title: Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.
abstract: One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT.
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Herrera
authors.affiliation: Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Ward
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Meagan R
authors.initials: MR
authors.lastname: Pitcher
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Percy
authors.affiliation: Greenwood Genetics Center, Greenwood, SC 29646, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Skinner
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufmann
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Glaze
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. jneul@ucsd.edu.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Neul
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D006985:Hyperventilation / Q000150:complications / Q000188:drug therapy; D008133:Long QT Syndrome / Q000150:complications / Q000188:drug therapy; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000473:pathology; D010641:Phenotype; D010672:Phenytoin / Q000627:therapeutic use; D011433:Propranolol; D015518:Rett Syndrome / Q000150:complications* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D014463:Ultrasonography
chemical_list: D000319:Adrenergic beta-Antagonists; D000927:Anticonvulsants; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D026941:Sodium Channel Blockers; D010672:Phenytoin; D011433:Propranolol
keywords: Arrhythmia; Long QT; MECP2; Phenytoin; Propranolol; Rett syndrome