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 maile...