Abstract：
BACKGROUND: Potassium ion channels play a crucial role in maintaining cellular electrical stability and are implicated in various epilepsies. Heterozygous pathogenic variants in KCNK4 cause a recognizable neurodevelopmental syndrome with facial dysmorphism, hypertrichosis, epilepsy, intellectual disability (ID), and gingival overgrowth (FHEIG). To date, no more than nine patients with FHEIG have been described worldwide and still little is known about epileptic phenotype in KCNK4-related disease.
METHODS: We identified a novel de novo p.(Gly139Arg) variant in KCNK4 in a patient with drug-resistant nocturnal seizures, mild ID, and dysmorphic features. In silico analyses of the variant strongly suggest a gain-of-function effect. We conducted a retrospective review of previously published cases, focusing on the epileptic features and response to various treatments.
RESULTS: To date, epilepsy has been reported in 8/10 patients with KCNK4-related disease. The mean age of seizure onset was 1.8 years, and the most common seizure type was focal to bilateral tonic-clonic (5/8). Sodium channel blockers and valproate were effective in the majority of patients, but in 3/8 the epilepsy was drug-resistant. Our patient showed improved seizure control after treatment with the carbonic anhydrase inhibitor sulthiame. Interestingly, the patient showed features of peripheral nerve hyperexcitability syndrome, a phenomenon not previously described in potassium channelopathies caused by increased K+ conductance.
CONCLUSIONS: Gain-of-function variants in KCNK4 cause a spectrum of epilepsies, ranging from benign isolated epilepsy to epileptic encephalopathy, with focal to bilateral tonic-clonic seizures being the most commonly observed. Importantly, a subgroup of patients present with a mild extra-neurological phenotype without characteristic facial dysmorphism or generalized hypertrichosis. This report expands the phenotypic spectrum of KNCK4-associated disease and provides new insights into the clinical heterogeneity of this rare neurodevelopmental syndrome.
METHODS: We identified a novel de novo p.(Gly139Arg) variant in KCNK4 in a patient with drug-resistant nocturnal seizures, mild ID, and dysmorphic features. In silico analyses of the variant strongly suggest a gain-of-function effect. We conducted a retrospective review of previously published cases, focusing on the epileptic features and response to various treatments.
RESULTS: To date, epilepsy has been reported in 8/10 patients with KCNK4-related disease. The mean age of seizure onset was 1.8 years, and the most common seizure type was focal to bilateral tonic-clonic (5/8). Sodium channel blockers and valproate were effective in the majority of patients, but in 3/8 the epilepsy was drug-resistant. Our patient showed improved seizure control after treatment with the carbonic anhydrase inhibitor sulthiame. Interestingly, the patient showed features of peripheral nerve hyperexcitability syndrome, a phenomenon not previously described in potassium channelopathies caused by increased K+ conductance.
CONCLUSIONS: Gain-of-function variants in KCNK4 cause a spectrum of epilepsies, ranging from benign isolated epilepsy to epileptic encephalopathy, with focal to bilateral tonic-clonic seizures being the most commonly observed. Importantly, a subgroup of patients present with a mild extra-neurological phenotype without characteristic facial dysmorphism or generalized hypertrichosis. This report expands the phenotypic spectrum of KNCK4-associated disease and provides new insights into the clinical heterogeneity of this rare neurodevelopmental syndrome.
摘要：
背景：钾离子通道在维持细胞电稳定性中起着至关重要的作用，并且与各种癫痫有关。KCNK4中的杂合致病变异导致可识别的神经发育综合征，伴有面部畸形，多毛症,癫痫,智力残疾（ID），和牙龈过度生长（FHEIG）。迄今为止,全球范围内对FHEIG患者的描述不超过9例,但对KCNK4相关疾病的癫痫表型知之甚少.
方法：我们在患有耐药性夜间癫痫发作的患者中，在KCNK4中发现了一种新的从头p。（Gly139Arg）变体，轻微的ID,和畸形特征。对该变体的计算机模拟分析强烈表明存在功能增益效应。我们对以前发表的病例进行了回顾性审查，专注于癫痫的特征和对各种治疗的反应。
结果：迄今为止，据报道，有8/10的KCNK4相关疾病患者出现癫痫。癫痫发作的平均年龄为1.8岁，最常见的发作类型是双侧强直阵挛性发作（5/8）。钠通道阻滞剂和丙戊酸盐对大多数患者有效，但在3/8的癫痫是耐药的。在使用碳酸酐酶抑制剂sulthiame治疗后，我们的患者癫痫发作控制得到了改善。有趣的是,患者表现出周围神经兴奋过度综合征的特征，钾电导增加引起的钾通道病中以前没有描述过的现象。
结论：KCNK4的功能增益变异导致一系列癫痫，从良性孤立性癫痫到癫痫性脑病，最常观察到的是局灶性至双侧强直阵挛性癫痫发作。重要的是,表现为轻度神经外表型而无特征性面部畸形或全身性多毛症的患者亚组。该报告扩展了KNCK4相关疾病的表型谱，并为这种罕见的神经发育综合征的临床异质性提供了新的见解。
方法：我们在患有耐药性夜间癫痫发作的患者中，在KCNK4中发现了一种新的从头p。（Gly139Arg）变体，轻微的ID,和畸形特征。对该变体的计算机模拟分析强烈表明存在功能增益效应。我们对以前发表的病例进行了回顾性审查，专注于癫痫的特征和对各种治疗的反应。
结果：迄今为止，据报道，有8/10的KCNK4相关疾病患者出现癫痫。癫痫发作的平均年龄为1.8岁，最常见的发作类型是双侧强直阵挛性发作（5/8）。钠通道阻滞剂和丙戊酸盐对大多数患者有效，但在3/8的癫痫是耐药的。在使用碳酸酐酶抑制剂sulthiame治疗后，我们的患者癫痫发作控制得到了改善。有趣的是,患者表现出周围神经兴奋过度综合征的特征，钾电导增加引起的钾通道病中以前没有描述过的现象。
结论：KCNK4的功能增益变异导致一系列癫痫，从良性孤立性癫痫到癫痫性脑病，最常观察到的是局灶性至双侧强直阵挛性癫痫发作。重要的是,表现为轻度神经外表型而无特征性面部畸形或全身性多毛症的患者亚组。该报告扩展了KNCK4相关疾病的表型谱，并为这种罕见的神经发育综合征的临床异质性提供了新的见解。
