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

José A. Herrera, Christopher S. Ward, Meagan R. Pitcher, Alan K. Percy, Steven Skinner, Walter E. Kaufmann, Daniel G. Glaze, Xander H.T. Wehrens, Jeffrey L. Neul

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Pages (from-to)363-371
    Number of pages9
    JournalDMM Disease Models and Mechanisms
    Volume8
    Issue number4
    DOIs
    StatePublished - Apr 1 2015

    Keywords

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

    ASJC Scopus subject areas

    • Neuroscience (miscellaneous)
    • Medicine (miscellaneous)
    • Immunology and Microbiology (miscellaneous)
    • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Herrera, J. A., Ward, C. S., Pitcher, M. R., Percy, A. K., Skinner, S., Kaufmann, W. E., Glaze, D. G., Wehrens, X. H. T., & Neul, J. L. (2015). Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs. DMM Disease Models and Mechanisms, 8(4), 363-371. https://doi.org/10.1242/dmm.020131