title: Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy.
abstract: OBJECTIVE
  Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons.
  
  
  METHODS
  Patients referred with possible I-SFN, who met the criteria of ≥2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses.
  
  
  RESULTS
  Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable.
  
  
  CONCLUSIONS
  We show for the first time that gain of function mutations in sodium channel Na(V)1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na(V)1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.
authors.affiliation: Department of Neurology, University Medical Center Maastricht, Maastricht, The Netherlands. c.faber@mumc.nl
authors.forename: Catharina G
authors.initials: CG
authors.lastname: Faber
authors.forename: Janneke G J
authors.initials: JG
authors.lastname: Hoeijmakers
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Ahn
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Cheng
authors.forename: Chongyang
authors.initials: C
authors.lastname: Han
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.forename: Mark
authors.initials: M
authors.lastname: Estacion
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
authors.forename: Els K
authors.initials: EK
authors.lastname: Vanhoutte
authors.forename: Monique M
authors.initials: MM
authors.lastname: Gerrits
authors.forename: Sulayman
authors.initials: S
authors.lastname: Dib-Hajj
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.forename: Ingemar S J
authors.initials: IS
authors.lastname: Merkies
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011115:Polyneuropathies / Q000175:diagnosis* / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels