Benign Infantile Seizures and Paroxysmal Dyskinesia Caused by an SCN8A Mutation
Benign Infantile Seizures and Paroxysmal Dyskinesia Caused by an SCN8A Mutation
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DOI：
10.1002/ana.24580
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发表时间：
2016-03-01
影响因子：
11.2
通讯作者：
Weber, Yvonne G.
中科院分区：
文献类型：
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作者：
Gardella, Elena;Becker, Felicitas;Weber, Yvonne G.
目的：良性家族性婴儿惊厥 (BFIS)、阵发性运动源性运动障碍 (PKD) 及其组合（称为婴儿惊厥和阵发性舞蹈手足徐动症 (ICCA)）是相关的常染色体显性遗传疾病。 PRRT2（富含脯氨酸的跨膜蛋白 2 基因）已被确定为所有 3 种情况的主要基因，发现在 80% 至 90% 的家族性病例和 30% 至 35% 的散发病例中发生突变。 方法：我们使用全外显子组或靶向基因组测序，在 PRRT2 阴性、BFIS 或 ICCA 无关家族中寻找遗传缺陷，并进行了详细的基因检测。 结果：在 3 个家族中，共有 16 名受影响成员，我们在 SCN8A 中发现了相同的共分离杂合错义突变 (c.4447G> A; p.E1483K)，编码电压门控钠通道。通过连锁分析排除了创始人效应。除 1 人外，所有个体的认知和运动里程碑、神经影像学和发作间期神经系统状态均正常。 15 名受影响成员在生命的第一年至第二年出现无发热局灶性或全身强直阵挛性癫痫发作；其中 5 人后来经历过一次无端癫痫发作。一名患者仅在学龄时出现癫痫发作。所有患者均未出现癫痫发作，大多数患者无需药物治疗。除 2 例外，所有病例的发作间期脑电图 (EEG) 均正常。16 名患者中有 5 名在青春期出现额外的短暂阵发性发作，要么是肌张力障碍/运动障碍，要么是“颤抖”发作，由伸展、运动启动或情绪刺激引发。在 1 例病例中，我们通过视频脑电图多描记术记录了典型的 PKD 发作，记录了皮质受累。 解释：我们的研究将 SCN8A 确定为一种新基因，其中反复突变导致 BFIS/ICCA，扩大了癫痫和运动障碍联合综合征的临床遗传谱。
Objective: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases.Methods: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup.Results: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G> A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement.Interpretation: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.