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. Zchner'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.

Public Health Relevance

This is an application to renew current R01 award that has funded our research on small-fiber neuropathy (SFN), which is increasingly linked to fibromyalgia and mysterious multi-symptom illnesses that include unexplained widespread pain, intolerance of exertion and gastrointestinal discomfort. We now propose to revise and optimize the tools we developed for SFN diagnosis for use by doctors and patients around the world and to work with the U.S. Food and Drug Administration to get their Qualification recommendations on how to improve the skin biopsies used globally to confirm SFN diagnoses. We will also collaborate with a leading neuropathy geneticist to sequence the genes of SFN patients we select with our tools that have genetic mutations likely to contribute fundamental knowledge about SFN.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Pain Systems Study Section (SPS)
Program Officer
Mohapatra, Durga Prasanna
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Massachusetts General Hospital
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Lodahl, Mette; Treister, Roi; Oaklander, Anne Louise (2018) Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy. Pain Rep 3:e633
Liu, Xiaolei; Treister, Roi; Lang, Magdalena et al. (2018) IVIg for apparently autoimmune small-fiber polyneuropathy: first analysis of efficacy and safety. Ther Adv Neurol Disord 11:1756285617744484
Oaklander, Anne Louise; Lunn, Michael Pt; Hughes, Richard Ac et al. (2017) Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev 1:CD010369
AbdelRazek, Mahmoud A; Chwalisz, Bart; Oaklander, Anne Louise et al. (2017) Evidence of small-fiber neuropathy (SFN) in two patients with unexplained genital sensory loss and sensory urinary cystopathy. J Neurol Sci 380:82-84
Hamrah, Pedram; Sahin, Afsun; Oaklander, Anne Louise (2017) Widespread effects of clinically unilateral focal nerve injuries. Pain 158:1175-1176
Treister, Roi; Lodahl, Mette; Lang, Magdalena et al. (2017) Initial Development and Validation of a Patient-Reported Symptom Survey for Small-Fiber Polyneuropathy. J Pain 18:556-563
Oaklander, Anne Louise (2016) Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies. Neurotherapeutics 13:108-17
Oaklander, Anne Louise (2016) What is the meaning of ""small-fiber polyneuropathy"" in fibromyalgia? An alternate answer. Pain 157:1366-7
Lang, Magdalena; Treister, Roi; Oaklander, Anne Louise (2016) Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy. J Neurol 263:2515-2527
Treister, R; O'Neil, K; Downs, H M et al. (2015) Validation of the composite autonomic symptom scale 31 (COMPASS-31) in patients with and without small fiber polyneuropathy. Eur J Neurol 22:1124-30

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