Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions

Overview

Journal Front Neurol

Specialty Neurology

Date 2021 Apr 12

PMID 33841294

Citations 21

Authors

Ibitayo Abigail Ademuwagun

Solomon Oladapo Rotimi

Steffen Syrbe

Yvonne Ukamaka Ajamma

Ezekiel Adebiyi

Affiliations

Soon will be listed here.

Abstract

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are , and genes that are highly expressed in the brain. Genomic studies have revealed inherited and mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

Citing Articles

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.

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.

Seizure Susceptibility in E-cigarette Users: Navigating the Clinical Management and Public Health Considerations.

Toluwalashe S, Aremu O, Ekerin O, Lawal A, Oluwatobi F, Adebayo V Subst Use. 2024; 18:29768357241304298.

PMID: 39618920 PMC: 11607758. DOI: 10.1177/29768357241304298.

Salty Battle to Sudden Death: Young vs. Old, Brain vs. Heart.

Iyer S, Simeone K Epilepsy Curr. 2024; 24(6):437-439.

PMID: 39540134 PMC: 11556351. DOI: 10.1177/15357597241289672.

Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels.

Akbari Ahangar A, Elhanafy E, Blanton H, Li J iScience. 2024; 27(9):110678.

PMID: 39286500 PMC: 11404175. DOI: 10.1016/j.isci.2024.110678.

References

Higurashi N, Uchida T, Lossin C, Misumi Y, Okada Y, Akamatsu W . A human Dravet syndrome model from patient induced pluripotent stem cells. Mol Brain. 2013; 6:19. PMC: 3655893. DOI: 10.1186/1756-6606-6-19. View

Mukuku O, Nawej P, Bugeme M, Nduu F, Mawaw P, Luboya O . Epidemiology of Epilepsy in Lubumbashi, Democratic Republic of Congo. Neurol Res Int. 2020; 2020:5621461. PMC: 7204195. DOI: 10.1155/2020/5621461. View

Michiels J, Te Morsche R, Jansen J, Drenth J . Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7. Arch Neurol. 2005; 62(10):1587-90. DOI: 10.1001/archneur.62.10.1587. 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

Lossin C, Wang D, Rhodes T, Vanoye C, George Jr A . Molecular basis of an inherited epilepsy. Neuron. 2002; 34(6):877-84. DOI: 10.1016/s0896-6273(02)00714-6. View

Sharkey L, Cheng X, Drews V, Buchner D, Jones J, Justice M . The ataxia3 mutation in the N-terminal cytoplasmic domain of sodium channel Na(v)1.6 disrupts intracellular trafficking. J Neurosci. 2009; 29(9):2733-41. PMC: 2679640. DOI: 10.1523/JNEUROSCI.6026-08.2009. 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

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

Chen S, Gurha P, Lombardi R, Ruggiero A, Willerson J, Marian A . The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circ Res. 2013; 114(3):454-68. PMC: 3946717. DOI: 10.1161/CIRCRESAHA.114.302810. View

10.

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

11.

Lossin C . A catalog of SCN1A variants. Brain Dev. 2008; 31(2):114-30. DOI: 10.1016/j.braindev.2008.07.011. View

12.

Claes L, Deprez L, Suls A, Baets J, Smets K, Van Dyck T . The SCN1A variant database: a novel research and diagnostic tool. Hum Mutat. 2009; 30(10):E904-20. DOI: 10.1002/humu.21083. View

13.

Wolff M, Johannesen K, Hedrich U, Masnada S, Rubboli G, Gardella E . Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain. 2017; 140(5):1316-1336. DOI: 10.1093/brain/awx054. View

14.

Audenaert D, Claes L, Ceulemans B, Lofgren A, Van Broeckhoven C, De Jonghe P . A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology. 2003; 61(6):854-6. DOI: 10.1212/01.wnl.0000080362.55784.1c. View

15.

Blanchard M, Willemsen M, Walker J, Dib-Hajj S, Waxman S, Jongmans M . De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet. 2015; 52(5):330-7. PMC: 4413743. DOI: 10.1136/jmedgenet-2014-102813. View

16.

Ogiwara I, Nakayama T, Yamagata T, Ohtani H, Mazaki E, Tsuchiya S . A homozygous mutation of voltage-gated sodium channel β(I) gene SCN1B in a patient with Dravet syndrome. Epilepsia. 2012; 53(12):e200-3. DOI: 10.1111/epi.12040. View

17.

Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L . Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004; 41(3):171-4. PMC: 1735695. DOI: 10.1136/jmg.2003.012153. View

18.

Ramadan W, Patel N, Anazi S, Kentab A, Bashiri F, Hamad M . Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy. Clin Genet. 2017; 92(3):327-331. DOI: 10.1111/cge.12999. View

19.

Scheffer I, Harkin L, Grinton B, Dibbens L, Turner S, Zielinski M . Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain. 2006; 130(Pt 1):100-9. DOI: 10.1093/brain/awl272. View

20.

Tammaro P, Conti F, Moran O . Modulation of sodium current in mammalian cells by an epilepsy-correlated beta 1-subunit mutation. Biochem Biophys Res Commun. 2002; 291(4):1095-101. DOI: 10.1006/bbrc.2002.6570. View