title: p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder.
abstract: BACKGROUND
  Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation.
  
  
  METHODS
  Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature.
  
  
  RESULTS
  The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit.
  
  
  CONCLUSIONS
  The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.
authors.affiliation: From the Pain Center, Department of Anesthesiology, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland (M.R.S., C.J.L., I.D.); Service of Medical Genetics, Department of Laboratories, Lausanne University Hospital (CHUV), Lausanne, Switzerland (Z.A.B.); Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland (T.K., M.S., M.W.S., C.W.); Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland (T.K., C.W.); Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland (E.R.); Department of Clinical Research, University of Bern, Bern, Switzerland (H.A.); and Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland (I.D.).
authors.forename: Marc R
authors.initials: MR
authors.lastname: Suter
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.forename: Cédric J
authors.initials: CJ
authors.lastname: Laedermann
authors.forename: Thierry
authors.initials: T
authors.lastname: Kuntzer
authors.forename: Muriel
authors.initials: M
authors.lastname: Schaller
authors.forename: Maurice W
authors.initials: MW
authors.lastname: Stauffacher
authors.forename: Eliane
authors.initials: E
authors.lastname: Roulet
authors.forename: Hugues
authors.initials: H
authors.lastname: Abriel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Decosterd
authors.forename: Christian
authors.initials: C
authors.lastname: Wider
mesh_terms: D000293:Adolescent; D000328:Adult; D000639:Amitriptyline / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002460:Cell Line; D002648:Child; D003080:Cold Temperature; D004247:DNA / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010957:Plasmids; D013001:Somatoform Disorders / Q000235:genetics*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D000639:Amitriptyline; D004247:DNA