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Review

Advances in genetic testing and optimization of clinical management in children and adults with epilepsy

ORCID Icon, , , , , , , , , , , , , , ORCID Icon & ORCID Icon show all
Pages 251-269 | Received 04 Jul 2019, Accepted 06 Jan 2020, Published online: 27 Jan 2020

References

  • Striano P. Epilepsy towards the next decade: new trends and hopes in epileptology. Basel: Springer International Publishing; 2015.
  • Andrade DM, Minassian BA. Genetics of epilepsies. Expert Rev Neurother. 2007;7:727–734.
  • Orsini A, Zara F, Striano P. Recent advances in epilepsy genetics. Neurosci Lett. 2018;667:4–9.
  • Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Curr Opin Neurol. 2017;30:193–199.
  • Mantegazza M, Rusconi R, Scalmani P, et al. Epileptogenic ion channel mutations: from bedside to bench and, hopefully, back again. Epilepsy Res. 2010;92:1–29.
  • Nicita F, De Liso P, Danti FR, et al. The genetics of monogenic idiopathic epilepsies and epileptic encephalopathies. Seizure. 2012;21:3–11.
  • Perry MS, Poduri A. Two studies, one message: high yield of genetic testing in infants and young children with severe epilepsies. Epilepsy Curr. 2018;18:24–26.
  • Bianchi A. Definition of the phenotype for genetic studies. Chapter 5. In perinatal brain damage: from pathogenesis to neuroprotection. London-Paris: John Libbey Eurotext; 2009.
  • Olson HE, Poduri A, Pearl PL. Genetic forms of epilepsies and other paroxysmal disorders. Semin Neurol. 2014;34:266–279.
  • Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58:522–530.
  • Fisher RS, Cross JH, D’Souza C, et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia. 2017;58:531–542.
  • Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–319.
  • Kwan P, Brodie MJ. Definition of refractory epilepsy: defining the indefinable? Lancet Neurol. 2010;9:27–29.
  • Peljto AL, Barker-Cummings C, Vasoli VM, et al. Familial risk of epilepsy: a population-based study. Brain. 2014;137:795–805.
  • Christensen J, Overgaard M, Parner ET, et al. Risk of epilepsy and autism in full and half siblings-A population-based cohort study. Epilepsia. 2016;57:2011–2018.
  • Bennett RL, French KS, Resta RG, et al. Standardized human pedigree nomenclature: update and assessment of the recommendations of the national society of genetic counselors. J Genet Couns. 2008;17:424–433.
  • Seneviratne U, Cook MJ, D’Souza WJ. Electroencephalography in the diagnosis of genetic generalized epilepsy syndromes. Front Neurol. 2017;8:499.
  • Giannakodimos S, Panayiotopoulos CP. Eyelid myoclonia with absences in adults: a clinical and video-EEG study. Epilepsia. 1996;37:36–44.
  • Hrachovy RA, Frost JD Jr. Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/west syndrome). J Clin Neurophysiol. 2003;20:408–425.
  • Guerrini R, Pellacani S. Benign childhood focal epilepsies. Epilepsia. 2012;53:9–18.
  • Kim SH, Korff CM, Kim AJ, et al. A practical, simple, and useful method of categorizing interictal EEG features in children. Neurology. 2015;85:471–478.
  • Assi L, Saklawi Y, Karam PE, et al. Treatable genetic metabolic epilepsies. Curr Treat Options Neurol. 2017;19:30.
  • Papetti L, Parisi P, Leuzzi V, et al. Metabolic epilepsy: an update. Brain Dev. 2013;35:827–841.
  • Wolf B. The neurology of biotinidase deficiency. Mol Genet Metab. 2011;104:27–34.
  • Kirkham FJ. Indications for the performance of neuroimaging in children. Handbook of Clinical Neurology. 2016;136:1275–1290.
  • Bernasconi A, Cendes F, Theodore WH, et al. Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the international league against epilepsy neuroimaging. Epilepsia. 2019;60:1054–1068.
  • Lange M, Kasper B, Bohring A, et al. 47 patients with FLNA associated periventricular nodular heterotopia. Orphanet J Rare Dis. 2015;10:134.
  • El Achkar CM, Olson HE, Poduri A, et al. The genetics of the epilepsies. Curr Neurol Neurosci Rep. 2015;15:39.
  • Epilepsy Phenome/Genome Project & Epi4K Consortium. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy. Ann Neurol. 2015;78:323–328.
  • de Kovel CG, Trucks H, Helbig I, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 2010;133:23–32.
  • Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010;6:e1000962.
  • Mullen SA, Carvill GL, Bellows S, et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 2013;81:1507–1514.
  • Striano P, Coppola A, Paravidino R, et al. Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization. Arch Neurol. 2012;69:322–330.
  • Olson H, Shen Y, Avallone J, et al. Copy number variation plays an important role in clinical epilepsy. Ann Neurol. 2014;75:943–958.
  • Møller RS, Dahl HA, Helbig I. The contribution of next generation sequencing to epilepsy genetics. Expert Rev Mol Diagn. 2015;15:1531–1538.
  • Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7:91.
  • Mefford HC. Clinical genetic testing in epilepsy. Epilepsy Curr. 2015;15:197–201.
  • Weber YG, Biskup S, Helbig KL, et al. The role of genetic testing in epilepsy diagnosis and management. Expert Rev Mol Diagn. 2017;17:739–750.
  • Costain G, Cordeiro D, Matviychuk D, et al. Clinical application of targeted next-generation sequencing panels and whole exome sequencing in childhood epilepsy. Neuroscience. 2019;418:291–310.
  • Jang SS, Kim SY, Kim H, et al. Diagnostic yield of epilepsy panel testing in patients with seizure onset within the first year of life. Front Neurol. 2019;10:988.
  • Staněk D, Laššuthová P, Štěrbová K, et al. Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life. Orphanet J Rare Dis. 2018;13:71.
  • Ko A, Youn SE, Kim SH, et al. Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy. Epilepsy Res. 2018;141:48–55.
  • Dunn P, Albury CL, Maksemous N, et al. Next generation sequencing methods for diagnosis of epilepsy syndromes. Front Genet. 2018;9:20.
  • Trump N, McTague A, Brittain H, et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet. 2016;53:310–317.
  • Bowdin S, Gilbert A, Bedoukian E, et al. Recommendations for the integration of genomics into clinical practice. Genet Med. 2016;18:1075–1084.
  • Tetreault M, Bareke E, Nadaf J, et al. Whole-exome sequencing as a diagnostic tool: current challenges and future opportunities. Expert Rev Mol Diagn. 2015;15:749–760.
  • Lindy AS, Stosser MB, Butler E, et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018;59:1062–1071.
  • Bennett CA, Petrovski S, Oliver KL, et al. ExACtly zero or once: A clinically helpful guide to assessing genetic variants in mild epilepsies. Neurol Genet. 2017;3:e163. eCollection 2017 Aug.
  • Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405–424.
  • Dunn P, Albury CL, Maksemous N, et al. Next generation sequencing methods for diagnosis of epilepsy syndromes. Front Genet. 2018;9:20.
  • Cheung SW, Bi W. Novel applications of array comparative genomic hybridization in molecular diagnostics. Expert Rev Mol Diagn. 2018;18:531–542.
  • Monlong J, Girard SL, Meloche C, et al. Global characterization of copy number variants in epilepsy patients from whole genome sequencing. PLoS Genet. 2018;14:e1007285.
  • Pirooznia M, Goes FS, Zandi PP. Whole-genome CNV analysis: advances in computational approaches. Front Genet. 2015;6:138.
  • Nolan D, Carlson M. Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. J Child Neurol. 2016;31:887–894.
  • Schwarze K, Buchanan J, Taylor JC, et al. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet Med. 2018;20:1122–1130.
  • Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia. 2010;51:676–685.
  • Arsov T, Mullen SA, Damiano JA, et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia. 2012;53:e204–7.
  • Larsen J, Johannesen KM, Ek J, et al. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia. 2015;56:e203–8.
  • Suzuki T, Delgado-Escueta AV, Aguan K, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet. 2004;36:842–849.
  • Zara F, Specchio N, Striano P, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013;54:425–436.
  • Gardella E, Becker F, Møller RS, et al. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol. 2016;79:428–436.
  • Grinton BE, Heron SE, Pelekanos JT, et al. Familial neonatal seizures in 36 families: clinical and genetic features correlate with outcome. Epilepsia. 2015;56:1071–1080.
  • Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia. 2015;56:685–691.
  • van Vliet R, Breedveld G, de Rijk-van Andel J, et al. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology. 2012;79:777–784.
  • Trivisano M, Terracciano A, Milano T, et al. Mutation of CHRNA2 in a family with benign familial infantile. Epilepsia. 2015;56:e53–7.
  • Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain. 2019;142:2303–2318.
  • Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet. 2011;43:1252–1255.
  • Heron SE, Grinton BE, Kivity S, et al. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet. 2012;90:152–160.
  • Méneret A, Grabli D, Depienne C, et al. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology. 2012;79:170–174.
  • Lemke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067–1072.
  • Licchetta L, Pippucci T, Baldassari S, et al. Sleep-related hypermotor epilepsy (SHE): contribution of known genes in 103 patients. Seizure. 2019;74:60–64.
  • Menghi V, Bisulli F, Tinuper P, et al. Sleep-related hypermotor epilepsy: prevalence, impact and management strategies. Nat Sci Sleep. 2018;10:317–326.
  • Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology. 2016;86:1834–1842.
  • Aridon P, Marini C, Di Resta C, et al. Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet. 2006;79:342–350.
  • 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;44:1188–1190.
  • Korenke GC, Eggert M, Thiele H, et al. Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia. 2016;57:e60–3.
  • Michelucci R, Pasini E, Malacrida S, et al. Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations. Epilepsia. 2013;54:1288–1297.
  • Rosanoff MJ, Ottman R. Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology. 2008;71:567–571.
  • Ottman R, Winawer MR, Kalachikov S, et al. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology. 2004;62:1120–1126.
  • Bisulli F, Tinuper P, Scudellaro E, et al. A de novo LGI1 mutation in sporadic partial epilepsy with auditory features. Ann Neurol. 2004;56:455–456.
  • Dazzo E, Fanciulli M, Serioli E, et al. Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Am J Hum Genet. 2015;96:992–1000.
  • Berkovic SF, Scheffer IE. Febrile seizures: genetics and relationship to other epilepsy syndromes. Curr Opin Neurol. 1998;11:129–134.
  • Kivity S, Oliver KL, Afawi Z, et al. SCN1A clinical spectrum includes the self-limited focal epilepsies of childhood. Epilepsy Res. 2017;131:9–14.
  • Bonanni P, Malcarne M, Moro F, et al. Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations. Epilepsia. 2004;45:149–158.
  • Zhang YH, Burgess R, Malone JP, et al. Genetic epilepsy with febrile seizures plus: refining the spectrum. Neurology. 2017;89:1210–1219.
  • Kalser J, Cross JH. The epileptic encephalopathy jungle - from Dr West to the concepts of aetiology-related and developmental encephalopathies. Curr Opin Neurol. 2018;31:216–222.
  • McTague A, Howell KB, Cross JH, et al. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15:304–316.
  • Jehi L, Wyllie E, Devinsky O. Epileptic encephalopathies: optimizing seizure control and developmental outcome. Epilepsia. 2015;56:1486–1489.
  • Carvill GL, McMahon JM, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet. 2015;96:808–815.
  • Nieh SE, Sherr EH. Epileptic encephalopathies: new genes and new pathways. Neurotherapeutics. 2014;11:796–806.
  • Kuzniecky R. Epilepsy and malformations of cortical development: new developments. Curr Opin Neurol. 2015;28:151–157.
  • Jamuar SS, Lam AT, Kircher M, et al. Somatic mutations in cerebral cortical malformations. N Engl J Med. 2014;371:733–743.
  • Barkovich AJ, Guerrini R, Kuzniecky RI, et al. A developmental and genetic classification for malformations of cortical development: update. Brain. 2012;135:1348–1369.
  • Guerrini R, Dobyns WB. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 2014;13:710–726.
  • Pavone P, Praticò AD, Rizzo R, et al. A clinical review on megalencephaly: A large brain as a possible sign of cerebral impairment. Medicine (Baltimore). 2017;96:e6814.
  • Rivière JB, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44:934–940.
  • Mirzaa GM, Conway RL, Gripp KW, et al. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactylypolymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A. 2012;158A:269–291.
  • Guerrini R, Filippi T. Neuronal migration disorders, genetics, and epileptogenesis. J Child Neurol. 2005;20:287–299.
  • Fry AE, Cushion TD, Pilz DT. The genetics of lissencephaly. Am J Med Genet C Semin Med Genet. 2014;166C:198–210.
  • Kim JK, Lee JH. Mechanistic target of rapamycin pathway in epileptic disorders. J Korean Neurosurg Soc. 2019;62:272–287.
  • Romaniello R, Arrigoni F, Cavallini A, et al. Brain malformations and mutations in α- and β-tubulin genes: a review of the literature and description of two new cases. Dev Med Child Neurol. 2014;56:354–360.
  • Parrini E, Ramazzotti A, Dobyns WB, et al. Periventricular heterotopia: phenotypic heterogeneity and correlation with filamin A mutations. Brain. 2006;129:1892–1906.
  • Kielar M, Phan Dinh Tuy F, Bizzotto S, et al. Mutations in Eml1/EML1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Med Sci. 2014;30:1087–1090.
  • Shahwan A, Farrell M, Delanty N, et al. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4:239–248.
  • Kälviäinen R. Progressive myoclonus epilepsies. Semin Neurol. 2015;35:293–299.
  • Muona M, Berkovic SF, Dibbens LM, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015;47:39–46.
  • Vanni N, Fruscione F, Ferlazzo E, et al. Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann Neurol. 2014;76:206–212.
  • Opri R, Fabrizi GM, Cantalupo G, et al. Progressive myoclonus epilepsy in congenital generalized lipodystrophy type 2: report of 3 cases and literature review. Seizure. 2016;42:1–6.
  • Franceschetti S, Gambardella A, Canafoglia L, et al. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia. 2006;47:640–643.
  • Canafoglia L, Gennaro E, Capovilla G, et al. Electroclinical presentation and genotype-phenotype relationships in patients with Unverricht-Lundborg disease carrying compound heterozygous CSTB point and indel mutations. Epilepsia. 2012;53:2120–2127.
  • Ferlazzo E, Canafoglia L, Michelucci R, et al. Mild Lafora disease: clinical, neurophysiologic, and genetic findings. Epilepsia. 2014;55:e129–33.
  • Casciato S, Gambardella S, Mascia A, et al. Severe and rapidly-progressive Lafora disease associated with NHLRC1 mutation: a case report. Int J Neurosci. 2017;127:1150–1153.
  • Striano P, Vari MS, Mazzocchetti C, et al. Management of genetic epilepsies: from empirical treatment to precision medicine. Pharmacol Res. 2016;107:426–429.
  • Klepper J. GLUT1 deficiency syndrome in clinical practice. Epilepsy Res. 2012;100:272–277.
  • Pearson TS, Akman C, Hinton VJ, et al. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013;13:342.
  • Mercimek-Mahmutoglu S, Cordeiro D, Cruz V, et al. Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet. Eur J Paediatr Neurol. 2014;18:741–746.
  • Platzer K, Yuan H, Schutz H, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet. 2017;54:460–470.
  • Ramaswami M, Gautam M, Kamb A, et al. Human potassium channel genes: molecular cloning and functional expression. Mol Cell Neurosci. 1990;1:214–223.
  • Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia. 2016;57:2019–2030.
  • Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet. 2016;2:e96.
  • Ihara Y, Tomonoh Y, Deshimaru M, 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.
  • Bearden D, Strong A, Ehnot J, et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76:457–461.
  • Yang YR, Kang DS, Lee C, et al. Primary phospholipase C and brain disorders. Adv Biol Regul. 2016;61:80–85.
  • Campistol J, Plecko B. Treatable newborn and infant seizures due to inborn errors of metabolism. Epileptic Disord. 2015;17:229–242.
  • Tanabe Y, Taira T, Shimotake A, et al. An adult female with proline-rich transmembrane protein 2 related paroxysmal disorders manifesting paroxysmal kinesigenic choreoathetosis and epileptic seizures. Rinsho Shinkeigaku. 2019;59:144–148.
  • Chou IC, Lin SS, Lin WD, et al. Successful control with carbamazepine of family with paroxysmal kinesigenic dyskinesia of PRRT2 mutation. Biomedicine (Taipei). 2014;4:15.
  • Howell KB, McMahon JM, Carvill GL, et al. SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology. 2015;85:958–966.
  • Sanders SJ, Campbell AJ, Cottrell JR, et al. Progress in understanding and treating SCN2A-mediated disorders. Trends Neurosci. 2018;41:442–456.
  • Dilena R, Striano P, Gennaro E, et al. Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy. Brain Dev. 2017;39:345–348.
  • Flor-Hirsch H, Heyman E, Livneh A, et al. Lacosamide for SCN2Arelated intractable neonatal and infantile seizures. Epileptic Disord. 2018;20:440–446.
  • Johannesen KM, Gardella E, Encinas AC, et al. The spectrum of intermediate scn8a-related epilepsy. Epilepsia. 2019;60(5):830-844.
  • Liu Y, Schubert J, Sonnenberg L, et al. Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain. 2019;142:376–390.
  • Schwantje M, Verhagen LM, van Hasselt PM, et al. Glucose transporter type 1 deficiency syndrome and the ketogenic diet. J Inherit Metab Dis. 2019Oct 12. doi: 10.1002/jimd.12175. [Epub ahead of print]
  • French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388:2153–2163.
  • Okanishi T, Fujimoto A, Nishimura M, et al. The efficacy of everolimus for refractory seizures in childhood onset epilepsy with tuberous sclerosis complex. Brain Nerve. 2019;71:611–616.
  • Canpolat M, Gumus H, Kumandas S, et al. The use of rapamycin in patients with tuberous sclerosis complex: long-term results. Epilepsy Behav. 2018;88:357–364.
  • Schubert-Bast S, Rosenow F, Klein KM, et al. The role of mTOR inhibitors in preventing epileptogenesis in patients with TSC: current evidence and future perspectives. Epilepsy Behav. 2019;91:94–98.
  • Baumgart A, Spiczak S, Verhoeven-Duif NM, et al. Atypical vitamin B6 deficiency: a rare cause of unexplained neonatal and infantile epilepsies. J Child Neurol. 2014;29:704–707.
  • Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45:546–551.
  • Sadowski K, Kotulska-Jóźwiak K, Jóźwiak S, et al. Role of mTOR inhibitors in epilepsy treatment. Pharmacol Rep. 2015;67:636–646.
  • Griffith JL, Wong M. The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol. 2018;13:49–58.
  • Catterall WA. Dravet syndrome: a sodium channel interneuronopathy. Curr Opin Physiol. 2018;2:42–50.
  • Sun Y, Paşca SP, Portmann T, et al. A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet syndrome patients. Elife. 2016;5:e13073.
  • Perucca P. Genetics of focal epilepsies: what do we know and where are we heading? Epilepsy Curr. 2018;18:356–362.
  • Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. Pediatr Neurol. 2017;68:18–34 e3.
  • Richards KL, Milligan CJ, Richardson RJ, et al. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death. Proc Natl Acad Sci USA. 2018;115:E8077–85.
  • Therapeutics S. Stoke Therapeutics Presents Data Showing Single Dose of ASO Therapy Restores Normal Protein Levels in Animal Model of Genetic Epilepsy. 2018. cited 2018 Dec 26. https://www.stoketherapeutics.com/wpcontent/uploads/Stoke-PR-Dec-1-1.pdf
  • Perucca P, Perucca E. Identifying mutations in epilepsy genes: impact on treatment selection. Epilepsy Res. 2019;152:18–30.
  • Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190–198.
  • De Sarro G, Ongini E, Bertorelli R, et al. Excitatory amino acid neurotransmission through both NMDA and non-NMDA receptors is involved in the anticonvulsant activity of felbamate in DBA/2 mice. Eur J Pharmacol. 1994;262:11–19.
  • Reif PS, Tsai MH, Helbig I, et al. Precision medicine in genetic epilepsies: break of dawn? Expert Rev Neurother. 2017;17:381–392.
  • Volkmann RA, Fanger CM, Anderson DR, et al. MPX-004 and MPX-007: new pharmacological tools to study the physiology of NMDA receptors containing the GluN2A subunit. PLoS One. 2016;11:e0148129.
  • Zhu S, Paoletti P. Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol. 2015;20:14–23.
  • Addis L, Virdee JK, Vidler LR, et al. Epilepsy associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency-molecular profiling and functional rescue. Sci Rep. 2017;7:66.
  • Strehlow V, Heyne HO, Vlaskamp DRM, et al. GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain. 2019;142:80–92.
  • Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428:486.
  • McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364:1134–1143.
  • Baulac S, Ishida S, Marsan E, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol. 2015;77:675–683.
  • Mikati MA, Jiang YH, Carboni M, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015;78:995–999.
  • Billakota S, Andresen JM, Gay BC, et al. Personalized medicine: vinpocetine to reverse effects of GABRB3 mutation. Epilepsia. 2019;60:2459–2465.

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