Kessi Miriam, Peng Jing, Duan Haolin, He Hailan, Chen Baiyu, Xiong Juan, Wang Ying, Yang Lifen, Wang Guoli, Kiprotich Karlmax, Bamgbade Olumuyiwa A, He Fang, Yin Fei
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China.
Front Mol Neurosci. 2022 May 19;15:807202. doi: 10.3389/fnmol.2022.807202. eCollection 2022.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy.
This systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype-phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets.
The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021.
We identified pathogenic variants of ( = 24), ( = 8), ( = 2), and ( = 6) that were associated with epilepsy in 74 cases (43 , 20 , 2 , and 9 ). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising ( = 4), ( = 2), ( = 2), and ( = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults ( = 10) than children ( = 2). variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as variants p.S632W and delPPP (p.719-721), were associated with different phenotypes. p.L157V and p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers.
We recommend clinicians to include genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.
超极化激活的环核苷酸门控（HCN）电流可减少树突总和，抑制树突钙峰，并使抑制性γ-氨基丁酸（GABA）介导的突触后电位得以产生，从而抑制癫痫。然而，尚不清楚HCN电流增加是否会引发癫痫。我们推测HCN通道基因的功能获得性（GOF）和功能丧失性（LOF）变异可能导致癫痫。
本系统评价旨在总结HCN通道病在癫痫中的作用，更新患者的遗传学发现，建立基因型与表型的相关性，并讨论动物模型、GOF和LOF机制以及潜在的治疗靶点。
本评价按照系统评价和Meta分析的首选报告项目声明进行，涵盖截至2021年8月的所有年份。
我们在74例患者（43例、20例、2例和9例）中鉴定出与癫痫相关的、、和的致病性变异。癫痫与GOF和LOF变异相关，其机制尚不确定。不到一半的病例实现无癫痫发作，部分患者发展为药物难治性癫痫。在这74例患者中，12例（16.2%）死亡，包括（4例）、（2例）、（2例）和（4例）。在死亡病例中，10例（83%）死于癫痫性猝死（SUDEP），2例（16.7%）死于心肺功能衰竭。SUDEP在成人（10例）中比儿童（2例）更常见。变异p.M234R、p.C329S、p.V414M、p.M153I和p.M305L，以及变异p.S632W和delPPP（p.719 - 721）与不同表型相关。p.L157V和p.R550C与遗传性全身性癫痫相关。有几种HCN动物模型、药理学靶点和调节剂，但尚未开发出确切的药物。目前，尚无HCN通道开放剂。
我们建议临床医生将基因纳入癫痫基因检测面板。研究人员应通过确定每个已鉴定的致病性变异的特定神经元亚型和神经解剖位置，探索GOF和LOF变异可能的潜在机制。研究人员应鉴定具有高结合亲和力的特定HCN通道开放剂和阻滞剂。这些信息将明确HCN通道病在癫痫中的作用，并为开发靶向治疗提供机会。
