Evaluation of Small-Fiber Polyneuropathy in Youth

项目摘要/摘要 这是R01NS093653奖的续展申请，该奖项一直在资助奥克兰实验室的研究 关于小纤维神经病。SFN是一种新近发现的导致慢性疼痛的周围神经疾病， 通常从脚开始并向上扩散，难以完成日常活动和胃肠道不适。 2013年，该团队研究了41名儿童和年轻人，出人意料地报告了大多数人患有SFN的证据。直到 那时，只有患有糖尿病、化疗或其他中毒暴露的老年人才知道SFN，而且 疾病。实验室发现了一种新的疾病--早发性SFN(EoSFN)。对许多人来说，这迫使他们退出 从学校或工作中脱轨，破坏年轻病人的生活轨迹。当时实验室报告称，41%的成年人 纤维肌痛患者也有SFN的客观证据，这意味着全球可能有10万名SFN患者， R01NS093653资助他们开发用于收集症状数据的标准化工具(SSS Small- 纤维症状调查)和检查异常(磁块一般神经病检查工具)和列表 最好的血液测试来筛选潜在的原因。PI还领导着麻省总医院的神经病理实验室 通过检查患者小腿的微小皮肤活检来确定SFN的诊断，以测量 小纤维神经末梢，并将其与正常的活组织检查进行比较。所以实验室建立了神经病登记处，一个 关系数据库现在包含下载的电子病历以及临床和研究测试 来自&gt；的6500人接受了SFN评估。它目前包括6394个活组织检查结果和1000个SS和磁铁 每年新增1000多名患者。PI也是NIH和FDA资助的CONCEPPT的一部分 专家委员会现在公布了第一个关于SFN的正式病例定义，其中包括以下要求 研究。这些需要已经被SSS、磁铁和皮肤捕捉到的特定异常 活组织检查。现在目标1建议使用注册参与者加上新患者和健康志愿者来适应 并验证SSS和磁铁是否适用于任何医生的一般医疗用途和儿童使用。目标2将 与食品和药物管理局的生物标志物资格认证计划合作，以获得FDA的裁决 关于提高皮肤活检检测质量和准确性的实验室要求。目标3开始全基因组 对SFN的原因和风险进行研究。它招募具有CONCEPPT定义的SFN的注册患者，并添加更多 通过该实验室的NeuropathyCommons网站及其全球合作者。苏什内尔博士的美国迈阿密神经遗传学 实验室将分析符合条件的参与者的基因组，以研究导致或 增加SFN的风险。越来越多的遗传性神经病正在变得可以治疗，奥克兰德博士帮助发表了 第一个有效治疗HSAN1病毒的方法。最终和未来的目标是跟踪大量的SFN患者和 家庭使用安全的网络和手机版本的SSS和磁铁，并邮寄皮肤活检。 这些将使他们能够绘制SFN的症状和自然病史，识别新的致病途径和潜在的 并跟踪儿童和新治疗的患者，以监测长期结果和治疗效果。

Project Summary/Abstract This is a renewal application for the R01NS093653 award that has been funding the Oaklander lab's research on small-fiber neuropathy. SFN is a recently recognized peripheral nerve illness that causes chronic pain, usually starting in the feet and spreading up, difficulty completing routine activities and gastrointestinal distress. In 2013, the team studied 41 children and young adults, unexpectedly reporting evidence of SFN in most. Until then, SFN was known only in older adults with diabetes, chemotherapy or other toxic exposures and serious diseases. The lab had discovered a new condition–early onset SFN (eoSFN). For many, it forced withdrawal from school or work, derailing young patients' life trajectories. When the lab then reported that 41% of adults with fibromyalgia also had objective evidence of SFN, implying there might be > 100,000 SFN patients globally, R01NS093653 funded them to develop standardized tools for collecting data about symptoms (the SSS small- fiber symptom survey) and exam abnormalities (the MAGNET Mass General Neuropathy Exam Tool) and a list of best blood tests to screen for potential causes. The PI also directs Mass General's neuropathology lab that confirms SFN diagnoses by examining tiny skin biopsies from patients' lower leg to measure the density of small-fiber nerve endings and compare it to biopsies from normal. So the lab built the Neuropathy Registry, a relational database now containing downloaded electronic medical records plus clinical and research testing from >6500 people evaluated for SFN. It currently includes 6394 biopsy results and >1000 SSS and MAGNETs with more than 1000 new patients added yearly. The PI is also part of the NIH and FDA funded CONCEPPT committee of experts now publishing the 1st formal case definition for SFN, with inclusion requirements for research. These require specific abnormalities that are already captured by the SSS, MAGNET, and skin biopsy. Now Aim 1 proposes to use Registry participants plus new patients and healthy volunteers to adapt and validate the SSS and MAGNET for general medical use by any doctor and for use in children. Aim 2 will collaborate with the Food and Drug Administration's Biomarker Qualification Program to obtain an FDA ruling on lab requirements to improve the quality and accuracy of skin biopsy testing. Aim 3 begins whole-genome study of causes and risks for SFN. It recruits Registry patients with CONCEPPT-defined SFN and adds more via the lab's NeuropathyCommons website and its global collaborators. Dr. Züchner's U. Miami neurogenetics lab will analyze the genomes of qualifying participants to study known and unknown genes that cause or increase risk for SFN. More genetic neuropathies are becoming treatable and Dr. Oaklander helped publish the 1st effective treatment for HSAN1. The final and future goal is to track large numbers of SFN patients and families using secure web and cell-phone versions of the SSS and MAGNET and mailed-in skin biopsies. These will allow them to map SFN's symptoms and natural history, identify new causal pathways and potential treatments, and track children and newly treated patients to monitor long-term outcomes and treatment effects.