Pathogenic mechanisms and precision therapy research progress of voltage-gated sodium channels in hereditary epilepsy_Journal of Epilepsy

Authors：

YANG Xinyu ,  LIU Chao

Neurology Center, The First Hospital of Changsha·Changsha Hospital Affiliated to Xiangya Medical College, Central South University, Changsha 410005, China;

Corresponding?author：

LIU Chao, Email: liuchao0452@163.com

Keywords：

Voltage-gated sodium channel; Hereditary epilepsy; Loss of function; Gain of function; Precision therapy

DOI：

10.7507/2096-0247.202604011

Video：

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Abstract Full text Figures/Tables Video References Cited by

Epilepsy is a highly prevalent neurological disorder worldwide. With the widespread application of genetic testing, the critical role of genetic factors in epilepsy has been increasingly recognized. Mutations in voltage-gated sodium channels constitute the primary etiology of hereditary epilepsy. Composed of α and β subunits, these channels exhibit prominent cell-type specificity and developmental temporal dependence in their distribution across the central nervous system. Sodium channel mutations exert bidirectional pathogenic effects, namely loss of function (LOF) and gain of function (GOF). LOF mutations induce network disinhibition by impairing the function of GABAergic inhibitory interneurons, whereas GOF mutations directly amplify the firing of excitatory pyramidal neurons and trigger hyperexcitability. The combined effects of LOF and GOF determine epileptic phenotypes and drug responsiveness. This paper systematically reviews the structure, genetic characteristics and bidirectional pathogenic mechanisms of sodium channels, the phenotypic spectrum of key subtypes (SCN1A, SCN2A, SCN3A, SCN8A, SCN1B), research models, as well as precision therapeutic strategies. It provides up-to-date research advances for mechanistic investigation and individualized precision clinical diagnosis and treatment of hereditary epilepsy.

Citation： YANG Xinyu, LIU Chao. Pathogenic mechanisms and precision therapy research progress of voltage-gated sodium channels in hereditary epilepsy. Journal of Epilepsy, 2026, 12(5): 422-429. doi: 10.7507/2096-0247.202604011 Copy

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2.	Thakran S, Guin D, Singh P, et al. Genetic landscape of common epilepsies: advancing towards precision in treatment[J]. Int J Mol Sci, 2020, 21(20): 7784.
3.	Mulley JC, Scheffer IE, Petrou S, et al. SCN1A mutations and epilepsy [J]. Hum Mutat. 2005; 25(6): 535-542.
4.	Catterall WA. Voltage-gated sodium channels at 60: structure, function and pathophysiology[J]. J Physiol, 2012, 590(11): 2577-2589.
5.	Goldin AL. Resurgence of sodium channel research[J]. Annu Rev Physiol, 2001, 63: 871-894.
6.	Meisler MH, Hill SF, Yu W. Sodium channelopathies in neurodevelopmental disorders[J]. Nat Rev Neurosci, 2021, 22(3): 152-166.
7.	Catterall WA, Lenaeus MJ, Gamal El-Din TM. Structure and pharmacology of voltage-gated sodium and calcium channels[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 133-154.
8.	Heinemann SH, Terlau H, Stühmer W, et al. Calcium channel characteristics conferred on the sodium channel by single mutations[J]. Nature, 1992, 356(6368): 441-443.
9.	West JW, Patton DE, Scheuer T, et al. A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation[J]. Proc Natl Acad Sci USA, 1992, 89(22): 10910-10914.
10.	Grieco TM, Malhotra JD, Chen C, et al. Open-channel block by the cytoplasmic tail of sodium channel beta4 as a mechanism for resurgent sodium current[J]. Neuron, 2005, 45(2): 233-244.
11.	Brackenbury WJ, Isom LL. Na channel β subunits: overachievers of the ion channel family[J]. Front Pharmacol, 2011, 2: 53.
12.	Chen C, Calhoun JD, Zhang Y, et al. Identification of the cysteine residue responsible for disulfide linkage of Na⁺ channel α and β2 subunits[J]. J Biol Chem, 2012, 287(46): 39061-39069.
13.	Buffington SA, Rasband MN. Na⁺ channel-dependent recruitment of Na_Vβ4 to axon initial segments and nodes of Ranvier[J]. J Neurosci, 2013, 33(14): 6191-6202.
14.	Rasband MN. The axon initial segment and the maintenance of neuronal polarity[J]. Nat Rev Neurosci, 2010, 11(8): 552-562.
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17.	Boiko T, Rasband MN, Levinson SR, et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon[J]. Neuron, 2001, 30(1): 91-104.
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19.	Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy[J]. Am J Hum Genet, 2001, 68(6): 1327-1332.
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28.	Wagnon JL, Korn MJ, Parent R, et al. Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy[J]. Hum Mol Genet, 2015, 24(2): 506-515.
29.	Chever O, Zerimech S, Scalmani P, et al. Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and Na_V1.1 channels [J]. J Clin Invest, 2021, 131(21): e142203.
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33.	Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome [J]. Epilepsia, 2011, 52 Suppl 2: 24-29.
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37.	中國抗癲癇協會創新與轉化專業委員會, 中華醫學會兒科學分會罕見病學組, 中華醫學會兒科學分會神經學組. Dravet綜合征診斷與治療的中國專家共識[J]. 癲癇雜志, 2024, 10(1): 1-11.Special Committee on Innovation and Translation, China Association Against Epilepsy; Rare Diseases Subgroup, Society of Pediatrics, Chinese Medical Association; Neurology Subgroup, Society of Pediatrics, Chinese Medical Association. Chinese expert consensus on the diagnosis and treatment of Dravet syndrome[J]. Journal of Epilepsy, 2024, 10(1): 1-11.
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39.	Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders[J]. Brain, 2017, 140(5): 1316-1336.
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43.	Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy[J]. Neurology, 2015, 84(5): 480-489.
44.	Wagnon JL, Barker BS, Ottolini M, et al. Loss-of-function variants of SCN8A in intellectual disability without seizures[J]. Neurol Genet, 2017, 3(4): e170.
45.	Gertler TS, Carvill GL. SCN8A: when neurons are so excited, they just can't hide it[J]. Epilepsy Curr, 2019, 19(4): 269-271.
46.	Johnson JP, Focken T, Khakh K, et al. NBI-921352, a first-in-class, Na_V1.6 selective, sodium channel inhibitor that prevents seizures in SCN8A gain-of-function mice, and wild-type mice and rats [J]. Elife, 2022, 11: e72468.
47.	Beckh S, Noda M, Lübbert H, Numa S. Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development[J]. EMBO J, 1989, 8(12): 3611-3616.
48.	Zaman T, Helbig KL, Clatot J, et al. SCN3A-related neurodevelopmental disorder: a spectrum of epilepsy and brain malformation [J]. Ann Neurol, 2020, 88(2): 348-362.
49.	Smith RS, Kenny CJ, Ganesh V, et al. Sodium channel SCN3A (Na_V1.3) regulation of human cerebral cortical folding and oral motor development [J]. Neuron, 2018, 99(5): 905-913. e7.
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1. Thijs RD, Surges R, O'Brien TJ, et al. Epilepsy in adults[J]. Lancet, 2019, 393(10172): 689-701.
2. Thakran S, Guin D, Singh P, et al. Genetic landscape of common epilepsies: advancing towards precision in treatment[J]. Int J Mol Sci, 2020, 21(20): 7784.
3. Mulley JC, Scheffer IE, Petrou S, et al. SCN1A mutations and epilepsy [J]. Hum Mutat. 2005; 25(6): 535-542.
4. Catterall WA. Voltage-gated sodium channels at 60: structure, function and pathophysiology[J]. J Physiol, 2012, 590(11): 2577-2589.
5. Goldin AL. Resurgence of sodium channel research[J]. Annu Rev Physiol, 2001, 63: 871-894.
6. Meisler MH, Hill SF, Yu W. Sodium channelopathies in neurodevelopmental disorders[J]. Nat Rev Neurosci, 2021, 22(3): 152-166.
7. Catterall WA, Lenaeus MJ, Gamal El-Din TM. Structure and pharmacology of voltage-gated sodium and calcium channels[J]. Annu Rev Pharmacol Toxicol, 2020, 60: 133-154.
8. Heinemann SH, Terlau H, Stühmer W, et al. Calcium channel characteristics conferred on the sodium channel by single mutations[J]. Nature, 1992, 356(6368): 441-443.
9. West JW, Patton DE, Scheuer T, et al. A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation[J]. Proc Natl Acad Sci USA, 1992, 89(22): 10910-10914.
10. Grieco TM, Malhotra JD, Chen C, et al. Open-channel block by the cytoplasmic tail of sodium channel beta4 as a mechanism for resurgent sodium current[J]. Neuron, 2005, 45(2): 233-244.
11. Brackenbury WJ, Isom LL. Na channel β subunits: overachievers of the ion channel family[J]. Front Pharmacol, 2011, 2: 53.
12. Chen C, Calhoun JD, Zhang Y, et al. Identification of the cysteine residue responsible for disulfide linkage of Na⁺ channel α and β2 subunits[J]. J Biol Chem, 2012, 287(46): 39061-39069.
13. Buffington SA, Rasband MN. Na⁺ channel-dependent recruitment of Na_Vβ4 to axon initial segments and nodes of Ranvier[J]. J Neurosci, 2013, 33(14): 6191-6202.
14. Rasband MN. The axon initial segment and the maintenance of neuronal polarity[J]. Nat Rev Neurosci, 2010, 11(8): 552-562.
15. Hu W, Tian C, Li T, et al. Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation [J]. Nat Neurosci, 2009, 12(8): 996-1002.
16. Ogiwara I, Miyamoto H, Morita N, et al. Na_V1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation [J]. J Neurosci, 2007, 27(22): 5903-5914.
17. Boiko T, Rasband MN, Levinson SR, et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon[J]. Neuron, 2001, 30(1): 91-104.
18. Meng H, Xu HQ, Yu L, et al. The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype[J]. Hum Mutat, 2015, 36(6): 573-580.
19. Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy[J]. Am J Hum Genet, 2001, 68(6): 1327-1332.
20. Klassen T, Davis C, Goldman A, et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy[J]. Cell, 2011, 145(7): 1036-1048.
21. Brunklaus A, Lal D. Sodium channel epilepsies and neurodevelopmental disorders: from disease mechanisms to clinical application[J]. Dev Med Child Neurol, 2020, 62(7): 784-792.
22. Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms[J]. Epilepsia, 2010, 51(9): 1650-1658.
23. Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy[J]. Nat Neurosci, 2006, 9(9): 1142-1149.
24. Tai C, Abe Y, Westenbroek RE, et al. Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome[J]. Proc Natl Acad Sci USA, 2014, 111(30): E3139-E3148.
25. Martin MS, Dutt K, Papale LA, et al. Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities[J]. J Biol Chem, 2010, 285(13): 9823-9834.
26. Rusina E, Simonti M, Duprat F, et al. Voltage-gated sodium channels in genetic epilepsy: up and down of excitability[J]. J Neurochem, 2024, 168(12): 3872-3890.
27. Mao M, Mattei C, Rollo B, et al. Distinctive in vitro phenotypes in iPSC-derived neurons from patients with gain- and loss-of-function SCN2A developmental and epileptic encephalopathy[J]. J Neurosci, 2024, 44(8): e0692232023.
28. Wagnon JL, Korn MJ, Parent R, et al. Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy[J]. Hum Mol Genet, 2015, 24(2): 506-515.
29. Chever O, Zerimech S, Scalmani P, et al. Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and Na_V1.1 channels [J]. J Clin Invest, 2021, 131(21): e142203.
30. Lemaire L, Desroches M, Krupa M, et al. Modeling Na_V1.1/SCN1A sodium channel mutations in a microcircuit with realistic ion concentration dynamics suggests differential GABAergic mechanisms leading to hyperexcitability in epilepsy and hemiplegic migraine [J]. PLoS Comput Biol, 2021, 17(7): e1009239.
31. Makinson CD, Tanaka BS, Sorokin JM, et al. Regulation of Thalamic and Cortical Network Synchrony by SCN8A [J]. Neuron. 2017;93(5): 1165-1179. e6.
32. Scheffer IE, Nabbout R. SCN1A-related phenotypes: epilepsy and beyond [J]. Epilepsia, 2019, 60 Suppl 3: S17-S24.
33. Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome [J]. Epilepsia, 2011, 52 Suppl 2: 24-29.
34. Zhang YH, Burgess R, Malone JP, et al. Genetic epilepsy with febrile seizures plus: Refining the spectrum[J]. Neurology, 2017, 89(12): 1210-1219.
35. Brunklaus A, Brünger T, Feng T, et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications[J]. Brain, 2022, 145(11): 3816-3831.
36. Dutton SB, Makinson CD, Papale LA, et al. Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility[J]. Neurobiol Dis, 2013, 49: 211-220.
37. 中國抗癲癇協會創新與轉化專業委員會, 中華醫學會兒科學分會罕見病學組, 中華醫學會兒科學分會神經學組. Dravet綜合征診斷與治療的中國專家共識[J]. 癲癇雜志, 2024, 10(1): 1-11.Special Committee on Innovation and Translation, China Association Against Epilepsy; Rare Diseases Subgroup, Society of Pediatrics, Chinese Medical Association; Neurology Subgroup, Society of Pediatrics, Chinese Medical Association. Chinese expert consensus on the diagnosis and treatment of Dravet syndrome[J]. Journal of Epilepsy, 2024, 10(1): 1-11.
38. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group [J]. Lancet, 2000, 356(9242): 1638-1642.
39. Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders[J]. Brain, 2017, 140(5): 1316-1336.
40. Sanders SJ, Campbell AJ, Cottrell JR, et al. Progress in understanding and treating SCN2A-mediated disorders[J]. Trends Neurosci, 2018, 41(7): 442-456.
41. Xu R, Thomas EA, Jenkins M, et al. A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel[J]. Mol Cell Neurosci, 2007, 35(2): 292-301.
42. Li M, Jancovski N, Jafar-Nejad P, et al. Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model[J]. J Clin Invest, 2021, 131(23): e152079.
43. Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy[J]. Neurology, 2015, 84(5): 480-489.
44. Wagnon JL, Barker BS, Ottolini M, et al. Loss-of-function variants of SCN8A in intellectual disability without seizures[J]. Neurol Genet, 2017, 3(4): e170.
45. Gertler TS, Carvill GL. SCN8A: when neurons are so excited, they just can't hide it[J]. Epilepsy Curr, 2019, 19(4): 269-271.
46. Johnson JP, Focken T, Khakh K, et al. NBI-921352, a first-in-class, Na_V1.6 selective, sodium channel inhibitor that prevents seizures in SCN8A gain-of-function mice, and wild-type mice and rats [J]. Elife, 2022, 11: e72468.
47. Beckh S, Noda M, Lübbert H, Numa S. Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development[J]. EMBO J, 1989, 8(12): 3611-3616.
48. Zaman T, Helbig KL, Clatot J, et al. SCN3A-related neurodevelopmental disorder: a spectrum of epilepsy and brain malformation [J]. Ann Neurol, 2020, 88(2): 348-362.
49. Smith RS, Kenny CJ, Ganesh V, et al. Sodium channel SCN3A (Na_V1.3) regulation of human cerebral cortical folding and oral motor development [J]. Neuron, 2018, 99(5): 905-913. e7.
50. Meadows LS, Malhotra J, Loukas A, et al. Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1[J]. J Neurosci, 2002, 22(24): 10699-10709.
51. Aeby A, Sculier C, Bouza AA, et al. SCN1B-linked early infantile developmental and epileptic encephalopathy [J]. Ann Clin Transl Neurol, 2019, 6(12): 2354-2367.
52. Chen C, Westenbroek RE, Xu X, et al. Mice lacking sodium channel beta1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture[J]. J Neurosci, 2004, 24(16): 4030-4042.
53. Siekierska A, Isrie M, Liu Y, et al. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy[J]. Neurology, 2016, 86(23): 2162-2170.
54. Fruscione F, Valente P, Sterlini B, et al. PRRT2 controls neuronal excitability by negatively modulating Na⁺ channel 1.2/1.6 activity [J]. Brain, 2018, 141(4): 1000-1016.
55. Lopez AY, Wang X, Xu M, et al. Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder[J]. Mol Psychiatry, 2017, 22(10): 1464-1472.
56. Bechi G, Scalmani P, Schiavon E, et al. Pure haploinsufficiency for Dravet syndrome Na(V)1.1 (SCN1A) sodium channel truncating mutations [J]. Epilepsia, 2012, 53(1): 87-100.
57. Jiao J, Yang Y, Shi Y, et al. Modeling Dravet syndrome using induced pluripotent stem cells (iPSCs) and directly converted neurons[J]. Hum Mol Genet, 2013, 22(21): 4241-4252.
58. Liu Y, Lopez-Santiago LF, Yuan Y, et al. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism[J]. Ann Neurol, 2013, 74(1): 128-139.
59. Han S, Tai C, Westenbroek RE, et al. Autistic-like behaviour in Scn1a^+/- mice and rescue by enhanced GABA-mediated neurotransmission[J]. Nature, 2012, 489(7416): 385-390.
60. Baraban SC, Dinday MT, Hortopan GA. Drug screening in SCN1A zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment[J]. Nat Commun, 2013, 4: 2410.
61. Hines ML, Carnevale NT. The NEURON simulation environment[J]. Neural Comput, 1997, 9(6): 1179-1209.
62. Spampanato J, Aradi I, Soltesz I, et al. Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus[J]. J Neurophysiol, 2004, 91(5): 2040-2050.
63. Han Z, Chen C, Christiansen A, et al. Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome[J]. Sci Transl Med, 2020, 12(558): eaaz6100.
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Journal of Epilepsy

Pathogenic mechanisms and precision therapy research progress of voltage-gated sodium channels in hereditary epilepsy

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