Precision medicine in genetic epilepsies: break of dawn?

Expert Review of Neurotherapeutics

Volumn 17, Issue 4, 2017, Pages 381-392

  Reif, Philipp Sebastian ^a   Tsai, Meng Han ^b   Helbig, Ingo ^c,d,e   Rosenow, Felix ^a,f   Klein, Karl Martin ^a,f  

^a GOETHE UNIVERSITY   (Germany)

^b CHANG GUNG MEMORIAL HOSPITAL   (Taiwan)

^c CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^d UNIVERSITY OF KIEL   (Germany)

^e BEN GURION UNIVERSITY OF THE NEGEV   (Israel)

^f PHILIPPS UNIVERSITY MARBURG   (Germany)

Author keywords

Epilepsy genetics; personalized medicine; precision medicine; translational epilepsy research

Indexed keywords

ANTICONVULSIVE AGENT; DEPDC5 PROTEIN; GLUCOSE TRANSPORTER 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 2A; N METHYL DEXTRO ASPARTIC ACID RECEPTOR 2B; NPRL2 PROTEIN; NPRL3 PROTEIN; POTASSIUM CHANNEL; POTASSIUM CHANNEL KCNQ2; POTASSIUM CHANNEL KV1.2; PROTEIN; SODIUM CHANNEL NAV1.1; SODIUM CHANNEL NAV1.2; SODIUM CHANNEL NAV1.6; SODIUM DEPENDENT POTASSIUM CHANNEL T1; UNCLASSIFIED DRUG;

ANTICONVULSANT THERAPY; EPILEPSY; EPILEPTOGENESIS; GENE MUTATION; HUMAN; KETOGENIC DIET; MOLECULAR PATHOLOGY; NONHUMAN; PERSONALIZED MEDICINE; REVIEW; GENETICS; MUTATION;

ANTICONVULSANTS; EPILEPSY; HUMANS; KETOGENIC DIET; MUTATION; PRECISION MEDICINE;

EID: 85014972989     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1080/14737175.2017.1253476     Document Type: Review

References (162)

1. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy:an unblinded randomised controlled trial. Lancet. 2007;369:1016–1026.
2. Thomas P, Valton L, Genton P., Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain. 2006;129:1281–1292.
3. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314–319.
4. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis:an observational cohort study. Lancet Neurol. 2013;12:157–165.
5. Lennox WG. The heredity of epilepsy as told by relatives and twins. J Am Med Assoc. 1951;146:529–536.
6. Vadlamudi L, Andermann E, Lombroso CT, et al. Epilepsy in twins:insights from unique historical data of William Lennox. Neurology. 2004;62:1127–1133.
7. Berkovic SF, Howell RA, Hay DA, et al. Epilepsies in twins:genetics of the major epilepsy syndromes. Ann Neurol. 1998;43:435–445.
8. 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.
9. International League Against Epilepsy. Genetic determinants of common epilepsies:a meta-analysis of genome-wide association studies. Lancet Neurol. 2014;13:893–903.
10. Steffens M, Leu C, Ruppert AK, et al. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum Mol Genet. 2012;21:5359–5372.
11. Thomas RH, Berkovic SF. The hidden genetics of epilepsy-a clinically important new paradigm. Nat Rev Neurol. 2014;10:283–292.•• Review on the genetics of epilepsy.
12. Epilepsy Phenome/Genome Project, Epi4K. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–221.
13. EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360–370.
14. Chung W, Hung S, Hong H, et al. Medical genetics:a marker for Stevens-Johnson syndrome. Nature. 2004;428:486.
15. Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327–1332.
16. Marini C, Mei D, Temudo T, et al. Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities. Epilepsia. 2007;48:1678–1685.
17. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clin ical phenotypes. Brain. 1997;120:479–490.
18. Harkin LA, McMahon JM, Iona X, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain. 2007;130:843–852.
19. Ogiwara I, Miyamoto H, Morita N, 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;27:5903–5914.
20. Martin MS, Dutt K, Papale LA, et al. Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities. J Biol Chem. 2010;285:9823–9834.
21. Yu FH, Mantegazza M, Westenbroek RE, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci. 2006;9:1142–1149.
22. Zuberi SM, Brunklaus A, Birch R, et al. Genotype-phenotype associations in SCN1A-related epilepsies. Neurology. 2011;76:594–600.
23. Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39:508–512.
24. Brunklaus A, Ellis R, Reavey E, et al. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain. 2012;135:2329–2336.• Review of 241 patients with SCN1A-positive Dravet syndrome describing seizure aggravation with carbamazepine and lamotrigine.
25. Dalic L, Mullen SA, Roulet Perez E, et al. Lamotrigine can be beneficial in patients with Dravet syndrome. Dev Med Child Neurol. 2015;57:200–202.
26. Tang B, Dutt K, Papale L, et al. A BAC transgenic mouse model reveals neuron subtype-specific effects of a generalized epilepsy with febrile seizures plus (GEFS+) mutation. Neurobiol Dis. 2009;35:91–102.
27. Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures:task force report for the ILAE commission of pediatrics. Epilepsia. 2015;56:1185–1197.
28. Chiron C. Stiripentol. Neurotherapeutics. 2007;4:123–125.
29. Sada N, Lee S, Katsu T, et al. Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015;347:1362–1367.
30. McCann UD, Seiden LS, Rubin LJ, et al. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence. JAMA. 1997;278:666–672.
31. Dahl CF, Allen MR, Urie PM, et al. Valvular regurgitation and surgery associated with fenfluramine use:an analysis of 5743 individuals. BMC Med. 2008;6:34.
32. Fuller RW, Snoddy HD, Robertson DW. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats:uptake inhibition versus release. Pharmacol Biochem Behav. 1988;30:715–721.
33. Ceulemans B, Boel M, Leyssens K, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia. 2012;53:1131–1139.
34. Ceulemans B, Schoonjans A, Marchau F, et al. Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. Epilepsia. 2016;57:e129–34.
35. Seidner G, Alvarez MG, Yeh JI, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet. 1998;18:188–191.
36. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med. 1991;325:703–709.
37. Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Investig. 2008;118:2157–2168.
38. Suls A, Dedeken P, Goffin K, et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain. 2008;131:1831–1844.
39. Suls A, Mullen SA, Weber YG, et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol. 2009;66:415–419.
40. 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.
41. Mullen SA, Marini C, Suls A, et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Archives of Neurology. 2011;68:1152–1155.
42. Mullen SA, Suls A, de Jonghe P, et al. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology. 2010;75:432–440.
43. Striano P, Weber YG, Toliat MR, et al. GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology. 2012;78:557–562.
44. Arsov T, Mullen SA, Rogers S, et al. Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol. 2012;72:807–815.• Identification of SLC2A1 mutations in patients with genetic generalized epilepsy and discussion of the ketogenic diet in milder cases of GLUT1 deficiency.
45. Klepper J, Diefenbach S, Kohlschütter A, et al. Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot Essent Fatty Acids. 2004;70:321–327.
46. Kass HR, Winesett SP, Bessone SK, et al. Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure. 2016;35:83–87.
47. Gumus H, Bayram AK, Kardas F, et al. The effects of ketogenic diet on seizures, cognitive functions, and other neurological disorders in classical phenotype of glucose transporter 1 deficiency syndrome. Neuropediatrics. 2015;46:313–320.
48. Fujii T, Ito Y, Takahashi S, et al. Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan:a nationwide survey. Brain Dev. 2016. DOI:10.1016/j.braindev.2016.01.002
49. Amalou S, Gras D, Ilea A, et al. Use of modified Atkins diet in glucose transporter type 1 deficiency syndrome. Dev Med Child Neurol. 2016 cited 2016 Jun8. DOI:10.1111/dmcn.13167
50. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:25–29.
51. Miles DK, Holmes GL. Benign neonatal seizures. J Clin Neurophysiol. 1990;7:369–379.
52. 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.
53. Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy:emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71:15–25.
54. Weckhuysen S, Ivanovic V, Hendrickx R, et al. Extending the KCNQ2 encephalopathy spectrum:clinical and neuroimaging findings in 17 patients. Neurology. 2013;81:1697–1703.
55. Kato M, Yamagata T, Kubota M, et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia. 2013;54:1282–1287.
56. Orhan G, Bock M, Schepers D, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75:382–394.
57. Miceli F, Soldovieri MV, Ambrosino P, et al. Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J Neurosci. 2015;35:3782–3793.
58. Devaux J, Abidi A, Roubertie A, et al. A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity. Epilepsia. 2016;57:e87–93.
59. Wang J, Li Y, Hui Z, et al. Functional analysis of potassium channels in Kv7.2 G271V mutant causing early onset familial epilepsy. Brain Res. 2015;1616:112–122.
60. 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.
61. 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.
62. Numis AL, Angriman M, Sullivan JE, et al. KCNQ2 encephalopathy:delineation of the electroclinical phenotype and treatment response. Neurology. 2014;82:368–370.
63. Pisano T, Numis AL, Heavin SB, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia. 2015;56:685–691.• Study of 15 patients with KCNQ2 encephalopathy recommending sodium channel blockers as first-line treatment.
64. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372:657–668.
65. Saxena A, Sampson JR. Epilepsy in tuberous sclerosis:phenotypes, mechanisms, and Treatments. Semin Neurol. 2015;35:269–276.
66. Curatolo P, Moavero R, Roberto D, et al. Genotype/phenotype correlations in tuberous sclerosis complex. Semin Pediatr Neurol. 2015;22:259–273.
67. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–1811.
68. Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74:679–687.
69. Franz DN, Agricola K, Mays M, et al. Everolimus for subependymal giant cell astrocytoma:5-year final analysis. Ann Neurol. 2015;78:929–938.
70. 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 cited 2016 Sep6. DOI:10.1016/S0140-6736(16)31419-2
71. 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.
72. Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet. 2013;45:552–555.
73. Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clin Genet. 2014;86:570–574.
74. Scheffer IE, Phillips HA, O’Brien CE, et al. Familial partial epilepsy with variable foci:a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann Neurol. 1998;44:890–899.
75. Xiong L, Labuda M, Li DS, et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet. 1999;65:1698–1710.
76. Callenbach P, van den Maagdenberg AM, Hottenga JJ, et al. Familial partial epilepsy with variable foci in a Dutch family:clinical characteristics and confirmation of linkage to chromosome 22q. Epilepsia. 2003;44:1298–1305.
77. Berkovic SF, Serratosa JM, Phillips HA, et al. Familial partial epilepsy with variable foci:clinical features and linkage to chromosome 22q12. Epilepsia. 2004;45:1054–1060.
78. Morales-Corraliza J, Gómez-Garre P, Sanz R, et al. Familial partial epilepsy with variable foci:a new family with suggestion of linkage to chromosome 22q12. Epilepsia. 2010;51:1910–1914.
79. Klein KM, O’Brien TJ, Praveen K, et al. Familial focal epilepsy with variable foci mapped to chromosome 22q12:expansion of the phenotypic spectrum. Epilepsia. 2012;53:e151–5.
80. Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82:2101–2106.
81. Striano P, Serioli E, Santulli L, et al. DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia. 2015;56:e168–71.
82. Lal D, Reinthaler EM, Schubert J, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75:788–792.
83. Carvill GL, Crompton DE, Regan BM, et al. Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol Genet. 2015;1:e17.
84. Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340:1100–1106.
85. Scheffer IE, Heron SE, Regan BM, et al. Mutations in mTOR regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75:782–787.• Identification of cortical dysplasia in patients with DEPDC5 mutations and discussion of mTOR inhibitors as a potential precision medicine approach.
86. 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.
87. Scerri T, Riseley JR, Gillies G, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol. 2015;2:575–580.
88. Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016;79:120–131.
89. Sim JC, Scerri T, Fanjul-Fernández M, et al. Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol. 2016;79:132–137.
90. Weckhuysen S, Marsan E, Lambrecq V, et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia. 2016;57:994–1003.
91. Korenke G, 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.
92. Liao Y, Anttonen AK, Liukkonen E, et al. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology. 2010;75:1454–1458.
93. Heron SE, Crossland KM, Andermann E, et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002;360:851–852.
94. 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.• Review of 12 own and 34 reported cases with SCN2A encephalopathy discussing sodium channel blockers as potential precision medicine approach.
95. Ogiwara I, Ito K, Sawaishi Y, et al. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology. 2009;73:1046–1053.
96. Nakamura K, Kato M, Osaka H, et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology. 2013;81:992–998.
97. Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–241.
98. 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.
99. Kamiya K, Kaneda M, Sugawara T, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J Neurosci. 2004;24:2690–2698.
100. Baasch AL, Huning I, Gilissen C, et al. Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures, severe intellectual disability, optic atrophy, muscular hypotonia, and brain abnormalities. Epilepsia. 2014;55:e25–9.
101. Meisler MH, O’Brien JE, Sharkey LM. Sodium channel gene family:epilepsy mutations, gene interactions and modifier effects. J Physiol. 2010;588:1841–1848.
102. Misra SN, Kahlig KM, George AL, Jr. Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. Epilepsia. 2008;49:1535–1545.
103. Horvath GA, Demos M, Shyr C, et al. Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathiesa potential treatment target? Mol Genet Metab. 2016;117:42–48.
104. Wagnon JL, Meisler MH. Recurrent and non-recurrent mutations of SCN8A in epileptic encephalopathy. Front Neurol. 2015;6:104.
105. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825–830.
106. Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology. 2015;84:480–489.• Study of 17 patients with SCN8A encephalopathy describing the phenotypic spectrum and the effect of sodium channel blockers.
107. Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia. 2014;55:994–1000.
108. Trudeau MM, Dalton JC, Day JW, et al. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet. 2006;43:527–530.
109. Veeramah KR, O’Brien JE, Meisler MH, 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;90:502–510.
110. Kong W, Zhang Y, Gao Y, et al. SCN8A mutations in Chinese children with early onset epilepsy and intellectual disability. Epilepsia. 2015;56:431–438.
111. Wagnon JL, Korn MJ, Parent R, et al. Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy. Hum Mol Genet. 2015;24:506–515.
112. Blanchard MG, Willemsen MH, Walker JB, et al. De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet. 2015;52:330–337.
113. Boerma RS, Braun KP, van den Broek MP, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsya molecular neuropharmacological approach. Neurotherapeutics. 2016;13:192–197.
114. Dyment DA, Tétreault M, Beaulieu CL, et al. Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy:a retrospective study. Clin Genet. 2015;88:34–40.
115. Mercimek-Mahmutoglu S, Patel J, Cordeiro D, et al. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015;56:707–716.
116. Vaher U, Nõukas M, Nikopensius T, et al. De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders. J Child Neurol. 2014;29:NP202–6.
117. Takahashi S, Yamamoto S, Okayama A, et al. Electroclinical features of epileptic encephalopathy caused by SCN8A mutation. Pediatr Int. 2015;57:758–762.
118. Anand G, Collett-White F, Orsini A, et al. Autosomal dominant SCN8A mutation with an unusually mild phenotype. Eur J Paediatr Neurol. 2016;20:761–765.
119. Singh R, Jayapal S, Goyal S, et al. Early-onset movement disorder and epileptic encephalopathy due to de novo dominant SCN8A mutation. Seizure. 2015;26:69–71.
120. de Kovel CGF, Meisler MH, Brilstra EH, et al. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res. 2014;108:1511–1518.
121. Estacion M, O’Brien JE, Conravey A, et al. A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis. 2014;69:117–123.
122. Barker BS, Ottolini M, Wagnon JL, et al. The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin. Epilepsia. 2016. DOI:10.1111/epi.13461
123. 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;44:1255–1259.
124. Bhattacharjee A, Gan L, Kaczmarek LK. Localization of the Slack potassium channel in the rat central nervous system. J Comp Neurol. 2002;454:241–254.
125. Yuan A, Santi CM, Wei A, et al. The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron. 2003;37:765–773.
126. 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.
127. Vanderver A, Simons C, Schmidt JL, et al. Identification of a novel de novo p.Phe932Ile KCNT1 mutation in a patient with leukoencephalopathy and severe epilepsy. Pediatr Neurol. 2014;50:112–114.
128. McTague A, Appleton R, Avula S, et al. Migrating partial seizures of infancy:expansion of the electroclinical, radiological and pathological disease spectrum. Brain. 2013;136:1578–1591.
129. Coppola G, Plouin P, Chiron C, et al. Migrating partial seizures in infancy:a malignant disorder with developmental arrest. Epilepsia. 1995;36:1017–1024.
130. Moller RS, Heron SE, Larsen LH, et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia. 2015;56:e114–20.
131. Ishii A, Shioda M, Okumura A, et al. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene. 2013;531:467–471.
132. Kim GE, Kaczmarek LK. Emerging role of the KCNT1 Slack channel in intellectual disability. Front Cell Neurosci. 2014;8:209.
133. Villa C, Combi R. Potassium channels and human epileptic phenotypes:an updated overview. Front Cell Neurosci. 2016;10:81.
134. Yang B, Gribkoff VK, Pan J, et al. Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology. 2006;51:896–906.
135. Milligan CJ, Li M, Gazina EV, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014;75:581–590.
136. Bearden D, Strong A, Ehnot J, et al. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76:457–461.
137. Mikati MA, Jiang Y, Carboni M, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015;78:995–999.•• Report on the application of quinidine in two patients with epilepsy due to KCNT1 mutations. Functional evaluation of the specific mutation is recommended before starting quinidine treatment.
138. Chong PF, Nakamura R, Saitsu H, et al. Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation. Ann Neurol. 2016;79:502–503.
139. 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.
140. Brew HM, Gittelman JX, Silverstein RS, et al. Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol. 2007;98:1501–1525.
141. Syrbe S, Hedrich UB, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet. 2015;47:393–399.
142. Pena SDJ, Coimbra RLM. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2:proposal for a new channelopathy. Clin Genet. 2015;87:e1–3.
143. Ramaswami M, Gautam M, Kamb A, et al. Human potassium channel genes:molecular cloning and functional expression. Mol Cell Neurosci. 1990;1:214–223.
144. Glasgow NG, Siegler Retchless B, Johnson JW. Molecular bases of NMDA receptor subtype-dependent properties. J Physiol. 2015;593:83–95.
145. 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.
146. Reutlinger C, Helbig I, Gawelczyk B, et al. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region. Epilepsia. 2010;51:1870–1873.
147. Lesca G, Rudolf G, Labalme A, 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;53:1526–1538.
148. Lemke JR, Lal D, Reinthaler EM, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067–1072.
149. Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45:1073–1076.
150. 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.
151. Lemke JR, Hendrickx R, Geider K, et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol. 2014;75:147–154.
152. Turner SJ, Mayes AK, Verhoeven A, et al. GRIN2A:an aptly named gene for speech dysfunction. Neurology. 2015;84:586–593.
153. Wirrell EC. Benign epilepsy of childhood with centrotemporal spikes. Epilepsia. 1998;39(Suppl 4):S32–41.
154. Marwick K, Skehel P, Hardingham G, et al. Effect of a GRIN2A de novo mutation associated with epilepsy and intellectual disability on NMDA receptor currents and Mg(2+) block in cultured primary cortical neurons. Lancet. 2015;385(Suppl 1):S65.
155. Yuan H, Hansen KB, Zhang J, et al. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun. 2014;5:3251.
156. Monyer H, Burnashev N, Laurie DJ, et al. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12:529–540.
157. Vicini S, Wang JF, Li JH, et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J Neurophysiol. 1998;79:555–566.
158. 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.
159. 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.
160. Harty TP, Rogawski MA. Felbamate block of recombinant N-methyl-D-aspartate receptors:selectivity for the NR2B subunit. Epilepsy Res. 2000;39:47–55.
161. Pellock JM. Felbamate. Epilepsia. 1999;40(Suppl 5):S57–62.
162. 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.