Genetic Discoveries Drive Molecular Analyses and Targeted Therapeutic Options in the Epilepsies

Current Neurology and Neuroscience Reports

Volumn 15, Issue 10, 2015, Pages

  Dhindsa, Ryan S ^a   Goldstein, David B ^a  

^a Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

Epilepsy genetics; Epilepsy models; Epileptic encephalopathies; Multielectrode arrays; Precision medicine

Indexed keywords

BRYOSTATIN; CLEMIZOLE; MEMANTINE; PROTEIN KINASE C INHIBITOR; PROTEIN KINASE C INHIBITOR PMA; QUINIDINE; UNCLASSIFIED DRUG; ANTICONVULSIVE AGENT;

ALG13 GENE; ANTICONVULSANT ACTIVITY; BENIGN CHILDHOOD EPILEPSY; BRAIN DISEASE; CAS9 GENE; CAUSAL ATTRIBUTION; CDKL5 GENE; CHD2 GENE; CHRNB2 GENE; CLINICAL EFFECTIVENESS; CONCEPTUAL FRAMEWORK; COPY NUMBER VARIATION; CRISPR GENE; DNM1 GENE; DRUG EFFICACY; DRUG TARGETING; EPILEPSY; EPILEPSY OF INFANCY WITH MIGRATING FOCAL SEIZURE; EPILEPTIC ENCEPHALOPATHY; EXPERIMENTAL EPILEPSY; FOCAL EPILEPSY; GABRB3 GENE; GENE; GENE FREQUENCY; GENE FUNCTION; GENE IDENTIFICATION; GENE TARGETING; GENERALIZED EPILEPSY; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC MARKER; GENETIC RISK; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; GRIN2A GENE; HUMAN; KCNT1 GENE; KETOGENIC DIET; LGI1 GENE; MICROARRAY KIT; MOUSE MODEL; MULTIELECTRODE ARRAY; MUTATIONAL ANALYSIS; NEUROPATHOLOGY; NONHUMAN; PATCH CLAMP TECHNIQUE; PHARMACOGENETICS; PRACTICE GUIDELINE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SCN1A GENE; SEVERE MYOCLONIC EPILEPSY IN INFANCY; SINGLE NUCLEOTIDE POLYMORPHISM; STXBP1 GENE; SYN1 GENE; TRANSGENIC ZEBRAFISH; ANIMAL; ELECTRODE IMPLANT; GENETIC PREDISPOSITION; GENETICS; MUTATION; PATHOPHYSIOLOGY;

ANIMALS; ANTICONVULSANTS; ELECTRODES, IMPLANTED; EPILEPSY; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MUTATION;

EID: 84940639930     PISSN: 15284042     EISSN: 15346293     Source Type: Journal    
DOI: 10.1007/s11910-015-0587-4     Document Type: Review

References (95)

1. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793–5.
2. Delanty N, Goldstein DB. Diagnostic exome sequencing: a new paradigm in neurology. Neuron. 2013;80(4):841–3.
3. England MJ, Liverman CT, Schultz AM, Strawbridge LM. Epilepsy across the spectrum: promoting health and understanding. A summary of the institute of medicine report. Epilepsy Behav E&B. 2012;25(2):266–76.
4. Speed D, O'Brien TJ, Palotie A, Shkura K, Marson AG, Balding DJ, et al. Describing the genetic architecture of epilepsy through heritability analysis. Brain J Neurol. 2014;137(Pt 10):2680–9.
5. Berkovic SF, Howell RA, Hay DA, Hopper JL. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998;43(4):435–45.
6. Miller LL, Pellock JM, DeLorenzo RJ, Meyer JM, Corey LA. Univariate genetic analyses of epilepsy and seizures in a population-based twin study: the Virginia twin registry. Genet Epidemiol. 1998;15(1):33–49.
7. Kjeldsen MJ, Kyvik KO, Christensen K, Friis ML. Genetic and environmental factors in epilepsy: a population-based study of 11900 Danish twin pairs. Epilepsy Res. 2001;44(2-3):167–78.
8. Peljto AL, Barker-Cummings C, Vasoli VM, Leibson CL, Hauser WA, Buchhalter JR, et al. Familial risk of epilepsy: a population-based study. Brain J Neurol. 2014;137(Pt 3):795–805.
9. Thomas RH, Berkovic SF. The hidden genetics of epilepsy—a clinically important new paradigm. Nat Rev Neurol. 2014;10(5):283–92.
10. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508(7497):469–76.
11. Helbig I, Scheffer IE, Mulley JC, Berkovic SF. Navigating the channels and beyond: unravelling the genetics of the epilepsies. Lancet Neurol. 2008;7(3):231–45.
12. Christensen J, Pedersen MG, Pedersen CB, Sidenius P, Olsen J, Vestergaard M. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet. 2009;373(9669):1105–10.
13. Kariuki SM, Rockett K, Clark TG, Reyburn H, Agbenyega T, Taylor TE, et al. The genetic risk of acute seizures in African children with falciparum malaria. Epilepsia. 2013;54(6):990–1001.
14. Dichgans M. Genetics of ischaemic stroke. Lancet Neurol. 2007;6(2):149–61.
15. Crompton DE, Scheffer IE, Taylor I, Cook MJ, McKelvie PA, Vears DF, et al. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance. Brain J Neurol. 2010;133(11):3221–31.
16. Speed D, Hoggart C, Petrovski S, Tachmazidou I, Coffey A, Jorgensen A, et al. A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy. Hum Mol Genet. 2014;23(1):247–58.
17. Consortium E, Consortium EM, Steffens M, Leu C, Ruppert AK, Zara F, 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(24):5359–72.
18. Kasperaviciute D, Catarino CB, Heinzen EL, Depondt C, Cavalleri GL, Caboclo LO, et al. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. Brain J Neurol. 2010;133(Pt 7):2136–47.
19. Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.
20. ILAE Consortium on Complex Epilepsies. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 2014;13(9):893–903.
21. Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB. Rare variants create synthetic genome-wide associations. PLoS Biol. 2010;8(1):e1000294.
22. Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41(2):160–2.
23. Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Human Genet. 2010;86(5):707–18.
24. Mefford HC, Muhle H, Ostertag P, von Spiczak S, Buysse K, Baker C, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010;6(5):e1000962.
25. de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain J Neurol. 2010;133(Pt 1):23–32.
26. Dulac O. Epileptic encephalopathy. Epilepsia. 2001;42 Suppl 3:23–6.
27. Epi4K Consortium. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217–21.
28. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–30.
29. Kodera H, Kato M, Nord AS, Walsh T, Lee M, Yamanaka G, et al. Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy. Epilepsia. 2013;54(7):1262–9.
30. Euro Epinomics- R. E. S. 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(4):360–70. In this large scale collaboration, the EuroEPINOMICS and Epi4K consortia examined de novo mutations in 356 trios. They identified causal mutations in 12 % of the trios and interestingly, 75 % of these mutations occurred in genes involved in vesicle trafficing. This finding suggests that synaptic dysregulation plays an important role in the epileptic encephalopathies.
31. Veeramah KR, Johnstone L, Karafet TM, Wolf D, Sprissler R, Salogiannis J, et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia. 2013;54(7):1270–81.
32. Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, et al. A de novo paradigm for mental retardation. Nat Genet. 2010;42(12):1109–12.
33. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485(7397):242–5.
34. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012;488(7412):471–5.
35. Heinzen EL, Neale BM, Traynelis SF, Allen AS, Goldstein DB. The Genetics of Neuropsychiatric Diseases: Looking In and Beyond the Exome. Annu Rev Neurosci. 2015.
36. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9(8):e1003709.
37. Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, et al. A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014;46(9):944–50.
38. Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012;40:W452–7. Web Server issue.
39. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Current protocols in human genetics / editorial board, Jonathan L Haines [et al]. 2013;Chapter 7:Unit7 20.
40. Grone BP, Baraban SC. Animal models in epilepsy research: legacies and new directions. Nat Neurosci. 2015;18(3):339–43.
41. Fetcho JR. The utility of zebrafish for studies of the comparative biology of motor systems. J Exp Zool B Mol Dev Evol. 2007;308(5):550–62.
42. Holder N, Xu Q. The zebrafish: an overview of its early development. Methods Mol Biol. 2008;461:483–91.
43. Best JD, Alderton WK. Zebrafish: an in vivo model for the study of neurological diseases. Neuropsychiatr Dis Treat. 2008;4(3):567–76.
44. Hortopan GA, Dinday MT, Baraban SC. Zebrafish as a model for studying genetic aspects of epilepsy. Dis Model Mech. 2010;3(3-4):144–8.
45. Stewart AM, Desmond D, Kyzar E, Gaikwad S, Roth A, Riehl R, et al. Perspectives of zebrafish models of epilepsy: what, how and where next? Brain Res Bull. 2012;87(2-3):135–43.
46. Bill BR, Petzold AM, Clark KJ, Schimmenti LA, Ekker SC. A primer for morpholino use in zebrafish. Zebrafish. 2009;6(1):69–77.
47. Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, et al. Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat Biotechnol. 2013;31(3):227–9.
48. Baraban SC, Dinday MT, Hortopan GA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential dravet syndrome treatment. Nat Commun. 2013;4:2410. In this paper, Baraban and colleagues illustrate the power of the zebrafish model for drug discovery by creating an Scn1a mutant line and testing a re-purposed drug library. They found that clemizole may be a promising candidate drug for the treatment of Dravet syndrome.
49. Teng Y, Xie X, Walker S, Rempala G, Kozlowski DJ, Mumm JS, et al. Knockdown of zebrafish Lgi1a results in abnormal development, brain defects and a seizure-like behavioral phenotype. Hum Mol Genet. 2010;19(22):4409–20.
50. Suls A, Jaehn JA, Kecskes A, Weber Y, Weckhuysen S, Craiu DC, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 2013;93(5):967–75.
51. Schubert J, Siekierska A, Langlois M, May P, Huneau C, Becker F, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet. 2014;46(12):1327–32.
52. Hafezparast M, Ahmad-Annuar A, Wood NW, Tabrizi SJ, Fisher EM. Mouse models for neurological disease. Lancet Neurol. 2002;1(4):215–24.
53. Harper A. Mouse models of neurological disorders—a comparison of heritable and acquired traits. Biochim Biophys Acta. 2010;1802(10):785–95.
54. Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, et al. CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell. 2014;159(2):440–55.
55. Sander JD, Joung JK. CRISPR-Cas systems for editing, regulating and targeting genomes. Nat Biotechnol. 2014;32(4):347–55.
56. Boumil RM, Letts VA, Roberts MC, Lenz C, Mahaffey CL, Zhang ZW, et al. A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. PLoS Genet. 2010;6(8).
57. Dhindsa RS, Bradrick SS, Yao X, Heinzen EL, Petrovski S, Krueger BJ, et al. Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet. 2015;1(1):e4.
58. Valentin A. Techniques used to study epilepsy in the laboratory: experimental techniques in basic neurophysiology. In: Gonzalo A, Valentin A, editors. Introduction to epilepsy. 1. New York: Cambridge University Press; 2012. p. 32.
59. Drapeau P, Ali DW, Buss RR, Saint-Amant L. In vivo recording from identifiable neurons of the locomotor network in the developing zebrafish. J Neurosci Methods. 1999;88(1):1–13.
60. Wei H-p, Yao Y-y, Zhang R-w, Zhao X-f, Du J-l. Activity-induced long-term potentiation of excitatory synapses in developing zebrafish retina in vivo. Neuron. 2012;75(3):479–89.
61. Nagtegaal AP, Borst JGG. In vivo dynamic clamp study of Ih in the mouse inferior colliculus. J Neurophysiol. 2010;104(2):940–8.
62. Ma C, Donnelly DF, LaMotte RH. In vivo visualization and functional characterization of primary somatic neurons. J Neurosci Methods. 2010;191(1):60–5.
63. Yajuan X, Xin L, Zhiyuan L. A comparison of the performance and application differences between manual and automated patch-clamp techniques. Curr Chem Genomics. 2012;6:87–92.
64. Zhao Y, Inayat S, Dikin DA, Singer JH, Ruoff RS, Troy JB. Patch clamp technique: review of the current state of the art and potential contributions from nanoengineering. Proc Inst Mech Eng N J Nanoengineering Nanosystems. 2009;222:1–11.
65. Spira ME, Hai A. Multi-electrode array technologies for neuroscience and cardiology. Nat Nanotechnol. 2013;8(2):83–94.
66. Chen C, Chen L, Lin Y, Zeng S, Luo Q. The origin of spontaneous synchronized burst in cultured neuronal networks based on multi-electrode arrays. Biosystems. 2006;85(2):137–43.
67. Valdivia P, Martin M, LeFew WR, Ross J, Houck KA, Shafer TJ. Multi-well microelectrode array recordings detect neuroactivity of ToxCast compounds. Neurotoxicology. 2014;44:204–17.
68. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron. 2013;78(3):510–22.
69. Lignani G, Raimondi A, Ferrea E, Rocchi A, Paonessa F, Cesca F, et al. Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity. Hum Mol Genet. 2013;22(11):2186–99.
70. Gullo F, Manfredi I, Lecchi M, Casari G, Wanke E, Becchetti A. Multi-electrode array study of neuronal cultures expressing nicotinic beta2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy. Front Neural Circuits. 2014;8:87.
71. Zhu X, Need AC, Petrovski S, Goldstein DB. One gene, many neuropsychiatric disorders: lessons from Mendelian diseases. Nat Neurosci. 2014;17(6):773–81.
72. Lancaster MA, Knoblich JA. Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 2014;9(10):2329–40.
73. Petrovski S, Kwan P. Unraveling the genetics of common epilepsies: approaches, platforms, and caveats. Epilepsy Behav E&B. 2013;26(3):229–33.
74. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342(5):314–9.
75. Baranano KW, Hartman AL. The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol. 2008;10(6):410–9.
76. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008;7(6):500–6.
77. Klepper J, Scheffer H, Leiendecker B, Gertsen E, Binder S, Leferink M, et al. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics. 2005;36(5):302–8.
78. Pascual JM, Wang D, Hinton V, Engelstad K, Saxena CM, Van Heertum RL, et al. Brain glucose supply and the syndrome of infantile neuroglycopenia. Arch Neurol. 2007;64(4):507–13.
79. Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 2009;31(7):545–52.
80. Thammongkol S, Vears DF, Bicknell-Royle J, Nation J, Draffin K, Stewart KG, et al. Efficacy of the ketogenic diet: which epilepsies respond? Epilepsia. 2012;53(3):e55–9.
81. Galanopoulou AS, Moshe SL. Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: a view from preclinical studies. Neurobiol Dis. 2015;79:135–49.
82. Cunliffe VT, Baines RA, Giachello CN, Lin WH, Morgan A, Reuber M, et al. Epilepsy research methods update: understanding the causes of epileptic seizures and identifying new treatments using non-mammalian model organisms. Seizure. 2015;24:44–51.
83. 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(11):1255–9.
84. 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(11):1188–90.
85. 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(4):581–90. Milligan et al. use patch clamping to illustrate that large potassium currents resulting from epilepsy causing mutations in KCNT1 can be reversed by quinidine, an FDA approved drug. This finding eventually led to targeted treatment in an EIMFS patient by Bearden et al.
86. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76(3):457–61.
87. Padilla KM, Antonio BM, Santos SC, Lin Z, Theile JW, Chapman ML, et al. Approaches to understanding human ion channel genetic variation and disease - an example with a KCNT1 variant and infantile epilepsy disorder. 2014.
88. 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(9):1073–6.
89. 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(9):1067–72.
90. 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(9):1061–6.
91. Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. Mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):190–8. Pierson et al. use exome sequencing to detect a de novo GRIN2A mutation in a proband suffering from an epileptic encephalopathy. Functional modeling and drug screening suggested that memantine may reverse the effects of the mutation. After receiving memantine treatment, the proband experienced a reduced seizure burden.
92. 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.
93. Perucca P, O'Brien TJ. Epilepsy in 2014. Novel and large collaborations drive advances in epilepsy. Nat Rev Neurol. 2015;11(2):74–6.
94. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde BW, 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(4):676–85.
95. Poduri A, Sheidley BR, Shostak S, Ottman R. Genetic testing in the epilepsies-developments and dilemmas. Nat Rev Neurol. 2014;10(5):293–9.