The hidden genetics of epilepsy - A clinically important new paradigm

Nature Reviews Neurology

Volumn 10, Issue 5, 2014, Pages 283-292

  Thomas, Rhys H ^a   Berkovic, Samuel F ^a  

^a NORTHERN HEALTH   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

QUINIDINE; RAPAMYCIN DERIVATIVE; GLUCOSE TRANSPORTER 1; NICOTINIC RECEPTOR ALPHA4;

CLINICAL FEATURE; COPY NUMBER VARIATION; COUNSELING; DRUG RESPONSE; EPILEPSY; EXOME; FAMILY HISTORY; FOCAL EPILEPSY; GAIN OF FUNCTION MUTATION; GENE SEQUENCE; GENETIC ASSOCIATION; GENETIC LINKAGE; GENETIC VARIABILITY; GENOME ANALYSIS; GENOTYPE ENVIRONMENT INTERACTION; HERITABILITY; HUMAN; INHERITANCE; KCNQ2 GENE; KCNT1 GENE; KETOGENIC DIET; MOLECULAR GENETICS; MONOGENIC DISORDER; MUTAGENESIS; MUTATOR GENE; NERVE STIMULATION; NEUROSURGERY; NONHUMAN; PHARMACOGENOMICS; PHENOTYPE; PRIORITY JOURNAL; PSYCHOPHARMACOTHERAPY; REVIEW; ANTICONVULSANT ACTIVITY; CLINICAL GENETICS; CLINICAL PRACTICE; DEPDC5 GENE; DIFFERENTIAL DIAGNOSIS; EPILEPTOGENESIS; FAMILIAL DISEASE; GENE; GENE STRUCTURE; GENETIC COUNSELING; GENETIC SCREENING; LENNOX GASTAUT SYNDROME; PERSONALIZED MEDICINE; PHENOTYPIC VARIATION; WEST SYNDROME;

DNA COPY NUMBER VARIATIONS; EPILEPSY; FAMILY HEALTH; GENETIC TESTING; GENOME; HUMANS; MUTATION;

EID: 84900862090     PISSN: 17594758     EISSN: 17594766     Source Type: Journal    
DOI: 10.1038/nrneurol.2014.62     Document Type: Review

References (114)

1. Reynolds, J. R. Epilepsy: Its Symptoms, Treatment, and Relation to Other Chronic Convulsive Diseases (Churchill, 1861
2. Lennox, W. G. Should they live?. Certain economic aspects of medicine. American Scholar 7, 454-466 (1938
3. Offen, M. L. Dealing with defectives. Foster Kennedy and William Lennox on eugenics. Neurology 61, 668-673 (2003
4. Lennox, W. G. The heredity of epilepsy as told by relatives and twins. JAMA 146, 529-536 (1951
5. Yu, S. et al. Fragile X genotype characterized by an unstable region of DNA. Science 252, 1179-1181 (1991
6. Mastrangelo, M., Celato, A. & Leuzzi, V. A diagnostic algorithm for the evaluation of early onset genetic-metabolic epileptic encephalopathies. Eur. J. Paediatr. Neurol. 16, 179-191 (2012
7. Crino, P. B., Nathanson, K. L. & Henske, E. P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345-1356 (2006
8. Fischer, A., Zalvide, J., Faurobert, E., Albiges-Rizo, C. & Tournier-Lasserve, E. Cerebral cavernous malformations: From CCM genes to endothelial cell homeostasis. Trends Mol. Med. 19, 302-308 (2013
9. Rett, A., Teubel, R. Neugeborenenkrämpfe im Rahmen einer epileptisch belasteten Familie[German]. Wien. Klin. Wochenschr. 74, 609-613 (1964
10. Crompton, D. E. et al. Familial mesial temporal lobe epilepsy: A benign epilepsy syndrome showing complex inheritance. Brain 133, 3221-3231 (2010
11. Helbig, I., Scheffer, I. E., Mulley, J. C. & Berkovic, S. F. Navigating the channels and beyond: Unravelling the genetics of the epilepsies. Lancet Neurol. 7, 231-245 (2008
12. Berkovic, S. F., Mulley, J. C., Scheffer, I. E. & Petrou, S. Human epilepsies: Interaction of genetic and acquired factors. Trends Neurosci. 29, 391-397 (2006
13. Christensen, J. et al. Long-Term risk of epilepsy after traumatic brain injury in children and young adults: A population-based cohort study. Lancet 373, 1105-1110 (2009
14. Kariuki, S. M. et al. The genetic risk of acute seizures in African children with falciparum malaria. Epilepsia 54, 990-1001 (2013
15. Hauser, W. A. & Kurland, L. T. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 16, 1-66 (1975
16. Shorvon, S. D., Andermann, F. & Guerrini, R. (Eds) The Causes of Epilepsy: Common and Uncommon Causes in Adults and Children (Cambridge University Press, 2011
17. Brenner, T. et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 54, 1028-1035 (2013
18. Quek, A. M. et al. Autoimmune epilepsy: Clinical characteristics and response to immunotherapy. Arch. Neurol. 69, 582-593 (2012
19. Dichgans, M. Genetics of ischaemic stroke. Lancet Neurol. 6, 149-161 (2007
20. Frattini, V. et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat. Genet. 45, 1141-1149 (2013
21. Barkovich, A. J., Guerrini, R., Kuzniecky, R. I., Jackson, G. D. & Dobyns, W. B. A developmental and genetic classification for malformations of cortical development: Update 2012. Brain 135, 1348-1369 (2012
22. Otte, W. M., Singla, M., Sander, J. W. & Singh, G. Drug therapy for solitary cysticercus granuloma: A systematic review and meta-Analysis. Neurology. 80, 152-162 (2013
23. Tsuobi, T. Epidemiology of febrile and afebrile convulsions in children in Japan. Neurology 34, 175-181 (1984
24. Berg, A. T. et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51, 676-685 (2010
25. King, M. A. et al. Epileptology of the first-seizure presentation: A clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet 352, 1007-1011 (1998
26. Corey, L. A., Pellock, J. M., Kjeldsen, M. J. & Nakken, K. O. Importance of genetic factors in the occurrence of epilepsy syndrome type: A twin study. Epilepsy Res. 97, 103-111 (2011
27. Annegers, J. F., Hauser, W. A., Anderson, V. E. & Kurland, L. T. The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology. 32, 174-179 (1982
28. Ottman, R. Genetic epidemiology of epilepsy. Epidemiol. Rev. 19, 120-128 (1997
29. Peljto, A. L. et al., Familial risk of epilepsy: A population-based study. Brain 137, 795-805 (2014
30. Dibbens, L. M., Heron, S. E. & Mulley, J. C. A polygenic heterogeneity model for common epilepsies with complex genetics. Genes Brain Behav. 6, 593-597 (2007
31. [No author listed] Concordance of clinical forms of epilepsy in families with several affected members. Italian League Against Epilepsy Genetic Collaborative Group. Epilepsia 34, 819-826 (1993
32. Heinzen, E. L. et al. Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy. Am. J. Hum. Genet. 91, 293-302 (2012
33. Klassen, T. et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 145, 1036-1048 (2011
34. The ENCODE Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799-816 (2007
35. Pennacchio, L. A. et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 271, 1731-1734 (1996
36. Cross-Disorder Group of the Psychiatric Genomics Consortium & Genetic Risk Outcome of Psychosis (GROUP) Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet 381, 1371-1379 (2013
37. The International Multiple Sclerosis Genetics Consortium and The Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214-219 (2011
38. Speed, D. 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. 23, 247-258 (2014
39. EPICURE Consortium & EMINet Consortium. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum. Mol. Genet. 21, 5359-5372 (2012
40. Kasperaviciute, D. et al. Common genetic variation and susceptibility to partial epilepsies: A genome-wide association study. Brain 133, 2136-2147 (2010
41. Steinlein, O. K. et al. A missense mutation in the neuronal nicotinic acetylcholine receptor a4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 11, 201-203 (1995
42. Mefford, H. C. et al., Rare copy number variants are an important cause of epileptic encephalopathies. Ann. Neurol. 70, 974-985 (2011
43. Mulley, J. C. & Mefford, H. C. Epilepsy and the new cytogenetics. Epilepsia 52, 423-432 (2011
44. Sebat, J. et al. Strong association of De novo copy number mutations with autism. Science 316, 445-449 (2007
45. De Kovel, C. G. et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133, 23-32 (2010
46. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237-241 (2008
47. Mefford, H. C. et al. Genome-wide copy number variation in epilepsy: Novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 6, e1000962 (2010
48. Epi4K Consortium & Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501, 217-221 (2013
49. Carvill, G. L. et al. Targeted resequencing in epileptic encephalopathies identifies De novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825-830 (2013
50. Kodera, H. Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy. Epilepsia 54, 1262-1269 (2013
51. Veeramah, K. R. et al. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54, 1270-1281 (2013
52. McIntosh, A. M. et al. Effects of vaccination on onset and outcome of Dravet syndrome: A retrospective study. Lancet Neurol. 9, 592-598 (2010
53. Berkovic, S. F. et al. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: A retrospective study. Lancet Neurol. 5, 488-492 (2006
54. Claes, L. et al. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum. Mutat. 21, 615-621 (2003
55. Harkin, L. A. et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130, 843-852 (2007
56. Vadlamudi, L. et al. Timing of De novo mutagenesis-A twin study of sodium-channel mutations. N. Engl. J. Med. 363, 1335-1340 (2010
57. Heron, S. E. et al. De novo SCN1A mutations in Dravet syndrome and related epileptic encephalopathies are largely of paternal origin. J. Med. Genet. 47, 137-141 (2010
58. Harkin, L. A. et al. Truncation of the GABAA-receptor ?2 subunit in a family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 70, 530-536 (2002
59. Depienne, C. et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resemble Dravet syndrome but mainly affects females. PLoS Genet. 5, e1000381 (2009
60. Deprez, L. et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology 75, 1159-1165 (2010
61. Marini, C. et al. Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy. Epilepsia 53, 2111-2119 (2012
62. Nakamura, K. et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81, 992-998 (2013
63. Kalscheuer, V. M. et al., Disruption of the serine/threonine kinase 9 gene causes severe X linked infantile spasms and mental retardation. Am. J. Hum. Genet. 72, 1401-1411 (2003
64. Kim, Y. O. et al. Head stereotypies in STXBP1 encephalopathy. Dev. Med. Child. Neurol. 55, 769-772 (2013
65. Lemke, J. R. et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 53, 1387-1398 (2012
66. Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S. & Goldstein, D. B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 9, e1003709 (2013
67. Kalachikov, S. et al. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat. Genet. 30, 335-341 (2002
68. Tan, N. C. et al. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology 63, 1090-1092 (2004
69. Dibbens, L. M. et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat. Genet. 45, 546-551 (2013
70. Ishida, S. et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat. Genet. 45, 552-555 (2013
71. Bar-Peled, L. et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100-1106 (2013
72. Scheffer, I. E. et al. Mutations in mTOR regulator DEPDC5 cause focal epilepsy with brain malformations. Ann. Neurol. http://dx.doi.org/10.1002/ana. 24126.
73. Lesca, G. et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat. Genet. 45, 1061-1066 (2013
74. Lemke, J. R. et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat. Genet. 45, 1067-1072 (2013
75. Carvill, G. L. et al. GRIN2A mutations cause epilepsy-Aphasia spectrum disorders. Nat. Genet. 45, 1073-1076 (2013
76. Heron, S. E. et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 44, 1188-1190 (2012
77. Barcia, G. et al. De novo gain of function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44, 1255-1259 (2012
78. Milligan, C. J. et al. KCNT1 gain of function in two epilepsy phenotypes is reversed by quinidine. Ann. Neurol. http://dx.doi.org/10.1002/ana.24128.
79. Biervert, C. et al. A potassium channel mutation in neonatal human epilepsy. Science 279, 403-406 (1998
80. Singh, N. A. et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat. Genet. 18, 25-29 (1998
81. Saitsu, H. et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann. Neurol. 72, 298-300 (2012
82. Weckhuysen, S. et al. KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15-25 (2012
83. Borgatti, R. et al. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology 63, 57-65 (2004
84. Thompson, R., Drew, C. J. & Thomas, R. H. Next generation sequencing in the clinical domain: Clinical advantages, practical and ethical challenges. Adv. Protein Chem. Struct. Biol. 89, 27-63 (2012
85. Hildebrand, M. S. et al., Recent advances in the molecular genetics of epilepsy. J. Med. Genet. 50, 271-279 (2013
86. Chen, W. J. et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat. Genet. 43, 1252-1255 (2011
87. Dixon-Salazar, T. J. et al. Exome sequencing can improve diagnosis and alter patient management. Sci. Transl. Med. 4, 138ra78 (2012
88. Le Fanu, J. Is modern genetics a blind alley?. Yes. BMJ 340, c1156 (2010
89. Niwano, K. et al. Lentiviral vector-mediated SERCA2 gene transfer protects against heart failure and left ventricular remodeling after myocardial infarction in rats. Mol. Ther. 16, 1026-1032 (2008
90. Kullmann, D. M., Schorge, S., Walker, M. C. & Wykes, R. C. Gene therapy in epilepsy-is it time for clinical trials?. Nat. Rev. Neurol. http://dx.doi.org/10.1038/nrneurol.2014.43.
91. Hammond, C. L., Thomas, R. H., Rees, M. I., Kerr, M. P. & Rapport, F. Implications for families of advances in understanding the genetic basis of epilepsy. Seizure 19, 675-679 (2010
92. Dibbens, L. M. et al. X linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat. Genet. 40, 776-781 (2008
93. Scheffer, I. E. et al. Epilepsy and mental retardation limited to females: An under-recognized disorder. Brain 131, 918-927 (2008
94. Morimoto, M. et al. SCN1A mutation mosaicism in a family with severe myoclonic epilepsy in infancy. Epilepsia 47, 1732-1736 (2006
95. Gennaro, E. et al. Somatic and germline mosaicisms in severe myoclonic epilepsy of infancy. Biochem. Biophys. Res. Commun. 341, 489-493 (2006
96. Depienne, C. et al. Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy. Hum. Mutat. 27, 389 (2006
97. Marini, C., Mei, D., Cross, H. J. & Guerrini, R. Mosaic SCN1A mutation in familial severe myoclonic epilepsy of infancy. Epilepsia 47, 1737-1740 (2006
98. Poduri, A. et al. Genetic testing in the epilepsies-developments and dilemmas. Nat. Rev. Neurol. http://dx.doi.org/10.1038/nrneurol.2014.60.
99. Mohamed, A. R. et al. Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring. Neurology 79, 2249-2257(2012
100. Scheffer, I. E. et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 130, 100-109 (2007
101. Neal, E. G. et al. The ketogenic diet for the treatment of childhood epilepsy: A randomised controlled trial. Lancet Neurol. 7, 500-506 (2008
102. Thammongkol, S. et al. Efficacy of the ketogenic diet: Which epilepsies respond?. Epilepsia 53, e55-e59 (2012
103. Suls, A. et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann. Neurol. 66, 415-419 (2009
104. Arsov, T. et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 53, e204-e207 (2007
105. Mullen, S. A., Suls, A., De Jonghe, P., Berkovic, S. F. & Scheffer, I. E. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 75, 432-440 (2010
106. De Vivo, D. C. et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N. Engl. J. Med. 325, 703-709 (1991
107. Bonnett, L. J., Tudur-Smith, C., Williamson, P. R. & Marson, A. G. Risk of recurrence after a first seizure and implications for driving: Further analysis of the multicentre study of early epilepsy and single seizures. BMJ 341, c6477 (2010
108. Chiron, C. & Dulac, O. The pharmacologic treatment of Dravet syndrome. Epilepsia 52 (Suppl. 2), 72-75 (2011
109. Chen, P. et al. Carbamazepine-induced toxic effects and HLA B. *1502 screening in Taiwan. N. Engl. J. Med. 364, 1126-1133 (2011
110. McCormack, M. et al. HLA A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N. Engl. J. Med. 364, 1134-1143 (2011
111. Dibbens, L. M. et al., Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: Precedent for disorders with complex inheritance. Hum. Mol. Genet. 18, 3626-3631 (2009
112. Inoue, Y. et al. Ring chromosome 20 and nonconvulsive status epilepticus. A new epileptic syndrome. Brain 120, 939-953 (1997
113. Conlin, L. K. et al., Molecular analysis of ring chromosome 20 syndrome reveals two distinct groups of patients. J. Med. Genet. 48, 1-9 (2011
114. Scheffer, I. E. & Berkovic, S. F. in Epilepsy: Problem Solving in Clinical Practice (eds Schmidt, D. & Schachter, S. C) 111-131 (Martin Duntz, 2000.