Not All SCN1A Epileptic Encephalopathies Are Dravet Syndrome: Early Profound Thr226Met Phenotype Sadleir LG, Mountier EI, Gill D, et al. Neurology. 2017;89(10):1035-1042. OBJECTIVE To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met. SCN1A Gain of Function in Early Infantile Encephalopathy Berecki G, Bryson A, Terhag J, et al. Ann Neurol. 2019; 85:514-525. OBJECTIVE To elucidate the biophysical basis underlying the distinct and severe clinical presentation in patients with the recurrent missense SCN1A variant, p.Thr226Met. Patients with this variant show a well-defined genotype-phenotype correlation and present with developmental and early infantile epileptic encephalopathy that is far more severe than typical SCN1A Dravet syndrome. METHODS Whole cell patch clamp and dynamic action potential clamp were used to study T226M Nav 1.1 channels expressed in mammalian cells. Computational modeling was used to explore the neuronal scale mechanisms that account for altered action potential firing. RESULTS T226M channels exhibited hyperpolarizing shifts of the activation and inactivation curves and enhanced fast inactivation. Dynamic action potential clamp hybrid simulation showed that model neurons containing T226M conductance displayed a left shift in rheobase relative to control. At current stimulation levels that produced repetitive action potential firing in control model neurons, depolarization block and cessation of action potential firing occurred in T226M model neurons. Fully computationally simulated neuron models recapitulated the findings from dynamic action potential clamp and showed that heterozygous T226M models were also more susceptible to depolarization block. INTERPRETATION From a biophysical perspective, the T226M mutation produces gain of function. Somewhat paradoxically, our data suggest that this gain of function would cause interneurons to more readily develop depolarization block. This "functional dominant negative" interaction would produce a more profound disinhibition than seen with haploinsufficiency that is typical of Dravet syndrome and could readily explain the more severe phenotype of patients with T226M mutation.

中文翻译：

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超越Dravet综合征：一种新型的，更严重的SCN1A相关的癫痫性脑病的特征。

并非所有SCN1A癫痫性脑病都是Dravet综合征：早期深刻的Thr226Met表型Sadleir LG，Mountier EI，Gill D等。神经病学。2017; 89（10）：1035-1042。目的定义一种独特的SCN1A发育性和癫痫性脑病，其起病早期，严重障碍和运动障碍。方法鉴定出9例儿童，他们患有严重的发育性和癫痫性脑病和SCN1A突变。结果我们确定了9名3至12岁的儿童；7名是男性。发作发作为6至12周，伴有半身发作，双侧强直阵挛性发作或痉挛。所有儿童均具有严重的发育障碍，且非语言，非活动能力，并且9名儿童中有7名需要进行胃造口术。所有人都发生运动亢进症，其特征是肌张力障碍和胆汁淤积症，伴有明显的口腔运动障碍，发病时间为2至20个月。八个有复发性错义SCN1A突变，p.Thr226Met。剩下的孩子有错义突变p.Pro1345Ser。突变发生在9个中的8个，从头开始；在剩下的情况下，母亲是消极的，而父亲则没有。结论在这里，我们提出了SCN1A的表型-基因型相关性。我们描述了一个独特的SCN1A表型，即婴儿SCN1A早期脑病，它很容易与Dravet综合征和遗传性癫痫伴高热惊厥加公认的实体区分开。这种疾病的发病年龄较早，严重的发育障碍和独特的运动过快症，将其与Dravet综合征区分开。值得注意的是，9名儿童中有8名具有复发性错义突变p.Thr226Met。SCN1A在婴儿早期脑病中的作用获得成功Berecki G，Bryson A，Terhag J等。Ann Neurol。2019; 85：514-525。目的阐明复发性错义SCN1A变体p.Thr226Met患者独特而严重的临床表现基础的生物物理基础。具有这种变异的患者表现出明确的基因型-表型相关性，并伴有发展性和早期婴儿癫痫性脑病，远比典型的SCN1A Dravet综合征严重。方法采用全细胞膜片钳和动态动作电位钳研究哺乳动物细胞中表达的T226M Nav 1.1通道。计算模型被用来探索神经元规模机制，解释了动作电位发射的改变。结果T226M通道表现出激活和失活曲线的超极化位移，并增强了快速失活。动态动作电位钳混合仿真显示，包含T226M电导的模型神经元相对于对照在流变碱中显示左移。在当前的刺激水平下，在对照模型神经元中产生重复的动作电位放电，在T226M模型神经元中发生去极化阻滞和动作电位放电停止。完全计算机模拟的神经元模型概括了动态动作电位钳的发现，并表明杂合的T226M模型也更易于去极化。解释从生物物理学的角度来看，T226M突变产生功能增强。有点自相矛盾的是，我们的数据表明，这种功能增强会导致中间神经元更容易发展去极化阻滞。这种“功能性显性负性”相互作用将产生比Dravet综合征典型的单倍功能不全更为深刻的抑制作用，并且可以很容易地解释T226M突变患者的更严重的表型。