Herrera José A, Ward Christopher S, Pitcher Meagan R, Percy Alan K, Skinner Steven, Kaufmann Walter E, Glaze Daniel G, Wehrens Xander H T, Neul Jeffrey L
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.
Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Dis Model Mech. 2015 Apr;8(4):363-71. doi: 10.1242/dmm.020131. Epub 2015 Feb 20.
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.
与雷特综合征（RTT，一种X连锁神经发育障碍）相关的死亡中有四分之一是突然且意外的。RTT与QTc间期延长（LQT）有关，而LQT相关的心律失常是意外死亡的一个潜在原因。RTT中LQT的护理标准是用β-肾上腺素能拮抗剂进行治疗；然而，最近的研究表明，用β-拮抗剂普萘洛尔对患有RTT的小鼠进行急性治疗并不能预防致命性心律失常。相比之下，用钠通道阻滞剂苯妥英进行急性治疗可预防心律失常。可能需要长期服用普萘洛尔才能产生疗效；因此，我们测试了长期用普萘洛尔或苯妥英对RTT小鼠的治疗效果。苯妥英完全消除了心律失常，而普萘洛尔则没有效果。令人惊讶的是，苯妥英还使体重和活动恢复正常，但却使呼吸模式恶化。为了探究钠通道阻滞剂对RTT患者QT的作用，我们对接受钠通道阻滞剂抗癫痫治疗前后的QT状态进行了回顾性分析。患有RTT和LQT的个体在开始接受钠通道阻滞剂抗癫痫治疗后，其QT间期状态有显著改善。因此，对于RTT患者LQT的临床管理应考虑使用钠通道阻滞剂。
