Browse > Article
http://dx.doi.org/10.5734/JGM.2021.18.1.8

Treatment strategies targeting specific genetic etiologies in epilepsy  

Kim, Hyo Jeong (Department of Pediatrics, Gachon University Gil Medical Center, Gachon University College of Medicine)
Kang, Hoon-Chul (Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine)
Publication Information
Journal of Genetic Medicine / v.18, no.1, 2021 , pp. 8-15 More about this Journal
Abstract
Recent genetic advances allow for identification of the genetic etiologies of epilepsy within individual patients earlier and more frequently than ever. Specific targeted treatments have emerged from improvements in understanding of the underlying epileptogenic pathophysiology. These targeted treatment strategies include modifications of ion channels or other cellular receptors and their function, mechanistic target of rapamycin signaling pathways, and substitutive therapies in hereditary metabolic epilepsies. In this review, we explore targeted treatments based on underlying pathophysiologic mechanisms in specific genetic epilepsies.
Keywords
Epilepsy; Genetics; Precision medicine;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci 2007;27:5903-14.   DOI
2 Chiron C. Stiripentol. Neurotherapeutics 2007;4:123-5.   DOI
3 Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE, Hodgson BL, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol 2014;75:782-7.   DOI
4 Iffland PH 2nd, Carson V, Bordey A, Crino PB. GATORopathies: the role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia 2019;60:2163-73.   DOI
5 Ribierre T, Deleuze C, Bacq A, Baldassari S, Marsan E, Chipaux M, et al. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J Clin Invest 2018;128:2452-8.   DOI
6 Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012;44:1188-90.   DOI
7 Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012;44:1255-9.   DOI
8 Ambrosino P, Soldovieri MV, Bast T, Turnpenny PD, Uhrig S, Biskup S, et al. De novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy. Ann Neurol 2018;83:1198-204.   DOI
9 Santi CM, Ferreira G, Yang B, Gazula VR, Butler A, Wei A, et al. Opposite regulation of Slick and Slack K+ channels by neuromodulators. J Neurosci 2006;26:5059-68.   DOI
10 Kim HJ, Yang D, Kim SH, Kim B, Kim HD, Lee JS, et al. The phenotype and treatment of SCN2A-related developmental and epileptic encephalopathy. Epileptic Disord 2020;22:563-70.   DOI
11 Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-Casero V, et al. SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015;85:958-66.   DOI
12 Reynolds C, King MD, Gorman KM. The phenotypic spectrum of SCN2A-related epilepsy. Eur J Paediatr Neurol 2020;24:117-22.   DOI
13 Nakamura K, Kato M, Osaka H, Yamashita S, Nakagawa E, Haginoya K, et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013;81:992-8.   DOI
14 Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR. Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci U S A 2000;97:5616-20.   DOI
15 Wolff M, Brunklaus A, Zuberi SM. Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond. Epilepsia 2019;60 Suppl 3:S59-67.
16 Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 2012;135(Pt 8):2329-36.   DOI
17 Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 2002;360:851-2.   DOI
18 Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017;140:1316-36.   DOI
19 Gardella E, Marini C, Trivisano M, Fitzgerald MP, Alber M, Howell KB, et al. The phenotype of SCN8A developmental and epileptic encephalopathy. Neurology 2018;91:e1112-24.
20 Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC, Fajardo KV, et al. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun 2014;5:3251.   DOI
21 Johannesen KM, Gardella E, Scheffer I, Howell K, Smith DM, Helbig I, et al. Early mortality in SCN8A-related epilepsies. Epilepsy Res 2018;143:79-81.   DOI
22 Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 2012;90:502-10.   DOI
23 Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol 2015;78:995-9.   DOI
24 Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18:25-9.   DOI
25 Borlot F, Abushama A, Morrison-Levy N, Jain P, Puthenveettil Vinayan K, Abukhalid M, et al. KCNT1-related epilepsy: an international multicenter cohort of 27 pediatric cases. Epilepsia 2020;61:679-92.   DOI
26 Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014;75:581-90.   DOI
27 Chong PF, Nakamura R, Saitsu H, Matsumoto N, Kira R. Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation. Ann Neurol 2016;79:502-3.   DOI
28 Mullen SA, Carney PW, Roten A, Ching M, Lightfoot PA, Churilov L, et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology 2018;90:e67-72.   DOI
29 Numis AL, Nair U, Datta AN, Sands TT, Oldham MS, Patel A, et al. Lack of response to quinidine in KCNT1-related neonatal epilepsy. Epilepsia 2018;59:1889-98.   DOI
30 Yoshitomi S, Takahashi Y, Yamaguchi T, Oboshi T, Horino A, Ikeda H, et al. Quinidine therapy and therapeutic drug monitoring in four patients with KCNT1 mutations. Epileptic Disord 2019;21:48-54.
31 Kim HJ, Yang D, Kim SH, Kim B, Kim HD, Lee JS, et al. Genetic and clinical features of SCN8A developmental and epileptic encephalopathy. Epilepsy Res 2019;158:106222.   DOI
32 Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, et al.; EuroEPINOMICS RES Consortium CRP. The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015;84:480-9.   DOI
33 Gardella E, Becker F, Moller RS, Schubert J, Lemke JR, Larsen LH, et al. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 2016;79:428-36.   DOI
34 Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014;55:994-1000.   DOI
35 Anand G, Collett-White F, Orsini A, Thomas S, Jayapal S, Trump N, et al. Autosomal dominant SCN8A mutation with an unusually mild phenotype. Eur J Paediatr Neurol 2016;20:761-5.   DOI
36 Bagnasco I, Dassi P, Ble R, Vigliano P. A relatively mild phenotype associated with mutation of SCN8A. Seizure 2018;56:47-9.   DOI
37 Pons L, Lesca G, Sanlaville D, Chatron N, Labalme A, Manel V, et al. Neonatal tremor episodes and hyperekplexia-like presentation at onset in a child with SCN8A developmental and epileptic encephalopathy. Epileptic Disord 2018;20:289-94.   DOI
38 Xiao Y, Xiong J, Mao D, Liu L, Li J, Li X, et al. Early-onset epileptic encephalopathy with de novo SCN8A mutation. Epilepsy Res 2018;139:9-13.   DOI
39 Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014;1:190-8.   DOI
40 Millichap JJ, Park KL, Tsuchida T, Ben-Zeev B, Carmant L, Flamini R, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2016;2:e96.   DOI
41 van Karnebeek CD, Jaggumantri S. Current treatment and management of pyridoxine-dependent epilepsy. Curr Treat Options Neurol 2015;17:335.   DOI
42 Klepper J, Vera JC, De Vivo DC. Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome. Ann Neurol 1998;44:286-7.   DOI
43 French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for treatment-resistant focalonset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016;388:2153-63.   DOI
44 Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Everolimus for treatment-refractory seizures in TSC: extension of a randomized controlled trial. Neurol Clin Pract 2018;8:412-20.   DOI
45 Weckhuysen S, Ivanovic V, Hendrickx R, Van Coster R, Hjalgrim H, Moller RS, et al.; KCNQ2 Study Group. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013;81:1697-703.   DOI
46 Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 2013;45:546-51.   DOI
47 Baulac S, Ishida S, Marsan E, Miquel C, Biraben A, Nguyen DK, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol 2015;77:675-83.   DOI
48 Seidner G, Alvarez MG, Yeh JI, O'Driscoll KR, Klepper J, Stump TS, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 1998;18:188-91.   DOI
49 Lenk GM, Jafar-Nejad P, Hill SF, Huffman LD, Smolen CE, Wagnon JL, et al. Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and Dravet syndrome. Ann Neurol 2020;87:339-46.   DOI
50 Catterall WA. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 2000;26:13-25.   DOI
51 Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013;45:1061-6.   DOI
52 Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010;42:1021-6.   DOI
53 Lesca G, Rudolf G, Labalme A, Hirsch E, Arzimanoglou A, Genton P, et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia 2012;53:1526-38.   DOI
54 Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 2013;45:1067-72.   DOI
55 Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011;104:48-60.   DOI
56 Klepper J, Leiendecker B. Glut1 deficiency syndrome and novel ketogenic diets. J Child Neurol 2013;28:1045-8.   DOI
57 Mills PB, Footitt EJ, Mills KA, Tuschl K, Aylett S, Varadkar S, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 2010;133(Pt 7):2148-59.   DOI
58 Coughlin CR 2nd, Tseng LA, Abdenur JE, Ashmore C, Boemer F, Bok LA, et al. Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 2021;44:178-92.   DOI
59 Han Z, Chen C, Christiansen A, Ji S, Lin Q, Anumonwo C, et al. Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Sci Transl Med 2020;12:eaaz6100.   DOI
60 Henske EP, Jozwiak S, Kingswood JC, Sampson JR, Thiele EA. Tuberous sclerosis complex. Nat Rev Dis Primers 2016;2:16035.   DOI
61 Kato M, Yamagata T, Kubota M, Arai H, Yamashita S, Nakagawa T, et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013;54:1282-7.   DOI
62 Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N, Bruneau N, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013;45:1073-6.   DOI
63 Liu Y, Schubert J, Sonnenberg L, Helbig KL, Hoei-Hansen CE, Koko M, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain 2019;142:376-90.   DOI
64 Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, et al.; BFNC Physician Consortium. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 2003;126(Pt 12):2726-37.   DOI
65 Grinton BE, Heron SE, Pelekanos JT, Zuberi SM, Kivity S, Afawi Z, et al. Familial neonatal seizures in 36 families: clinical and genetic features correlate with outcome. Epilepsia 2015;56:1071-80.   DOI
66 Weckhuysen S, Mandelstam S, Suls A, Audenaert D, Deconinck T, Claes LR, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012;71:15-25.   DOI
67 Numis AL, Angriman M, Sullivan JE, Lewis AJ, Striano P, Nabbout R, et al. KCNQ2 encephalopathy: delineation of the electroclinical phenotype and treatment response. Neurology 2014;82:368-70.   DOI
68 Ishida S, Picard F, Rudolf G, Noe E, Achaz G, Thomas P, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet 2013;45:552-5.   DOI
69 Mizuguchi M, Ikeda H, Kagitani-Shimono K, Yoshinaga H, Suzuki Y, Aoki M, et al. Everolimus for epilepsy and autism spectrum disorder in tuberous sclerosis complex: EXIST-3 substudy in Japan. Brain Dev 2019;41:1-10.   DOI
70 Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, et al.; EPISTOP Investigators. Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial. Ann Neurol 2021;89:304-14.   DOI
71 Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512-21.   DOI
72 Nolan D, Fink J. Genetics of epilepsy. Handb Clin Neurol 2018;148:467-91.   DOI
73 Kearney H, Byrne S, Cavalleri GL, Delanty N. Tackling epilepsy with high-definition precision medicine: a review. JAMA Neurol 2019;76:1109-16.   DOI
74 Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001;68:1327-32.   DOI
75 Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 2006;9:1142-9.   DOI
76 Orhan G, Bock M, Schepers D, Ilina EI, Reichel SN, Loffler H, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol 2014;75:382-94.   DOI
77 Pisano T, Numis AL, Heavin SB, Weckhuysen S, Angriman M, Suls A, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 2015;56:685-91.   DOI
78 Goto A, Ishii A, Shibata M, Ihara Y, Cooper EC, Hirose S. Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia 2019;60:1870-80.   DOI
79 Kim HJ, Yang D, Kim SH, Won D, Kim HD, Lee JS, et al. Clinical characteristics of KCNQ2 encephalopathy. Brain Dev 2021;43:244-50.   DOI
80 Miceli F, Soldovieri MV, Ambrosino P, De Maria M, Migliore M, Migliore R, et al. Early-onset epileptic encephalopathy caused by gainof-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci 2015;35:3782-93.   DOI
81 Harris JA, Murphy JA. Retigabine (ezogabine) as add-on therapy for partial-onset seizures: an update for clinicians. Ther Adv Chronic Dis 2011;2:371-6.   DOI
82 Ihara Y, Tomonoh Y, Deshimaru M, Zhang B, Uchida T, Ishii A, et al. Retigabine, a Kv7.2/Kv7.3-channel opener, attenuates drug-induced seizures in knock-in mice harboring Kcnq2 mutations. PLoS One 2016;11:e0150095.   DOI
83 Garin Shkolnik T, Feuerman H, Didkovsky E, Kaplan I, Bergman R, Pavlovsky L, et al. Blue-gray mucocutaneous discoloration: a new adverse effect of ezogabine. JAMA Dermatol 2014;150:984-9.   DOI
84 Kuersten M, Tacke M, Gerstl L, Hoelz H, Stulpnagel CV, Borggraefe I. Antiepileptic therapy approaches in KCNQ2 related epilepsy: a systematic review. Eur J Med Genet 2020;63:103628.   DOI