KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects
KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects
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DOI：
10.1136/jmedgenet-2015-103508
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发表时间：
2016-04-01
影响因子：
4
通讯作者：
Heron, Sarah E.
中科院分区：
文献类型：
--
作者：
Lim, Chiao Xin;Ricos, Michael G.;Heron, Sarah E.
钠门控钾通道亚基基因KCNT 1的突变最近成为几种不同癫痫疾病的原因。本文综述了与该基因相关的突变和表型谱，并讨论了患者中发现的合并症，包括智力残疾和精神病特征。该基因也可能与心脏疾病有关。39%的婴儿癫痫性脑病恶性移行性局灶性发作（MMFSI）患者中发现了KCNT 1错义突变，使其成为迄今为止发现的最重要的MMFSI致病基因。KCNT 1突变也在8例散发性和家族性常染色体显性夜间额叶癫痫（ADNFLE）的无关病例中描述。这些患者具有高频率的相关智力残疾和精神病学特征。KCNT 1的两个突变与ADNFLE和MMFSI相关，表明KCNT 1突变的基因型-表型关系并不简单。在几例除MMFSI外的婴儿癫痫性脑病患者中也描述了突变。值得注意的是，迄今为止描述的KCNT 1中的所有突变都是错义突变，并且电生理学研究表明它们导致钾电流增加。总之，这些遗传和电生理学研究提高了通过使用改变钾通道作用的药物治疗KCNT 1突变患者来提供精确药物的可能性，以特异性靶向其致病突变的生物学效应。这些审判目前正在进行中。更好地理解KCNT 1相关疾病的潜在机制将进一步改善相关严重癫痫发作疾病的治疗。
Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.