Natural History of Friedreich ataxia in children

摘要 Friedreich‘s共济失调(FRDA)是遗传性共济失调最常见的形式，大约每 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的病理生理反映了蛋白质Frataxin的缺乏。减少 Frataxin水平损害线粒体含铁硫簇的酶的功能和产生 三磷酸腺苷。最近，通过基因治疗改善FRDA小鼠模型中Frataxin缺乏的方法已经产生 逆转表型的显著益处，为FRDA的治疗提供了一种循证的方法 病人。缓解线粒体功能障碍也是一种有效的治疗方法。但是，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，以及无法针对生物反应最敏感的个人进行治疗， 孩子们。为了达到这个目标，我们将研究FRDA在儿童中的自然历史，了解 这个年龄段的疾病活跃度。 在第一个目标中，我们将评估患有FRDA的最年轻受试者疾病进展的潜在指标 (3个地点的n=100)这些将包括对计时走动的具体修订和修改(以确定测试 更适合年轻人使用，以及上肢协调的自动测量( CCF)，这在较老的FRDA对象中很有用。在目标2中，我们将评估Frataxin缺乏症的生化指标 和下游代谢功能，并了解它们在FRDA儿童连续监测中的作用。 外周样本(血液、口腔细胞、分离的血小板)将从一个大的异质队列中获得 FRDA受试者(n=100，3个部位)。然后我们将检测疾病严重程度的主要生物标记物Frataxin 水平，在样品中使用新设计的基于质谱学的分析，以了解这些水平如何反映 疾病状况。同时，我们将检查血小板代谢途径中线粒体衍生的变化。 检查Frataxin缺乏症的下游事件。最后，我们将检查生理测试(运动 诱发电位，肌肉的铬-CEST)，可以连接临床参数和生化测量。 累积起来，这些目标将定义这些方法在儿童FRDA临床测量中的效用， 并验证这样的方法，即为设计针对儿童的信息性试验所需的最终措施 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.