Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

Overview

Journal Front Pharmacol

Date 2020 Oct 5

PMID 33013363

Citations 51

Authors

Luis Felipe Santos Menezes

Elias Ferreira Sabia Junior

Diogo Vieira Tibery

Lilian Dos Anjos Carneiro

Elisabeth Ferroni Schwartz

Affiliations

Soon will be listed here.

Abstract

Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7.

Citing Articles

Transcriptomic analyses of human brains with Alzheimer's disease identified dysregulated epilepsy-causing genes.

Eteleeb A, Alves S, Buss S, Shafi M, Press D, Garcia-Cairasco N medRxiv. 2025; .

PMID: 39974070 PMC: 11838929. DOI: 10.1101/2025.01.02.25319900.

Voltage-gated sodium channels in excitable cells as drug targets.

Alsaloum M, Dib-Hajj S, Page D, Ruben P, Krainer A, Waxman S Nat Rev Drug Discov. 2025; .

PMID: 39901031 DOI: 10.1038/s41573-024-01108-x.

Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.

Medyanik A, Anisimova P, Kustova A, Tarabykin V, Kondakova E Biomolecules. 2025; 15(1).

PMID: 39858526 PMC: 11763800. DOI: 10.3390/biom15010133.

Tetrodotoxin: The State-of-the-Art Progress in Characterization, Detection, Biosynthesis, and Transport Enrichment.

Zhang X, Qiao K, Cui R, Xu M, Cai S, Huang Q Mar Drugs. 2024; 22(12).

PMID: 39728106 PMC: 11676112. DOI: 10.3390/md22120531.

A Comprehensive Overview of the Current Status and Advancements in Various Treatment Strategies against Epilepsy.

Waris A, Siraj M, Khan A, Lin J, Asim M, Alhumaydh F ACS Pharmacol Transl Sci. 2024; 7(12):3729-3757.

PMID: 39698272 PMC: 11650742. DOI: 10.1021/acsptsci.4c00494.

References

Meng H, Xu H, Yu L, Lin G, He N, Su T . The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat. 2015; 36(6):573-80. DOI: 10.1002/humu.22782. View

Nabbout R, Gennaro E, Dalla Bernardina B, Dulac O, Madia F, Bertini E . Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology. 2003; 60(12):1961-7. DOI: 10.1212/01.wnl.0000069463.41870.2f. View

Sun W, Wagnon J, Mahaffey C, Briese M, Ule J, Frankel W . Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice. J Physiol. 2012; 591(1):241-55. PMC: 3630783. DOI: 10.1113/jphysiol.2012.240168. View

Spampanato J, Kearney J, de Haan G, McEwen D, Escayg A, Aradi I . A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for beta subunit interaction. J Neurosci. 2004; 24(44):10022-34. PMC: 6730248. DOI: 10.1523/JNEUROSCI.2034-04.2004. View

Schiavon E, Sacco T, Cassulini R, Gurrola G, Tempia F, Possani L . Resurgent current and voltage sensor trapping enhanced activation by a beta-scorpion toxin solely in Nav1.6 channel. Significance in mice Purkinje neurons. J Biol Chem. 2006; 281(29):20326-37. DOI: 10.1074/jbc.M600565200. View

Singh N, Pappas C, Dahle E, Claes L, Pruess T, De Jonghe P . A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet. 2009; 5(9):e1000649. PMC: 2730533. DOI: 10.1371/journal.pgen.1000649. View

Allen A, Cossette P, Delanty N, Eichler E, Goldstein D, Han Y . De novo mutations in epileptic encephalopathies. Nature. 2013; 501(7466):217-21. PMC: 3773011. DOI: 10.1038/nature12439. View

McMichael G, Bainbridge M, Haan E, Corbett M, Gardner A, Thompson S . Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy. Mol Psychiatry. 2015; 20(2):176-82. DOI: 10.1038/mp.2014.189. View

de Kovel C, Meisler M, Brilstra E, van Berkestijn F, van t Slot R, van Lieshout S . Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res. 2014; 108(9):1511-8. PMC: 4490185. DOI: 10.1016/j.eplepsyres.2014.08.020. View

10.

Yang C, Hua Y, Zhang W, Xu J, Xu L, Gao F . Variable epilepsy phenotypes associated with heterozygous mutation in the SCN9A gene: report of two cases. Neurol Sci. 2018; 39(6):1113-1115. DOI: 10.1007/s10072-018-3300-y. View

11.

Ohmori I, Kahlig K, Rhodes T, Wang D, George Jr A . Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy. Epilepsia. 2006; 47(10):1636-42. DOI: 10.1111/j.1528-1167.2006.00643.x. View

12.

Kearney J, Plummer N, Smith M, Kapur J, Cummins T, Waxman S . A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience. 2001; 102(2):307-17. DOI: 10.1016/s0306-4522(00)00479-6. View

13.

Falco-Walter J, Scheffer I, Fisher R . The new definition and classification of seizures and epilepsy. Epilepsy Res. 2017; 139:73-79. DOI: 10.1016/j.eplepsyres.2017.11.015. View

14.

Estacion M, Waxman S . The response of Na(V)1.3 sodium channels to ramp stimuli: multiple components and mechanisms. J Neurophysiol. 2012; 109(2):306-14. DOI: 10.1152/jn.00438.2012. View

15.

Halvorsen M, Petrovski S, Shellhaas R, Tang Y, Crandall L, Goldstein D . Mosaic mutations in early-onset genetic diseases. Genet Med. 2015; 18(7):746-9. PMC: 4929028. DOI: 10.1038/gim.2015.155. View

16.

Esterhuizen A, Mefford H, Ramesar R, Wang S, Carvill G, Wilmshurst J . Dravet syndrome in South African infants: Tools for an early diagnosis. Seizure. 2018; 62:99-105. PMC: 6261486. DOI: 10.1016/j.seizure.2018.09.010. View

17.

Colosimo E, Gambardella A, Mantegazza M, Labate A, Rusconi R, Schiavon E . Electroclinical features of a family with simple febrile seizures and temporal lobe epilepsy associated with SCN1A loss-of-function mutation. Epilepsia. 2007; 48(9):1691-1696. DOI: 10.1111/j.1528-1167.2007.01153.x. View

18.

Yang Y, Huang C, Kuo C . Lidocaine, carbamazepine, and imipramine have partially overlapping binding sites and additive inhibitory effect on neuronal Na+ channels. Anesthesiology. 2010; 113(1):160-74. DOI: 10.1097/ALN.0b013e3181dc1dd6. View

19.

Bagnasco I, Dassi P, Ble R, Vigliano P . A relatively mild phenotype associated with mutation of SCN8A. Seizure. 2018; 56:47-49. DOI: 10.1016/j.seizure.2018.01.021. View

20.

Ebrahimi A, Houshmand M, Tonekaboni S, Fallah Mahboob Passand M, Zainali S, Moghadasi M . Two novel mutations in SCN1A gene in Iranian patients with epilepsy. Arch Med Res. 2010; 41(3):207-14. DOI: 10.1016/j.arcmed.2010.04.007. View