Department of Developmental Neurology, Medical University of Gdansk, Gdansk, Poland.
Laboratory of Protein Biochemistry, Intercollegiate Faculty of Biotechnology, University of Gdansk, Gdansk, Poland.
Seizure. 2024 Oct;121:114-122. doi: 10.1016/j.seizure.2024.08.008. Epub 2024 Aug 9.
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.
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.
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.
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.
钾离子通道在维持细胞电稳定性方面起着至关重要的作用，并与各种癫痫有关。KCNK4 中的杂合致病性变异导致一种可识别的神经发育综合征，具有面部畸形、多毛症、癫痫、智力障碍 (ID) 和牙龈过度生长 (FHEIG)。迄今为止，全世界仅描述了不超过 9 例 FHEIG 患者，对 KCNK4 相关疾病中的癫痫表型仍知之甚少。
我们在一名患有耐药性夜间发作、轻度 ID 和发育不良特征的患者中发现了 KCNK4 中的一种新的从头发生 p.(Gly139Arg)变异。该变异的计算机分析强烈提示具有获得性功能效应。我们对以前发表的病例进行了回顾性审查，重点关注癫痫特征和对各种治疗的反应。
迄今为止，KCNK4 相关疾病的 8/10 例患者报告有癫痫。发作的平均年龄为 1.8 岁，最常见的发作类型为局灶性双侧强直阵挛性 (5/8)。钠通道阻滞剂和丙戊酸钠对大多数患者有效，但 3/8 的癫痫耐药。我们的患者在使用碳酸酐酶抑制剂噻嗪治疗后癫痫发作得到了改善。有趣的是，该患者表现出周围神经兴奋性过高综合征的特征，这是以前在钾通道病中未描述过的现象，其原因是钾电导增加。
KCNK4 中的获得性功能变异导致一系列癫痫，从良性孤立性癫痫到癫痫性脑病不等，最常见的观察到局灶性双侧强直阵挛性发作。重要的是，一小部分患者表现出轻度的非神经外表现，没有特征性的面部畸形或全身性多毛症。本报告扩展了 KNCK4 相关疾病的表型谱，并为这一罕见神经发育综合征的临床异质性提供了新的见解。
