title: Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome.
abstract: BACKGROUND
  Timothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A (TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an INa blocker, mexiletine, to improve clinical manifestations in TS.
  
  
  RESULTS
  A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening. Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C. Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father's oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470-490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT-RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late INa with IC₅₀ of 17.6±1.9 µmol/L and attenuated brady-dependent QT prolongation and reduced QT-RR slope in the TS model using BayK 8644.
  
  
  CONCLUSIONS
  Mexiletine shortened QTc, attenuated QT-RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late INa.
authors.affiliation: Heart Center, Peking University People's Hospital, Beijing, People's Republic of China.
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Gao
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Xue
authors.forename: Dayi
authors.initials: D
authors.lastname: Hu
authors.forename: Wenling
authors.initials: W
authors.lastname: Liu
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.forename: Hongmei
authors.initials: H
authors.lastname: Sun
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Timothy
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Cuilan
authors.initials: C
authors.lastname: Li
authors.forename: Gan-Xin
authors.initials: GX
authors.lastname: Yan
mesh_terms: D000818:Animals; D001321:Autistic Disorder; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015150:Echocardiography, Doppler / Q000379:methods; D004562:Electrocardiography / Q000379:methods; D015716:Electrocardiography, Ambulatory / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008801:Mexiletine / Q000627:therapeutic use*; D023421:Models, Animal; D032342:Muscle Cells / Q000187:drug effects; D011817:Rabbits; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000187:drug effects*; D013576:Syndactyly / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome; D061567:Voltage-Gated Sodium Channel Blockers / Q000627:therapeutic use*
chemical_list: D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine
keywords: LQT8; T wave alternans; Timothy syndrome; atrioventricular block; late sodium current; mexiletine