Research progress in the genetic pathogenesis of epilepsy and plant-based drug therapy_Journal of Epilepsy

Authors：

JIA Minze ¹ ,  QIAO Yanyan ²

1. Beijing Chengzhi Life Science Co., Ltd., Beijing 100084, China;
2. Geriatric Department, Yuquan Hospital (Tsinghua University Integrated Traditional Chinese and Western Medicine Hospital), Tsinghua University, Beijing 100049, China;

Corresponding author：

QIAO Yanyan, Email: yan_qiao55@aliyun.com

Keywords：

Epilepsy; Genetic factors; Plant-based drug

DOI：

10.7507/2096-0247.202310002

Video：

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Epilepsy is a chronic brain dysfunction disease with complex and diverse causes, but 70%-80% of patients do not have obvious characteristic phenotypic symptoms. In order to provide precise treatment for epilepsy patients, research on the genetic pathogenic factors and pathogenesis of epilepsy has attracted much attention. Different types of epilepsy are constantly found to be closely related to mutations in specific genes, such as SCN1A, KCNA2, KCNT1, GABRA1, TSCs, CDKL5, and so on. Therefore, the development of broad-spectrum antiepileptic drugs is very difficult. However, plant-based drugs or functional ingredients derived from traditional medicinal herbs, such as cannabinol, aconitine, and dodecenal, will expand the development of safer and more effective anti epileptic drugs.

Citation： JIA Minze, QIAO Yanyan. Research progress in the genetic pathogenesis of epilepsy and plant-based drug therapy. Journal of Epilepsy, 2023, 9(6): 498-502. doi: 10.7507/2096-0247.202310002 Copy

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2.	Gandhi T, Panigrahi BK, Bhatia M, et al. Expert model for detection of epilepticactivity in EEG signature. Expert Systems with Applications, 2010, 37(4): 3513-3520.
3.	Niedermeyer E, Lopes da Silva F. Electroencephalography: basic principles, clinical applications, and related fields, 5th Ed. Lippincott Williams & Wilkins, Philadelphia, 2005: 526.
4.	Kjeldsen MJ, Corey LA, Christensen K, et al. Epileptic seizures and syndromes in twins: the importance of genetic factors. Epilepsy Res, 2003, 55: 137-146.
5.	Helbig I, Scheffer IE, Mulley JC, et al. Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol, 2008, 7: 231-245.
6.	Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy (Dravet syndrome). Epileptic Syndr Infancy Child Adolesc, 2005, 4: 89-113.
7.	Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+ 2. Nat Genet, 2000, 24: 343-345.
8.	Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. New Engl J Med, 2013, 368: 1971-1979.
9.	Comi AM. Presentation, diagnosis, pathophysiology and treatment of the neurologic features of Sturge-Weber Syndrome. Neurol, 2011, 17: 179-184.
10.	Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med. Genet, 2006, 43: 729-734.
11.	Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Curr Opin Neurol, 2017, 30(2): 193-199.
12.	Johannesen K, Marini C, Pfeffer S, et al. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology, 2016, 87(11): 1140-1151.
13.	Kodera H, Ohba C, Kato M, et al. De novo GABRA1 mutations in Ohtahara and West syndromes. Epilepsia, 2016, 57: 566-573.
14.	Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet, 2010, 42: 1021-1026.
15.	Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet, 2013, 45: 1073-1076.
16.	Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet, 2013, 45: 1061-1066.
17.	Syrbe S, Hedrich UBS, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet, 2015, 47: 393-399.
18.	Allou L, Julia S, Amsallem D, et al. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease. Clin Genet, 2017, 91(3): 431-440.
19.	Corbett MA, Bellows ST, Li M, et al. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology, 2016, 87(19): 1975-1984.
20.	Ohba C, Kato M, Takahashi N, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia, 2015, 56: e121-e128.
21.	Guerrini R, Balestrini S, Wirrell EC, et al. Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies. Neurology, 2021, 97: 817-831.
22.	Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia, 1998, 39(5): 508-512.
23.	Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia, 2015, 56(5): 685-691.
24.	Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain, 2019, 142(8): 2303-2318.
25.	Fruscione F, Valente P, Sterlini B, et al. PRRT2 controls neuronal excitability by negatively modulating Na⁺ channel 1.2/1.6 activity. Brain, 2018, 141(4): 1000-1016.
26.	Johannesen KM, Gardella E, Linnankivi T, et al. Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia, 2018, 59(2): 389-402.
27.	Löscher W. Single-target versus multi-target drugs versus combinations of drugs with multiple targets: preclinical and clinical evidence for the treatment or prevention of epilepsy. Front Pharmacol, 2021, 12: 730257.
28.	Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology, 2015, 84: 480-489.
29.	Rían W Manville, Geoffrey W. Abbott. Cilantro leaf harbors a potent potassium channel-activating anticonvulsant. FASEB J, 2019, 33(10): 11349-11363.
30.	Devinsky O, Cross JH, Laux FL, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med, 2017, 376: 2011-2020.
31.	Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med, 2018, 378(20): 1888-1897.
32.	Vanoye CG, Gurnett CA, Holland KD, et al. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis, 2014, 62: 313-322.
33.	Smith RS, Kenny CJ, Ganesh V, et al. Sodium channel SCN3A (NaV1. 3) regulation of human cerebral cortical folding and oral motor development. Neuron, 2018, 99(5): 905-913.
34.	Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal, 2003, 15(2): 151-159.
35.	Li X, Xu F, Xu H, et al. Structural basis for modulation of human NaV1. 3 by clinical drug and selective antagonist. Nat Commun, 2022, 13(1): 1286-1295.

1. Sanei S, Chambers JA. EEG signal processing, John Wiley & Sons Ltd, Chichester, 2007: 161.
2. Gandhi T, Panigrahi BK, Bhatia M, et al. Expert model for detection of epilepticactivity in EEG signature. Expert Systems with Applications, 2010, 37(4): 3513-3520.
3. Niedermeyer E, Lopes da Silva F. Electroencephalography: basic principles, clinical applications, and related fields, 5th Ed. Lippincott Williams & Wilkins, Philadelphia, 2005: 526.
4. Kjeldsen MJ, Corey LA, Christensen K, et al. Epileptic seizures and syndromes in twins: the importance of genetic factors. Epilepsy Res, 2003, 55: 137-146.
5. Helbig I, Scheffer IE, Mulley JC, et al. Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol, 2008, 7: 231-245.
6. Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy (Dravet syndrome). Epileptic Syndr Infancy Child Adolesc, 2005, 4: 89-113.
7. Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+ 2. Nat Genet, 2000, 24: 343-345.
8. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. New Engl J Med, 2013, 368: 1971-1979.
9. Comi AM. Presentation, diagnosis, pathophysiology and treatment of the neurologic features of Sturge-Weber Syndrome. Neurol, 2011, 17: 179-184.
10. Archer HL, Evans J, Edwards S, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med. Genet, 2006, 43: 729-734.
11. Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Curr Opin Neurol, 2017, 30(2): 193-199.
12. Johannesen K, Marini C, Pfeffer S, et al. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology, 2016, 87(11): 1140-1151.
13. Kodera H, Ohba C, Kato M, et al. De novo GABRA1 mutations in Ohtahara and West syndromes. Epilepsia, 2016, 57: 566-573.
14. Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet, 2010, 42: 1021-1026.
15. Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet, 2013, 45: 1073-1076.
16. Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet, 2013, 45: 1061-1066.
17. Syrbe S, Hedrich UBS, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet, 2015, 47: 393-399.
18. Allou L, Julia S, Amsallem D, et al. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease. Clin Genet, 2017, 91(3): 431-440.
19. Corbett MA, Bellows ST, Li M, et al. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology, 2016, 87(19): 1975-1984.
20. Ohba C, Kato M, Takahashi N, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia, 2015, 56: e121-e128.
21. Guerrini R, Balestrini S, Wirrell EC, et al. Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies. Neurology, 2021, 97: 817-831.
22. Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia, 1998, 39(5): 508-512.
23. Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia, 2015, 56(5): 685-691.
24. Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain, 2019, 142(8): 2303-2318.
25. Fruscione F, Valente P, Sterlini B, et al. PRRT2 controls neuronal excitability by negatively modulating Na⁺ channel 1.2/1.6 activity. Brain, 2018, 141(4): 1000-1016.
26. Johannesen KM, Gardella E, Linnankivi T, et al. Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia, 2018, 59(2): 389-402.
27. Löscher W. Single-target versus multi-target drugs versus combinations of drugs with multiple targets: preclinical and clinical evidence for the treatment or prevention of epilepsy. Front Pharmacol, 2021, 12: 730257.
28. Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology, 2015, 84: 480-489.
29. Rían W Manville, Geoffrey W. Abbott. Cilantro leaf harbors a potent potassium channel-activating anticonvulsant. FASEB J, 2019, 33(10): 11349-11363.
30. Devinsky O, Cross JH, Laux FL, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med, 2017, 376: 2011-2020.
31. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med, 2018, 378(20): 1888-1897.
32. Vanoye CG, Gurnett CA, Holland KD, et al. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis, 2014, 62: 313-322.
33. Smith RS, Kenny CJ, Ganesh V, et al. Sodium channel SCN3A (NaV1. 3) regulation of human cerebral cortical folding and oral motor development. Neuron, 2018, 99(5): 905-913.
34. Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal, 2003, 15(2): 151-159.
35. Li X, Xu F, Xu H, et al. Structural basis for modulation of human NaV1. 3 by clinical drug and selective antagonist. Nat Commun, 2022, 13(1): 1286-1295.

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