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Dis Model Mech. 2015 Apr;8(4):363-71. doi: 10.1242/dmm.020131. Epub 2015 Feb 20.

Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

Author information

1
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.
2
Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
3
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
4
Greenwood Genetics Center, Greenwood, SC 29646, USA.
5
Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
6
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
7
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.
8
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.

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.

KEYWORDS:

Arrhythmia; Long QT; MECP2; Phenytoin; Propranolol; Rett syndrome

PMID:
25713300
PMCID:
PMC4381335
DOI:
10.1242/dmm.020131
[Indexed for MEDLINE]
Free PMC Article

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