Natural History of Friedreich ataxia in children

摘要 弗里德赖希共济失调（FRDA）是遗传性共济失调的最常见形式，每例患者中约有1例受影响。 在美国和欧洲有5万人。症状通常在5至15岁之间开始 并随着时间的推移而恶化。FRDA的病理生理学反映了蛋白共济失调蛋白的缺乏。减少 共济失调蛋白水平损害线粒体含铁硫簇酶的功能和产生铁硫簇的能力， ATP最近，在FRDA小鼠模型中通过基因治疗改善共济失调蛋白缺乏已经产生了 在逆转表型方面有令人印象深刻的益处，为FRDA的治疗提供了一种循证方法 患者线粒体功能障碍的减轻也代表了有效的治疗方法。但如果 这些疗法的尝试是在今天进行的，它们将受到无法评估人类生物学的限制。 FRDA的细节，以及无法将治疗靶向于最具生物学反应的个体， 孩子为了实现这一目标，我们将研究儿童FRDA的自然史，了解FRDA的过程， 这个年龄段的疾病。 在第一个目标中，我们将评估最年轻的FRDA受试者疾病进展的潜在指标 （3个研究中心n = 100）这些将包括定时步行的具体修订和修改（以确定测试 更适合年轻人使用，上肢协调的自动测量（ CCFS），这对老年FRDA受试者有用。在目标2中，我们将评估共济失调蛋白缺乏的生化指标 和下游代谢功能，并了解其在FRDA系列儿童中的效用。 将从一个大型异质性队列中采集外周血样本（血液、口腔细胞、分离血小板） FRDA受试者（3个研究中心n = 100）。然后，我们将检测疾病严重程度的主要生物标志物，共济失调蛋白 水平，在样品中使用新设计的基于质谱的分析，以了解这些水平如何反映 疾病状态。与此同时，我们将研究血小板代谢途径中的脑源性改变 研究共济失调蛋白缺乏的下游事件。最后，我们将检查生理测试（运动 诱发电位，肌肉的Cr-CEST），可以将临床参数与生化测量联系起来。 这些目标将逐步确定这些方法在儿童FRDA临床测量中的效用， 并验证这些方法作为设计儿童信息试验所需的确定性措施， FRDA。

Abstract Friedreich’s ataxia (FRDA) is the most common form of hereditary ataxia, affecting approximately 1 in every 50,000 people in the United States and Europe. Symptoms typically begin between the ages of 5 and 15 years and worsen over time. The pathophysiology of FRDA reflects the deficiency of the protein frataxin. Reduced frataxin levels impair the function of mitochondrial iron-sulfur-cluster-containing enzymes and ability to produce ATP. Recently, amelioration of frataxin deficiency by gene therapy in mouse models of FRDA has produced impressive benefit in reversing the phenotype, providing an evidenced-based approach for treatment of FRDA patients. Mitigation of mitochondrial dysfunction also represents a valid therapeutic approach. However, if attempts at these therapies were made today, they would be limited by the inability to assess the human biology of FRDA in detail, as well as the inability to target therapies to the most biologically responsive individuals, children. To achieve this goal, we will study the natural history of FRDA in children, to understand the course of disease activity in this age group. In the first aim, we will assess potential measures of disease progression in the youngest subjects with FRDA (n=100 at 3 sites) These will include specific revisions and modifications of timed walks (in order to identify a test more suitable for use in young individuals, and an automated measure of upper extremity coordination (the CCFS) that is useful in older FRDA subjects. In aim 2 we will assess biochemical measures of frataxin deficiency and downstream metabolic function, and understand their utility in serial monitoring.in children with FRDA. Peripheral samples (blood, buccal cells, isolated platelets) will be obtained from a large heterogeneous cohort of subjects with FRDA (n=100 at 3 sites). We will then assay the primary biomarker of disease severity, frataxin level, in the samples with a newly devised mass spectrometry-based assay to understand how such levels reflect disease status. In parallel, we will examine mitochondrial-derived alterations in metabolic pathways in platelets to examine events downstream from frataxin deficiency. Finally we will examine physiological tests (motor evoked potentials, Cr-CEST of muscle) that can link clinical parameters with biochemical measurements. Cumulatively these aims will define the utility of such approaches in clinical measurement of FRDA in children, and validate such approaches as the definitive measures needed for design of informative trials in children with FRDA.