Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant.
Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant.
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DOI：
10.1111/epi.13601
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发表时间：
2017-01
期刊：
影响因子：
5.6
通讯作者：
Taglialatela M
中科院分区：
文献类型：
--
作者：
Millichap JJ;Miceli F;De Maria M;Keator C;Joshi N;Tran B;Soldovieri MV;Ambrosino P;Shashi V;Mikati MA;Cooper EC;Taglialatela M
编码Kv7.2神经元K+通道亚基的KCNQ2变异可导致一系列新生儿癫痫，从自限性癫痫到严重癫痫性脑病。大多数KCNQ2致病性变异导致功能丧失，而很少增加通道活性（功能获得）。我们在此为KCNQ2相关癫痫的新表型和功能谱提供证据：没有新生儿癫痫发作的婴儿痉挛与功能获得基因变异相关。通过国际注册，我们确定了4例不相关的新发杂合KCNQ2 c.593G>A, p.R198Q变异患者。所有患儿均足月出生，出院时无癫痫发作或脑病，但在4-6个月大时出现伴有心律失常（或改进性心律失常）的婴儿痉挛。最后随访（3-11岁），所有患者均无癫痫发作，并有严重的发育迟缓。体外实验表明，Kv7.2 R198Q亚基将电流激活门控转变为超极化电位，表明功能获得；在神经元中，Kv7.2和Kv7.2 R198Q亚基相似地分布在轴突初始段，这表明门控改变而不是亚细胞分布的改变有助于疾病的分子发病。我们得出结论，KCNQ2 R198Q是导致婴儿痉挛和脑病的KCNQ2变异新亚类的模型，没有新生儿癫痫发作。
Variants in KCNQ2 encoding for Kv7.2 neuronal K+ channel subunits lead to a spectrum of neonatal-onset epilepsies ranging from self-limiting forms to severe epileptic encephalopathy. Most KCNQ2 pathogenic variants cause loss-of-function, whereas few increase channel activity (gain-of-function). We herein provide evidence for a new phenotypic and functional profile in KCNQ2 related epilepsy: infantile spasms without prior neonatal seizures associated to a gain-of-function gene variant. Via an international registry, we identified four unrelated patients with de novo heterozygous KCNQ2 c.593G>A, p.R198Q variants. All were born at term and discharged home without seizures or concern of encephalopathy, but developed infantile spasms with hypsarrhythmia (or modified hypsarrhythmia) between the ages of 4-6 months. At last follow up (ages 3-11 years), all patients were seizure-free and had severe developmental delay. In vitro experiments showed that Kv7.2 R198Q subunits shifted current activation gating to hyperpolarized potentials, indicative of gain-of-function; in neurons, Kv7.2 and Kv7.2 R198Q subunits similarly populated the axon initial segment, suggesting that gating changes rather than altered sub-cellular distribution contribute to disease molecular pathogenesis. We conclude that KCNQ2 R198Q is a model for a new subclass of KCNQ2 variants causing infantile spasms and encephalopathy, without preceding neonatal seizures.
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