Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

中文翻译：

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功能 SCN1A 障碍谱的获得：新的癫痫表型和治疗意义。

脑电压门控钠通道 NaV1.1 (SCN1A) 功能丧失变异会导致严重的癫痫 Dravet 综合征，以及与伴有热性惊厥的遗传性癫痫相关的较轻表型。功能获得性 SCN1A 变异与家族性偏瘫性偏头痛 3 型相关。新的 SCN1A 相关表型已被描述，包括早期婴儿发育和癫痫性脑病伴有运动障碍，以及最近出现的新生儿关节挛缩症。在这里，我们描述了受影响个体的临床、遗传和功能评估。使用结构化临床问卷和文献，通过国际合作网络确定了 35 名患者。我们进行了全细胞电压钳电生理记录，比较了含有野生型和变异 NaV1.1 亚基的钠通道。结果与 Dravet 综合征和家族性偏瘫性偏头痛 3 型变异有关。我们确定了三种不同的临床表现，因发病年龄和关节弯曲和/或运动障碍的存在而异。受影响最严重的婴儿 (n = 13) 表现为先天性关节弯曲、出生后头 3 天的新生儿癫痫、强直性癫痫发作和呼吸暂停，并伴有明显的运动障碍和严重的智力障碍。21 名患者在 2 周至 3 个月大时出现严重的早期婴儿发育和癫痫性脑病以及运动障碍。一名患者在 3 个月后仅出现发育性和癫痫性脑病。相关的 SCN1A 变异聚集在与功能获得相关的通道失活区域，不同于 Dravet 综合征变异（比值比 = 17.8；置信区间 = 5.4-69.3；P = 1.3 × 10-7）。癫痫和家族性偏瘫性偏头痛 3 型变体的功能研究揭示门控特性的改变与神经元过度兴奋保持一致。虽然癫痫变异导致动作电流幅度的适度增加与功能的轻度增益一致，但家族性偏瘫性偏头痛 3 型变异对门控特性产生更大的影响，特别是持续电流的增加，导致动作电流幅度的大幅增加, 与更强的功能增益一致。临床上，16 个功能获得变异中有 13 个 (81%) 与钠通道阻滞剂治疗（卡马西平、奥卡西平、苯妥英、拉莫三嗪或拉考沙胺）的癫痫发作减少有关，没有症状恶化的证据。我们的研究扩展了 SCN1A 相关癫痫表型的功能获得范围，定义了关键临床特征，为 SCN1A 相关癫痫和家族性偏瘫性偏头痛 3 型之间的潜在疾病机制提供了新的见解，并将钠通道阻滞剂确定为潜在有效的疗法。在具有致病性 SCN1A 变异和非 Dravet 综合征表型的早发性癫痫中应考虑功能获得性疾病。奥卡西平、苯妥英、拉莫三嗪或拉考沙胺）而无症状加重的证据。我们的研究扩展了 SCN1A 相关癫痫表型的功能获得范围，定义了关键临床特征，为 SCN1A 相关癫痫和家族性偏瘫性偏头痛 3 型之间的潜在疾病机制提供了新的见解，并将钠通道阻滞剂确定为潜在有效的疗法。在具有致病性 SCN1A 变异和非 Dravet 综合征表型的早发性癫痫中应考虑功能获得性疾病。奥卡西平、苯妥英、拉莫三嗪或拉考沙胺）而无症状加重的证据。我们的研究扩展了 SCN1A 相关癫痫表型的功能获得范围，定义了关键临床特征，为 SCN1A 相关癫痫和家族性偏瘫性偏头痛 3 型之间的潜在疾病机制提供了新的见解，并将钠通道阻滞剂确定为潜在有效的疗法。在具有致病性 SCN1A 变异和非 Dravet 综合征表型的早发性癫痫中应考虑功能获得性疾病。对 SCN1A 相关癫痫和 3 型家族性偏瘫性偏头痛之间的潜在疾病机制提供了新的见解，并将钠通道阻滞剂确定为潜在有效的疗法。在具有致病性 SCN1A 变异和非 Dravet 综合征表型的早发性癫痫中应考虑功能获得性疾病。对 SCN1A 相关癫痫和 3 型家族性偏瘫性偏头痛之间的潜在疾病机制提供了新的见解，并将钠通道阻滞剂确定为潜在有效的疗法。在具有致病性 SCN1A 变异和非 Dravet 综合征表型的早发性癫痫中应考虑功能获得性疾病。