Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach.
Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach.
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DOI：
10.1007/s13311-015-0372-8
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发表时间：
2016-01
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影响因子：
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通讯作者：
Koeleman BP
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作者：
Boerma RS;Braun KP;van den Broek MP;van Berkestijn FM;Swinkels ME;Hagebeuk EO;Lindhout D;van Kempen M;Boon M;Nicolai J;de Kovel CG;Brilstra EH;Koeleman BP
SCN 8A的突变与癫痫和智力残疾有关。SCN 8A编码钠通道Nav1.6，其位于大脑中。SCN 8A中的功能获得性错义突变被认为导致含有Nav1.6的兴奋性神经元的放电增加，因此导致癫痫发作易感性增加。我们假设钠通道阻滞剂可以通过阻断过度活跃的Nav1.6从而抵消突变的影响，对SCN 8A相关癫痫患者产生有益影响。在此，我们描述了4例SCN 8A错义突变和癫痫患者，他们对高剂量苯妥英钠的反应非常好，当苯妥英钠药物减少时，癫痫发作控制丧失，而副作用相对较轻。在2例患者中，反复停用苯妥英钠导致癫痫发作复发。基于这些患者的研究结果和潜在的分子机制，我们认为（高剂量）苯妥英治疗是由于SCN 8A突变导致难以控制癫痫发作的患者的一种可能的治疗选择。本文的在线版本（doi：10.1007/s13311-015-0372-8）包含补充材料，可供授权用户使用。
Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation. The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.