KCNT1 基因变异相关癫痫及其治疗的研究进展_Journal of Epilepsy

Authors：

林欢 ,  蒋莉

重庆医科大学附属儿童医院神经内科, 国家儿童健康与疾病临床医学研究中心, 儿童发育疾病研究教育部重点实验室, 儿科学重庆市重点实验室（重庆 400014）;

Corresponding author：

蒋莉, Email: dr_jiangcqmu@163.com

Keywords：

KCNT1基因; 癫痫; 发病机制; 临床表现; 治疗

DOI：

10.7507/2096-0247.202112005

Video：

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KCNT1基因编码含有1 235个氨基酸的钠离子门控钾离子通道的α亚基，对调节神经元的膜兴奋性发挥着重要作用，其致病性变异可通过影响钾通道的功能导致癫痫。KCNT1基因变异相关癫痫患者表型具有显著临床异质性，可出现从轻度表型到严重表型的系列癫痫表型谱，为难治性癫痫大多数，严重表型患者可伴有运动、智能发育落后或倒退，预后极差。早期识别KCNT1基因变异相关癫痫，及时进行KCNT1基因检测，有利于KCNT1基因变异相关癫痫患者的精准治疗及预后评估。在此，本文就KCNT1基因变异相关癫痫的发病机制、临床特点及其治疗进行综述。

Citation： 林欢, 蒋莉. KCNT1 基因变异相关癫痫及其治疗的研究进展. Journal of Epilepsy, 2022, 8(3): 251-255. doi: 10.7507/2096-0247.202112005 Copy

1.	Noebels J. Precision physiology and rescue of brain ion channel disorders. J Gen Physiol, 2017, 149(5): 533-546.
2.	Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet, 2012, 44(11): 1188-1190.
3.	Barcia G, Fleming MR, Deligniere A, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet, 2012, 44(11): 1255-1259.
4.	Quraishi IH, Mercier MR, McClure H, et al. Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1. 1) Na(+)-activated K(+) channels. Sci Rep, 2020, 10(1): 3213.
5.	Hite RK, Yuan P, Li Z, et al. Cryo-electron microscopy structure of the Slo2. 2 Na(+)-activated K(+) channel. Nature, 2015, 527(7577): 198-203.
6.	Tamsett TJ, Picchione KE, Bhattacharjee A. NAD+ activates K/Na channels in dorsal root ganglion neurons. J Neurosci, 2009, 29(16): 5127-5134.
7.	Liu X, Stan Leung L. Sodium-activated potassium conductance participates in the depolarizing afterpotential following a single action potential in rat hippocampal CA1 pyramidal cells. Brain Res, 2004, 1023(2): 185-192.
8.	Franceschetti S, Lavazza T, Curia G, et al. Na+-activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons. J Neurophysiol, 2003, 89(4): 2101-2111.
9.	Yang B, Desai R, Kaczmarek LK. Slack and Slick K(Na) channels regulate the accuracy of timing of auditory neurons. J Neurosci, 2007, 27(10): 2617-2627.
10.	Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 2014, 23(12): 3200-3211.
11.	Niday Z, Tzingounis AV. Potassium channel gain of function in epilepsy: an unresolved paradox. Neuroscientist, 2018, 24(4): 368-380.
12.	Quraishi IH, Stern S, Mangan KP, et al. An epilepsy-associated KCNT1 mutation enhances excitability of human iPSC-derived neurons by increasing slack KNa currents. J Neurosci, 2019, 39(37): 7438-7449.
13.	Shore AN, Colombo S, Tobin WF, et al. Reduced GABAergic neuron excitability, altered synaptic connectivity, and seizures in a KCNT1 gain-of-eunction mouse model of childhood epilepsy. Cell Rep, 2020, 33(4): 108303.
14.	Bonardi C, Heyne H, Fiannacca M, et al. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain : a journal of neurology, 2021.
15.	Moller RS, Heron SE, Larsen LH, et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia, 2015, 56(9): e114e120.
16.	McTague A, Nair U, Malhotra S, et al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology, 2018, 90(1): 55-66.
17.	Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: exome screening and phenotype expansion. Epilepsia, 2016, 57(1): 12-17.
18.	Borlot F, Abushama A, Morrison-Levy N, et al. KCNT1-related epilepsy: an international multicenter cohort of 27 pediatric cases. Epilepsia, 2020, 61(4): 679-692.
19.	Gertler TS, Thompson CH, Vanoye CG, et al. Functional consequences of a KCNT1 variant associated with status dystonicus and early-onset infantile encephalopathy. Ann Clin Transl Neurol, 2019, 6(9): 1606-1615.
20.	Coppola G, Plouin P, Chiron C, et al. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia, 1995, 36(10): 1017-1024.
21.	Fang ZX, Xie LL, Yan LS, et al. Clinical and genetic characteristics of epilepsy of infancy with migrating focal seizures in Chinese children. Epilepsy Res, 2021, 174: 106669.
22.	Ohba C, Kato M, Takahashi N, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia, 2015, 56(9): e121-e128.
23.	Burgess R, Wang S, McTague A, et al. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann Neurol, 2019, 86(6): 821-831.
24.	康庆云, 廖红梅, 杨赛. KCNT1基因变异相关婴儿癫痫伴游走性局灶性发作患儿临床分析. 实用药物与临床, 2021, 24(4): 4.
25.	Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology, 2016, 86(19): 1834-1842.
26.	Lugaresi E, Cirignotta F, Montagna P. Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry, 1986, 49(4): 375-380.
27.	张欣, 林卫红. 常染色体显性遗传夜间额叶癫痫的基因学研究现状. 癫痫杂志, 2019, 5(2): 116-119.
28.	张欣, 赵丹阳, 李光健. 14个常染色体显性遗传夜间额叶癫痫家系患者的临床特点及脑电图分析. 临床神经病学杂志, 2020, 33(4): 278-282.
29.	陈洋, 胡小伟, 张秋. 常染色体显性遗传性夜间额叶癫痫的基因学研究进展. 临床神经病学杂志, 2017, 7(3): 3.
30.	Indurthi DC, Qudah T, Liao VW, et al. Revisiting autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry. Pharmacol Res, 2019, 139: 215-227.
31.	Barcia G, Chemaly N, Kuchenbuch M, et al. Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability. Neurol Genet, 2019, 5(6): e363.
32.	Kim GE, Kronengold J, Barcia G, et al. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep, 2014, 9(5): 1661-1672.
33.	Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet, 2016, 53(4): 217-225.
34.	Fitzgerald MP, Fiannacca M, Smith DM, et al. Treatment responsiveness in KCNT1-related epilepsy. Neurotherapeutics, 2019, 16(3): 848-857.
35.	Rizzo F, Ambrosino P, Guacci A, et al. Characterization of two de novoKCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci, 2016, 72: 54-63.
36.	Cole BA, Johnson RM, Dejakaisaya H, et al. Structure-based identification and characterization of inhibitors of the epilepsy-associated KNa11 (KCNT1) potassium channel. iScience, 2020, 23(5): 101100.
37.	Milligan CJ, Li M, Gazina EV, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol, 2014, 75(4): 581-590.
38.	Dilena R, DiFrancesco JC, Soldovieri MV, et al. Early treatment with Quinidine in 2 patients with epilepsy of infancy with migrating focal seizures (EIMFS) due to gain-of-function KCNT1 mutations: functional Studies, clinical responses, and critical issues for personalized therapy. Neurotherapeutics, 2018, 15(4): 1112-1126.
39.	Mullen SA, Carney PW, Roten A, et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology, 2018, 90(1): e67-e72.
40.	Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatr Neurol, 2015, 52(5): 544-547.
41.	Bearden D, Strong A, Ehnot J, et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol, 2014, 76(3): 457-461.
42.	Mikati MA, Jiang YH, Carboni M, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol, 2015, 78(6): 995-999.
43.	Passey CC, Erramouspe J, Castellanos P, et al. Concurrent quinidine and phenobarbital in the treatment of a patient with 2 KCNT1 mutations. Curr Ther Res Clin Exp, 2019, 90: 106-108.
44.	Yoshitomi S, Takahashi Y, Yamaguchi T, et al. Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations. Epileptic Disord, 2019, 21(1): 48-54.
45.	de Los Angeles Tejada M, Stolpe K, Meinild AK, et al. Clofilium inhibits Slick and Slack potassium channels. Biologics, 2012, 6: 465-470.
46.	吴军, 于海波. 大麻二酚在神经精神疾病中的作用与分子机制研究进展. 药学学报, 2020, 55(12): 2800-2810.
47.	Poisson K, Wong M, Lee C, et al. Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: an open-label, prospective, interventional study. Eur J Paediatr Neurol, 2020, 25: 77-81.

1. Noebels J. Precision physiology and rescue of brain ion channel disorders. J Gen Physiol, 2017, 149(5): 533-546.
2. Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet, 2012, 44(11): 1188-1190.
3. Barcia G, Fleming MR, Deligniere A, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet, 2012, 44(11): 1255-1259.
4. Quraishi IH, Mercier MR, McClure H, et al. Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1. 1) Na(+)-activated K(+) channels. Sci Rep, 2020, 10(1): 3213.
5. Hite RK, Yuan P, Li Z, et al. Cryo-electron microscopy structure of the Slo2. 2 Na(+)-activated K(+) channel. Nature, 2015, 527(7577): 198-203.
6. Tamsett TJ, Picchione KE, Bhattacharjee A. NAD+ activates K/Na channels in dorsal root ganglion neurons. J Neurosci, 2009, 29(16): 5127-5134.
7. Liu X, Stan Leung L. Sodium-activated potassium conductance participates in the depolarizing afterpotential following a single action potential in rat hippocampal CA1 pyramidal cells. Brain Res, 2004, 1023(2): 185-192.
8. Franceschetti S, Lavazza T, Curia G, et al. Na+-activated K+ current contributes to postexcitatory hyperpolarization in neocortical intrinsically bursting neurons. J Neurophysiol, 2003, 89(4): 2101-2111.
9. Yang B, Desai R, Kaczmarek LK. Slack and Slick K(Na) channels regulate the accuracy of timing of auditory neurons. J Neurosci, 2007, 27(10): 2617-2627.
10. Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet, 2014, 23(12): 3200-3211.
11. Niday Z, Tzingounis AV. Potassium channel gain of function in epilepsy: an unresolved paradox. Neuroscientist, 2018, 24(4): 368-380.
12. Quraishi IH, Stern S, Mangan KP, et al. An epilepsy-associated KCNT1 mutation enhances excitability of human iPSC-derived neurons by increasing slack KNa currents. J Neurosci, 2019, 39(37): 7438-7449.
13. Shore AN, Colombo S, Tobin WF, et al. Reduced GABAergic neuron excitability, altered synaptic connectivity, and seizures in a KCNT1 gain-of-eunction mouse model of childhood epilepsy. Cell Rep, 2020, 33(4): 108303.
14. Bonardi C, Heyne H, Fiannacca M, et al. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain : a journal of neurology, 2021.
15. Moller RS, Heron SE, Larsen LH, et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia, 2015, 56(9): e114e120.
16. McTague A, Nair U, Malhotra S, et al. Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology, 2018, 90(1): 55-66.
17. Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: exome screening and phenotype expansion. Epilepsia, 2016, 57(1): 12-17.
18. Borlot F, Abushama A, Morrison-Levy N, et al. KCNT1-related epilepsy: an international multicenter cohort of 27 pediatric cases. Epilepsia, 2020, 61(4): 679-692.
19. Gertler TS, Thompson CH, Vanoye CG, et al. Functional consequences of a KCNT1 variant associated with status dystonicus and early-onset infantile encephalopathy. Ann Clin Transl Neurol, 2019, 6(9): 1606-1615.
20. Coppola G, Plouin P, Chiron C, et al. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia, 1995, 36(10): 1017-1024.
21. Fang ZX, Xie LL, Yan LS, et al. Clinical and genetic characteristics of epilepsy of infancy with migrating focal seizures in Chinese children. Epilepsy Res, 2021, 174: 106669.
22. Ohba C, Kato M, Takahashi N, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia, 2015, 56(9): e121-e128.
23. Burgess R, Wang S, McTague A, et al. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann Neurol, 2019, 86(6): 821-831.
24. 康庆云, 廖红梅, 杨赛. KCNT1基因变异相关婴儿癫痫伴游走性局灶性发作患儿临床分析. 实用药物与临床, 2021, 24(4): 4.
25. Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology, 2016, 86(19): 1834-1842.
26. Lugaresi E, Cirignotta F, Montagna P. Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry, 1986, 49(4): 375-380.
27. 张欣, 林卫红. 常染色体显性遗传夜间额叶癫痫的基因学研究现状. 癫痫杂志, 2019, 5(2): 116-119.
28. 张欣, 赵丹阳, 李光健. 14个常染色体显性遗传夜间额叶癫痫家系患者的临床特点及脑电图分析. 临床神经病学杂志, 2020, 33(4): 278-282.
29. 陈洋, 胡小伟, 张秋. 常染色体显性遗传性夜间额叶癫痫的基因学研究进展. 临床神经病学杂志, 2017, 7(3): 3.
30. Indurthi DC, Qudah T, Liao VW, et al. Revisiting autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry. Pharmacol Res, 2019, 139: 215-227.
31. Barcia G, Chemaly N, Kuchenbuch M, et al. Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability. Neurol Genet, 2019, 5(6): e363.
32. Kim GE, Kronengold J, Barcia G, et al. Human slack potassium channel mutations increase positive cooperativity between individual channels. Cell Rep, 2014, 9(5): 1661-1672.
33. Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet, 2016, 53(4): 217-225.
34. Fitzgerald MP, Fiannacca M, Smith DM, et al. Treatment responsiveness in KCNT1-related epilepsy. Neurotherapeutics, 2019, 16(3): 848-857.
35. Rizzo F, Ambrosino P, Guacci A, et al. Characterization of two de novoKCNT1 mutations in children with malignant migrating partial seizures in infancy. Mol Cell Neurosci, 2016, 72: 54-63.
36. Cole BA, Johnson RM, Dejakaisaya H, et al. Structure-based identification and characterization of inhibitors of the epilepsy-associated KNa11 (KCNT1) potassium channel. iScience, 2020, 23(5): 101100.
37. Milligan CJ, Li M, Gazina EV, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol, 2014, 75(4): 581-590.
38. Dilena R, DiFrancesco JC, Soldovieri MV, et al. Early treatment with Quinidine in 2 patients with epilepsy of infancy with migrating focal seizures (EIMFS) due to gain-of-function KCNT1 mutations: functional Studies, clinical responses, and critical issues for personalized therapy. Neurotherapeutics, 2018, 15(4): 1112-1126.
39. Mullen SA, Carney PW, Roten A, et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology, 2018, 90(1): e67-e72.
40. Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatr Neurol, 2015, 52(5): 544-547.
41. Bearden D, Strong A, Ehnot J, et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol, 2014, 76(3): 457-461.
42. Mikati MA, Jiang YH, Carboni M, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol, 2015, 78(6): 995-999.
43. Passey CC, Erramouspe J, Castellanos P, et al. Concurrent quinidine and phenobarbital in the treatment of a patient with 2 KCNT1 mutations. Curr Ther Res Clin Exp, 2019, 90: 106-108.
44. Yoshitomi S, Takahashi Y, Yamaguchi T, et al. Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations. Epileptic Disord, 2019, 21(1): 48-54.
45. de Los Angeles Tejada M, Stolpe K, Meinild AK, et al. Clofilium inhibits Slick and Slack potassium channels. Biologics, 2012, 6: 465-470.
46. 吴军, 于海波. 大麻二酚在神经精神疾病中的作用与分子机制研究进展. 药学学报, 2020, 55(12): 2800-2810.
47. Poisson K, Wong M, Lee C, et al. Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: an open-label, prospective, interventional study. Eur J Paediatr Neurol, 2020, 25: 77-81.

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