Advances in the neurobiology and clinical diagnosis and treatment of hereditary developmental epileptic encephalopathies_Journal of Epilepsy

Authors：

ZHENG Xiaohong , ZHOU Youfeng ,  HU Chunhui

Department of Neurology, Fujian Children’s Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350014, China;

Corresponding author：

HU Chunhui, Email: huchunhui1989@126.com

Keywords：

Developmental epileptic encephalopathies; Neurobiological modelling; Gene; Therapy

DOI：

10.7507/2096-0247.202403005

Video：

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Developmental epileptic encephalopathies (DEEs) are a group of disorders characterized by early-onset seizures, abnormal electroencephalogram (EEG) patterns, and developmental delay or regression. They are characterized by complex etiology and are often refractory to treatment, severely impacting affected children, particularly infants and toddlers, and pose a challenge in pediatric neurology. In recent years, with the rise of precision medicine, an increasing number of pathogenic genes associated with DEEs have been discovered. However, the specific pathogenic mechanisms and signaling pathways of these genes in the body still require further investigation. This article primarily discusses the genetic patterns of DEEs and the selection of genetic testing, emphasizing the timing of genetic testing assisted by the epilepsy phenotype, especially in DEEs associated with single-gene mutations and new therapeutic drugs, to aid in clinical decision-making for DEEs. It also introduces the use of neurobiological models for DEE research to effectively advance epilepsy research, thereby enabling targeted gene therapy.

Citation： ZHENG Xiaohong, ZHOU Youfeng, HU Chunhui. Advances in the neurobiology and clinical diagnosis and treatment of hereditary developmental epileptic encephalopathies. Journal of Epilepsy, 2024, 10(3): 254-259. doi: 10.7507/2096-0247.202403005 Copy

1.	Scheffer IE, Liao JX. Deciphering the concepts behind "Epileptic encephalopathy" and "Developmental and epileptic encephalopathy". Eur J Paediatr Neurol, 2020, 24: 11-14.
2.	Specchio N, Curatolo P. Developmental and epileptic encephalopathies what we do and do not know. Brain, 2021, 144(1): 32-43.
3.	Matricardi S, Cestèle S, Trivisano M, et al. Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication. Epilepsia, 2023, 64(5): 1331-1347.
4.	Morrison-Levy N, Borlot F, Jain P, et al. Early-onset developmental and epileptic encephalopathies of infancy: an overview of the genetic basis and clinical features. Pediatr Neurol, 2021, 116: 85-94.
5.	Knowles JK, Helbig I, Metcalf CS, et al. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia, 2022, 63(10): 2461-2475.
6.	de la Torre A. The genetics of epilepsy in the clinical practice. Medicina (B Aires), 2023, 83(Suppl 4): 9-12.
7.	Bayat A, Bayat M, Rubboli G, et al. Epilepsy syndromes in the first year of life and usefulness of genetic testing for precision therapy. Genes (Basel), 2021, 812(7): 1051.
8.	Brunklaus A, Lal D. Sodium channel epilepsies and neurodevelopmental disorders: From disease mechanisms to clinical application. Dev Med Child Neurol, 2020, 62(7): 784-792.
9.	von Wrede R, Jeub M, Ariöz I, et al. Novel KCNH1 mutations associated with epilepsy: broadening the phenotypic spectrum of KCNH1-associated diseases. Genes (Basel), 2021, 21: 12(2)-132.
10.	Sampedro-Castañeda M, Baltussen LL, Lopes AT, et al. Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2. 3, altering inactivation kinetics and neuronal excitability. Nat Commun, 2023, 1114(1): 7830.
11.	金良, 陈语婕, 陈勇军. 发育性和癫痫性脑病遗传性病因及诊疗的研究进展. 遗传, 2023, 45(7): 553-567.
12.	Scott RC. Brains, complex systems and therapeutic opportunities in epilepsy. Seizure, 2021, 90: 155-159.
13.	Yu W, Hill SF, Xenakis JG, et al. Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse. Epilepsia, 2020, 61(12): 2847-2856.
14.	Shaimardanova AA, Chulpanova DS, Mullagulova AI, et al. Gene and cell therapy for epilepsy: a mini review. Front Mol Neurosci, 2022, 11;15: 868531.
15.	Previtali R, Prontera G, Alfei E, et al. Paradigm shift in the treatment of tuberous sclerosis: Effectiveness of everolimus. Pharmacol Res, 2023, 195: 106884.
16.	Lechuga L, Franz DN. Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures. Expert Rev Neurother, 2019, 19(10): 913-925.
17.	Overwater IE, Rietman AB, van Eeghen AM, et al. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives. Ther Clin Risk Manag, 2019, 15: 951-955.
18.	Johannessen Landmark C, Potschka H, Auvin S, et al. The role of new medical treatments for the management of developmental and epileptic encephalopathies: Novel concepts and results. Epilepsia, 2021, 62(4): 857-873.
19.	Privitera M, Bhathal H, Wong M, et al. Time to onset of cannabidiol (CBD) treatment effect in Lennox–Gastaut syndrome: analysis from two randomized controlled trials. Epilepsia, 2021, 62(5): 1130-1140.
20.	Specchio N, Pietrafusa N, Doccini V, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia, 2020, 61(11): 2405-2414.
21.	Balagura G, Cacciatore M, Grasso EA, et al. Fenfluramine for the treatment of Dravet syndrome and Lennox–Gastaut syndrome. CNS Drugs, 2020, 34(10): 1001-1007.
22.	Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia, 2021, 62(7): 98-102.
23.	Shcheglovitov A, Peterson RT. Screening platforms for genetic epilepsies-zebrafish, ipsc-derived neurons, and organoids. Neurotherapeutics, 2021, 18(3): 1478-1489.
24.	Hirose S, Tanaka Y, Shibata M, et al. Application of induced pluripotent stem cells in epilepsy. Mol Cell Neurosci, 2020, 108: 103535.
25.	Palmer EE, Howell K, Scheffer IE, et al. Natural history studies and clinical trial readiness for genetic developmental and epileptic encephalopathies. Neurotherapeutics, 2021, 18(3): 1432-1444.
26.	Tidball AM, Lopez-Santiago LF, Yuan Y, et al. Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons. Brain, 2020, 143(10): 3025-3040.
27.	Gordon A, Yoon SJ, Tran SS, et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat Neurosci, 2021, 24(3): 331-342.
28.	Morris G, Rowell R, Cunningham M, et al. Limitations of animal epilepsy research models: Can epileptic human tissue provide translational benefit? ALTEX, 2021, 38(3): 451-462.
29.	Takai A, Yamaguchi M, Yoshida H, et al. Investigating developmental and epileptic encephalopathy using drosophila melanogaster. Int J Mol Sci, 2020, 21(17): 6442.
30.	Çarçak N, Onat F, Sitnikova E, et al. Astrocytes as a target for therapeutic strategies in epilepsy: current insights. Front Mol Neurosci, 2023, 31(16): 1183775.
31.	Gawel K, Langlois M, Martins T, et al. Seizing the moment: zebrafish epilepsy models. Neurosci Biobehav Rev, 2020, 116: 1-20.
32.	D'Amora M, Galgani A, Marchese M, et al. Zebrafish as an innovative tool for epilepsy modeling: state of the art and potential future directions. Int J Mol Sci, 2023, 2224(9): 7702.
33.	Tiraboschi E, Martina S, van der Ent W, et al. New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome. Epilepsia, 2020, 61(3): 549-560.
34.	Suo G, Cao X, Zheng Y, et al. A de novo nonsense mutation of STXBP1 causes early-onset epileptic encephalopathy. Epilepsy Behav, 2021, 123: 108245.
35.	Deshpande LS, DeLorenzo RJ, Churn SB, et al. Neuronal-specific inhibition of endoplasmic reticulum Mg 2+/Ca 2+ ATPase Ca 2+ uptake in a mixed primary hippocampal culture model of status epilepticus. Brain Sci, 2020, 10(7): 438.
36.	Hansen SN, Holm A, Kauppinen S, et al. RNA therapeutics for epilepsy: an emerging modality for drug discovery. Epilepsia, 2023, 64(12): 3113-3129.

1. Scheffer IE, Liao JX. Deciphering the concepts behind "Epileptic encephalopathy" and "Developmental and epileptic encephalopathy". Eur J Paediatr Neurol, 2020, 24: 11-14.
2. Specchio N, Curatolo P. Developmental and epileptic encephalopathies what we do and do not know. Brain, 2021, 144(1): 32-43.
3. Matricardi S, Cestèle S, Trivisano M, et al. Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication. Epilepsia, 2023, 64(5): 1331-1347.
4. Morrison-Levy N, Borlot F, Jain P, et al. Early-onset developmental and epileptic encephalopathies of infancy: an overview of the genetic basis and clinical features. Pediatr Neurol, 2021, 116: 85-94.
5. Knowles JK, Helbig I, Metcalf CS, et al. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia, 2022, 63(10): 2461-2475.
6. de la Torre A. The genetics of epilepsy in the clinical practice. Medicina (B Aires), 2023, 83(Suppl 4): 9-12.
7. Bayat A, Bayat M, Rubboli G, et al. Epilepsy syndromes in the first year of life and usefulness of genetic testing for precision therapy. Genes (Basel), 2021, 812(7): 1051.
8. Brunklaus A, Lal D. Sodium channel epilepsies and neurodevelopmental disorders: From disease mechanisms to clinical application. Dev Med Child Neurol, 2020, 62(7): 784-792.
9. von Wrede R, Jeub M, Ariöz I, et al. Novel KCNH1 mutations associated with epilepsy: broadening the phenotypic spectrum of KCNH1-associated diseases. Genes (Basel), 2021, 21: 12(2)-132.
10. Sampedro-Castañeda M, Baltussen LL, Lopes AT, et al. Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2. 3, altering inactivation kinetics and neuronal excitability. Nat Commun, 2023, 1114(1): 7830.
11. 金良, 陈语婕, 陈勇军. 发育性和癫痫性脑病遗传性病因及诊疗的研究进展. 遗传, 2023, 45(7): 553-567.
12. Scott RC. Brains, complex systems and therapeutic opportunities in epilepsy. Seizure, 2021, 90: 155-159.
13. Yu W, Hill SF, Xenakis JG, et al. Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse. Epilepsia, 2020, 61(12): 2847-2856.
14. Shaimardanova AA, Chulpanova DS, Mullagulova AI, et al. Gene and cell therapy for epilepsy: a mini review. Front Mol Neurosci, 2022, 11;15: 868531.
15. Previtali R, Prontera G, Alfei E, et al. Paradigm shift in the treatment of tuberous sclerosis: Effectiveness of everolimus. Pharmacol Res, 2023, 195: 106884.
16. Lechuga L, Franz DN. Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures. Expert Rev Neurother, 2019, 19(10): 913-925.
17. Overwater IE, Rietman AB, van Eeghen AM, et al. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives. Ther Clin Risk Manag, 2019, 15: 951-955.
18. Johannessen Landmark C, Potschka H, Auvin S, et al. The role of new medical treatments for the management of developmental and epileptic encephalopathies: Novel concepts and results. Epilepsia, 2021, 62(4): 857-873.
19. Privitera M, Bhathal H, Wong M, et al. Time to onset of cannabidiol (CBD) treatment effect in Lennox–Gastaut syndrome: analysis from two randomized controlled trials. Epilepsia, 2021, 62(5): 1130-1140.
20. Specchio N, Pietrafusa N, Doccini V, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia, 2020, 61(11): 2405-2414.
21. Balagura G, Cacciatore M, Grasso EA, et al. Fenfluramine for the treatment of Dravet syndrome and Lennox–Gastaut syndrome. CNS Drugs, 2020, 34(10): 1001-1007.
22. Devinsky O, King L, Schwartz D, et al. Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder. Epilepsia, 2021, 62(7): 98-102.
23. Shcheglovitov A, Peterson RT. Screening platforms for genetic epilepsies-zebrafish, ipsc-derived neurons, and organoids. Neurotherapeutics, 2021, 18(3): 1478-1489.
24. Hirose S, Tanaka Y, Shibata M, et al. Application of induced pluripotent stem cells in epilepsy. Mol Cell Neurosci, 2020, 108: 103535.
25. Palmer EE, Howell K, Scheffer IE, et al. Natural history studies and clinical trial readiness for genetic developmental and epileptic encephalopathies. Neurotherapeutics, 2021, 18(3): 1432-1444.
26. Tidball AM, Lopez-Santiago LF, Yuan Y, et al. Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons. Brain, 2020, 143(10): 3025-3040.
27. Gordon A, Yoon SJ, Tran SS, et al. Long-term maturation of human cortical organoids matches key early postnatal transitions. Nat Neurosci, 2021, 24(3): 331-342.
28. Morris G, Rowell R, Cunningham M, et al. Limitations of animal epilepsy research models: Can epileptic human tissue provide translational benefit? ALTEX, 2021, 38(3): 451-462.
29. Takai A, Yamaguchi M, Yoshida H, et al. Investigating developmental and epileptic encephalopathy using drosophila melanogaster. Int J Mol Sci, 2020, 21(17): 6442.
30. Çarçak N, Onat F, Sitnikova E, et al. Astrocytes as a target for therapeutic strategies in epilepsy: current insights. Front Mol Neurosci, 2023, 31(16): 1183775.
31. Gawel K, Langlois M, Martins T, et al. Seizing the moment: zebrafish epilepsy models. Neurosci Biobehav Rev, 2020, 116: 1-20.
32. D'Amora M, Galgani A, Marchese M, et al. Zebrafish as an innovative tool for epilepsy modeling: state of the art and potential future directions. Int J Mol Sci, 2023, 2224(9): 7702.
33. Tiraboschi E, Martina S, van der Ent W, et al. New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome. Epilepsia, 2020, 61(3): 549-560.
34. Suo G, Cao X, Zheng Y, et al. A de novo nonsense mutation of STXBP1 causes early-onset epileptic encephalopathy. Epilepsy Behav, 2021, 123: 108245.
35. Deshpande LS, DeLorenzo RJ, Churn SB, et al. Neuronal-specific inhibition of endoplasmic reticulum Mg 2+/Ca 2+ ATPase Ca 2+ uptake in a mixed primary hippocampal culture model of status epilepticus. Brain Sci, 2020, 10(7): 438.
36. Hansen SN, Holm A, Kauppinen S, et al. RNA therapeutics for epilepsy: an emerging modality for drug discovery. Epilepsia, 2023, 64(12): 3113-3129.

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