Evaluation of Small-Fiber Polyneuropathy in Youth

项目概要/摘要 这是R 01 NS 093653奖的续期申请，该奖项一直资助奥克兰实验室的研究。 小纤维神经病的研究SFN是最近认识到的导致慢性疼痛的外周神经疾病， 通常从足部开始并向上蔓延，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，意外地报告了大多数人存在SFN的证据。直到 然后，SFN仅在患有糖尿病、化疗或其他有毒物质暴露的老年人中被发现， 疾病该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 从学校或工作中脱离出来，使年轻患者的生活轨迹脱轨。当实验室报告说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> 100，000名SFN患者， R 01 NS 093653资助他们开发标准化工具，用于收集有关症状的数据（SSS小型- 纤维症状调查）和检查异常（MAGNET Mass General Neuropathy Exam Tool）以及列表 最好的血液测试来筛选潜在的原因。PI还指导麻省总医院的神经病理学实验室， 通过检查患者小腿的微小皮肤活检来确定SFN诊断， 小纤维神经末梢，并将其与正常的活组织检查进行比较。因此，实验室建立了神经病登记处， 关系数据库，现在包含下载的电子医疗记录以及临床和研究测试 从>6500人评估SFN。它目前包括6394个活检结果和>1000个SSS和MAGNESTA 每年新增患者超过1000人。PI也是NIH和FDA资助的CONCEPPT的一部分 专家委员会现在发布了SFN的第一个正式案例定义， research.这些需要特定的异常，这些异常已经被SSS、MAGNET和皮肤捕获 活检现在目标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MAGNET是否可供任何医生和儿童使用。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 对实验室的要求，以提高皮肤活检测试的质量和准确性。目标3开始全基因组 研究SFN的原因和风险。它招募了具有CONCEPPT定义的SFN的登记研究患者，并增加了更多 通过实验室的NeuropathyCommons网站及其全球合作者。Dr. Züchner's U.迈阿密神经遗传学 实验室将分析合格参与者的基因组，以研究导致或 增加SFN风险。越来越多的遗传性神经病变得可以治疗，Oaklander博士帮助发表了 第一个有效的治疗HSAN 1。最终和未来的目标是跟踪大量的SFN患者， 家庭使用安全的网络和手机版本的SSS和MAGNET和邮寄的皮肤活检。 这些将使他们能够绘制SFN的症状和自然史，确定新的因果途径和潜在的 治疗，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.