济失调1型（21%）积累了持续的小脑症状和体征。这些数据将有助于制定临床治疗试验的结局指标。
Episodic ataxia type 1 is a rare autosomal dominant disorder that affects the cerebellum and peripheral nerves. In a cross-sectional, prospective study, Graves et al. describe clinical features of patients with and without mutations in the KCN1A gene, and suggest possible outcome measures for use in clinical trials.Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15-65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0-40) was an average of 3.15 for all participants (range 0-14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean = 50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed episodic ataxia type 1 and episodic ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed episodic ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.