title: Mexiletine-responsive erythromelalgia due to a new Na(v)1.7 mutation showing use-dependent current fall-off.
abstract: Inherited erythromelalgia (IEM), characterized by episodic burning pain and erythema of the extremities, is produced by gain-of-function mutations in sodium channel Na(v)1.7, which is preferentially expressed in nociceptive and sympathetic neurons. Most patients do not respond to pharmacotherapy, although occasional reports document patients as showing partial relief with lidocaine or mexiletine. A 7-year-old girl, with a two-year history of symmetric burning pain and erythema in her hands and feet, was diagnosed with erythromelalgia. Treatment with mexiletine reduced the number and severity of pain episodes. We report here a new IEM Na(v)1.7 mutation in this patient, and its response to mexiletine. SCN9A exons from the proband were amplified and sequenced. We identified a single nucleotide substitution (T2616G) in exon 15, not present in 200 ethnically-matched control alleles, which substitutes valine 872 by glycine (V872G) within DII/S5. Whole-cell patch-clamp analysis of wild-type and mutant Na(v)1.7 channels in mammalian cells show that V872G shifts activation by -10 mV, slows deactivation, and generates larger ramp currents. We observed a stronger use-dependent fall-off in current following exposure to mexiletine for V872G compared to wild-type channels. These observations suggest that some patients with IEM may show a favorable response to mexiletine due to a use-dependent effect on mutant Na(v)1.7 channels. Continued relief from pain, even after mexiletine was discontinued in this patient, might suggest that early treatment may slow the progression of the disease.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Chongyang
authors.initials: C
authors.lastname: Han
authors.forename: Lynda
authors.initials: L
authors.lastname: Tyrrell
authors.forename: Zhimiao
authors.initials: Z
authors.lastname: Lin
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001703:Biophysics; D002461:Cell Line, Transformed; D002648:Child; D002884:Chromosomes, Human, Pair 15; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004916:Erythromelalgia / Q000188:drug therapy* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008801:Mexiletine / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation / Q000235:genetics*; D062556:NAV1.7 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques / Q000379:methods; D017421:Sequence Analysis; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection / Q000379:methods; D014633:Valine / Q000235:genetics
chemical_list: D000889:Anti-Arrhythmia Agents; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D008801:Mexiletine; D014633:Valine; D005998:Glycine