The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.
The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.
复制标题
DOI：
10.1093/brain/awac210
复制
发表时间：
2022-11-21
期刊：
影响因子：
14.5
通讯作者：
Cestele, Sandrine
中科院分区：
文献类型：
--
作者：
Brunklaus, Andreas;Bruenger, Tobias;Feng, Tony;Fons, Carmen;Lehikoinen, Anni;Panagiotakaki, Eleni;Vintan, Mihaela-Adela;Symonds, Joseph;Andrew, James;Arzimanoglou, Alexis;Delima, Sarah;Gallois, Julie;Hanrahan, Donncha;Lesca, Gaetan;MacLeod, Stewart;Marjanovic, Dragan;McTague, Amy;Nunez-Enamorado, Noemi;Perez-Palma, Eduardo;Scott Perry, M.;Pysden, Karen;Russ-Hall, Sophie J.;Scheffer, Ingrid E.;Sully, Krystal;Syrbe, Steffen;Vaher, Ulvi;Velayutham, Murugan;Vogt, Julie;Weiss, Shelly;Wirrell, Elaine;Zuberi, Sameer M.;Lal, Dennis;Moller, Rikke S.;Mantegazza, Massimo;Cestele, Sandrine
脑电压门控钠通道NaV1.1（SCN 1A）功能丧失变体导致严重的癫痫Dravet综合征，以及与遗传性癫痫伴热性惊厥+相关的较温和表型。SCN 1A变异体的功能获得与家族性偏瘫性偏头痛3型相关已描述了新的SCN 1A相关表型，包括早期婴儿发育和癫痫性脑病伴运动障碍，以及最近的新生儿关节弯曲症。在这里，我们描述了受影响的个人的临床，遗传和功能评估。通过国际合作网络，使用结构化临床问卷和文献确定了35名患者。我们进行了全细胞电压钳电生理记录比较钠通道含有野生型与变异NaV1.1亚基。研究结果与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，不同的发病年龄和关节弯曲和/或运动障碍的存在。受影响最严重的婴儿（n = 13）表现为先天性关节弯曲、出生后3天内的新生儿癫痫发作、强直性癫痫发作和呼吸暂停，伴有严重的运动障碍和严重的智力残疾。 21名患者在2周至3个月大时出现严重的早期婴儿发育性和癫痫性脑病以及运动障碍。 1例患者在3个月后仅出现发育性和癫痫性脑病。 与Dravet综合征变体不同，相关的SCN 1A变体聚集在与功能获得相关的通道失活区域（优势比= 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了与神经元过度兴奋保持一致的门控特性的改变。虽然癫痫变体导致动作电流幅度适度增加，与轻度功能增益一致，但家族性偏瘫性偏头痛3型变体诱导对门控特性的更大影响，特别是持续电流的增加，导致动作电流幅度大幅增加，与更强的功能增益一致。 临床上，16种功能变体中有13种（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）后癫痫发作减少相关，无症状加重的证据。我们的研究扩展了SCN 1A相关癫痫表型的功能增益谱，定义了关键的临床特征，为SCN 1A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，并确定了钠通道阻滞剂作为潜在有效的治疗方法。在具有致病性SCN 1A变体和非Dravet综合征表型的早发性癫痫中，应考虑功能获得疾病。Brunklaus等人描述了一系列新型SCN 1A癫痫表型，具有功能特性的获得，范围从新生儿发育性和癫痫性脑病伴运动障碍和关节弯曲，到早发性发育性和癫痫性脑病伴和不伴运动障碍，其对钠通道阻断疗法有反应。
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. Brunklaus et al. describe a spectrum of novel SCN1A epilepsy phenotypes with gain of function properties ranging from neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis, to early onset developmental and epileptic encephalopathies with and without movement disorder, which respond to sodium channel blocking therapies.
登录
查看更多内容
DOI：
10.1093/brain/awac006
发表时间：
2022-12-19
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1007/s13311-015-0372-8
发表时间：
2016-01
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
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
通讯作者：
Koeleman BP
影响因子：
15.9
作者：
Chever, Oana;Zerimech, Sarah;Mantegazza, Massimo
通讯作者：
Mantegazza, Massimo
影响因子：
4.8
作者：
Dhifallah S;Lancaster E;Merrill S;Leroudier N;Mantegazza M;Cestèle S
通讯作者：
Cestèle S
影响因子：
5.3
作者：
Hedrich, Ulrike B. S.;Liautard, Camille;Lerche, Holger
通讯作者：
Lerche, Holger