Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K⁺ channel K_v1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype–phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype–phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.

中文翻译：

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KCNA2相关性脑病的临床频谱和基因型-表型关联

最近，描述了基因KCNA2的从头突变，该突变导致电压门控K ⁺通道K _v 1.2的显性负功能丧失或功能增强，从而在KCNA2内引起新的分子实体。癫痫性脑病。在此，我们报告了23例携带新型或已知KCNA2的癫痫性脑病患者（先前描述的8例）突变，旨在详细介绍与每个突变相关的临床表型，表征新近鉴定的突变的功能作用，并评估基因型与表型的关联。我们鉴定出五种新颖的突变，并确认了六种已知的突变，其中三种分别在三，五和七名患者中复发。十个突变是错义的，一个是截短突变。从头开始出现的病例可能有20例。使用非洲爪蟾卵母细胞的功能研究两微电极电压钳系统揭示了在八名患者中仅具有功能丧失效应（主要是显性负电流幅度降低）或仅在九名患者中具有功能获得性效应（电压依赖性激活的超极化移位，幅度增加）的突变耐心。在6例患者中，由于电压依赖性激活的超极化位移加上幅度降低或额外的超极化位移，附加的功能丧失（增益和功能丧失）使功能获得减少。灭活曲线。这些电生理发现与明显的表型特征相关。主要区别是：（i）在大多数功能丧失突变的病例中，主要的局灶性（功能丧失）与全身性（功能获得）癫痫发作以及相应的癫痫放电和明显的睡眠激活有关；（ii）在约有功能获得性突变的患者中，有更严重的癫痫，发育问题和共济失调以及小脑乃至整个大脑的萎缩；（iii）最严重的早期发作表型，有时伴有功能获得性和丧失功能突变的患者出现新生儿发作性癫痫和发育障碍，以及全身性和局灶性癫痫发作和脑电图异常。因此，我们的研究表明，在3个亚型患者中，基因型和表型之间的相关性得到了很好的体现。功能获得性突变的患者中，约有一半患有发育问题和共济失调，甚至小脑甚至整个大脑都萎缩；（iii）最严重的早期发作表型，有时伴有功能获得性和丧失功能突变的患者出现新生儿发作性癫痫和发育障碍，以及全身性和局灶性癫痫发作和脑电图异常。因此，我们的研究表明，在3个亚型患者中，基因型和表型之间的相关性得到了很好的体现。功能获得性突变的患者中，约有一半患有发育问题和共济失调，甚至小脑甚至整个大脑都萎缩；（iii）最严重的早期发作表型，有时伴有功能获得性和丧失功能突变的患者出现新生儿发作性癫痫和发育障碍，以及全身性和局灶性癫痫发作和脑电图异常。因此，我们的研究表明，在3个亚型患者中，基因型和表型之间的相关性得到了很好的体现。以及功能获得和功能丧失突变的患者的全身性和局灶性癫痫发作和脑电图异常。因此，我们的研究表明，在3个亚型患者中，基因型和表型之间的相关性得到了很好的体现。以及功能获得和功能丧失突变的患者的全身性和局灶性癫痫发作和脑电图异常。因此，我们的研究表明，在3个亚型患者中，基因型和表型之间的相关性得到了很好的体现。KCNA2脑病根据突变的电生理特征而定。