title: Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7.
abstract: Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.
authors.affiliation: Department of Physiology and Pathophysiology, University of Erlangen, Erlangen, Germany Department of Neurology, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Clinical Neurophysiology, University of Uppsala, Uppsala, Sweden Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway Department of Rheumatology, Skin and Infectious Diseases, Oslo University Hospital, Oslo, Norway Department of Vascular Surgery, Oslo University Hospital, Oslo, Norway AstraZeneca Translational Science Centre, Department of Clinical Neuroscience, Karolinska Institutet, Sweden AstraZeneca R&D, Macclesfield, United Kingdom Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA Department of Anesthesiology Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Namer
authors.forename: Kristin
authors.initials: K
authors.lastname: Ørstavik
authors.forename: Roland
authors.initials: R
authors.lastname: Schmidt
authors.forename: Inge-Petter
authors.initials: IP
authors.lastname: Kleggetveit
authors.forename: Christian
authors.initials: C
authors.lastname: Weidner
authors.forename: Cato
authors.initials: C
authors.lastname: Mørk
authors.forename: Mari Skylstad
authors.initials: MS
authors.lastname: Kvernebo
authors.forename: Knut
authors.initials: K
authors.lastname: Kvernebo
authors.forename: Hugh
authors.initials: H
authors.lastname: Salter
authors.forename: Thomas Hedley
authors.initials: TH
authors.lastname: Carr
authors.forename: Märta
authors.initials: M
authors.lastname: Segerdahl
authors.forename: Hans
authors.initials: H
authors.lastname: Quiding
authors.forename: Stephen George
authors.initials: SG
authors.lastname: Waxman
authors.forename: Hermann Otto
authors.initials: HO
authors.lastname: Handwerker
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Torebjörk
authors.forename: Ellen
authors.initials: E
authors.lastname: Jørum
authors.forename: Martin
authors.initials: M
authors.lastname: Schmelz
mesh_terms: D016022:Case-Control Studies; D004594:Electrophysiology; D004916:Erythromelalgia / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009431:Neural Conduction / Q000235:genetics / Q000502:physiology*; D009460:Neurologic Examination; D009619:Nociceptors / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D018408:Patch-Clamp Techniques; D010543:Peroneal Nerve / Q000473:pathology / Q000503:physiopathology; D010812:Physical Stimulation; D011930:Reaction Time / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics; D013912:Threonine / Q000235:genetics
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D007532:Isoleucine; D013912:Threonine