Genetics of Epilepsy

ABSTRACT

Epilepsy is a common and very heterogeneous neurologic disorder. Genetic factors are likely to play a role in most cases, either because the underlying cause of epilepsy is primarily genetic or because genes modulate susceptibility to an epileptogenic insult. Primarily genetic epilepsies include conditions in which altered brain development or neurodegeneration are at the basis of seizures, but also conditions in which the brain is grossly normal, and the main, if not only, clinical feature is epilepsy. These are called idiopathic epilepsies, though this definition may change in the future. A few idiopathic epilepsies are monogenic disorders due to mutations in a variety of genes affecting neuronal excitability, synaptic transmission, or network development. Most cases have a complex etiology that combines predisposing genetic variants with nongenetic factors. Few of these have been identified so far and only in very few affected individuals, consisting mostly of deletions of critical chromosomal regions. Genetic factors also play a role in the response to antiepileptic drugs, affecting both their efficacy and their tolerability. There have been recent advances in discovering such factors, in particular those underlying risk to medication toxicity.

Epilepsy - Mendelian genetics - complex genetics - gene mapping - mutation analysis - genetic association studies - copy number variation - single nucleotide polymorphism - ion channel - neurotransmitter - brain development - brain metabolism - pharmacogenetics - drug response - drug toxicity

REFERENCES

• 1 Banerjee P N, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy-a review.  Epilepsy Res. 2009;  85 (1) 31-45
• 2 Mullen S A, Scheffer I E. Translational research in epilepsy genetics: sodium channels in man to interneuronopathy in mouse.  Arch Neurol. 2009;  66 (1) 21-26
• 3 Berkovic S F, Howell R A, Hay D A, Hopper J L. Epilepsies in twins: genetics of the major epilepsy syndromes.  Ann Neurol. 1998;  43 (4) 435-445
• 4 Poduri A, Lowenstein D. Epilepsy genetics—past, present, and future.  Curr Opin Genet Dev. 2011;  21 (3) 325-332
• 5 Commission on Classification and Terminology of the International League Against Epilepsy . Proposal for revised classification of epilepsies and epileptic syndromes.  Epilepsia. 1989;  30 (4) 389-399
• 6 Berg A T, Berkovic S F, Brodie M J 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) 676-685
• 7 Nakayama J. Progress in searching for the febrile seizure susceptibility genes.  Brain Dev. 2009;  31 (5) 359-365
• 8 Wallace R H, Berkovic S F, Howell R A, Sutherland G R, Mulley J C. Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21.  J Med Genet. 1996;  33 (4) 308-312
• 9 Johnson E W, Dubovsky J, Rich S S et al.. Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest.  Hum Mol Genet. 1998;  7 (1) 63-67
• 10 Peiffer A, Thompson J, Charlier C et al.. A locus for febrile seizures (FEB3) maps to chromosome 2q23-24.  Ann Neurol. 1999;  46 (4) 671-678
• 11 Nakayama J, Hamano K, Iwasaki N et al.. Significant evidence for linkage of febrile seizures to chromosome 5q14-q15.  Hum Mol Genet. 2000;  9 (1) 87-91
• 12 Nabbout R, Prud'homme J-F, Herman A et al.. A locus for simple pure febrile seizures maps to chromosome 6q22-q24.  Brain. 2002;  125 (Pt 12) 2668-2680
• 13 Nakayama J, Yamamoto N, Hamano K et al.. Linkage and association of febrile seizures to the IMPA2 gene on human chromosome 18.  Neurology. 2004;  63 (10) 1803-1807
• 14 Siren A, Nuutila A, Anttonen A et al.. Febrile seizures and idiopathic epilepsy: a clinical and genetic study in a Finnish family.  Epilepsia. 2006;  47 12
• 15 Scheffer I E, Berkovic S F. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes.  Brain. 1997;  120 (Pt 3) 479-490
• 16 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 (2) 149-158
• 17 Ito M, Yamakawa K, Sugawara T, Hirose S, Fukuma G, Kaneko S. Phenotypes and genotypes in epilepsy with febrile seizures plus.  Epilepsy Res. 2006;  70 (Suppl 1) S199-S205
• 18 Scheffer I, Berkovic S. Generalized (genetic) epilepsy with febrile seizures plus. In: Engel J, Pedley T eds.. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott, Williams & Wilkins; 2008: 2553-2558
• 19 Wallace R H, Wang D W, Singh R et al.. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B.  Nat Genet. 1998;  19 (4) 366-370
• 20 Gambardella A, Marini C. Clinical spectrum of SCN1A mutations.  Epilepsia. 2009;  50 (Suppl 5) 20-23
• 21 Macdonald R L, Kang J Q, Gallagher M J. Mutations in GABAA receptor subunits associated with genetic epilepsies.  J Physiol. 2010;  588 (Pt 11) 1861-1869
• 22 Marini C, Mei D, Parmeggiani L et al.. Protocadherin 19 mutations in girls with infantile-onset epilepsy.  Neurology. 2010;  75 (7) 646-653
• 23 Depienne C, Trouillard O, Bouteiller D et al.. Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females.  Hum Mutat. 2011;  32 (1) E1959-E1975
• 24 Dravet C. Les épilepsies graves de l'enfant.  Vie Med. 1978;  8 543-548
• 25 Dravet C. The core Dravet syndrome phenotype.  Epilepsia. 2011;  52 (Suppl 2) 3-9
• 26 Zupanc M L. Clinical evaluation and diagnosis of severe epilepsy syndromes of early childhood.  J Child Neurol. 2009;  24 (8, Suppl) 6S-14S
• 27 Ohtahara S et al.. On the specific age dependent epileptic syndrome: the early- infantile epileptic encephalopathy with suppression-burst. [in Japanese with English abstract].  No To Hattatsu. 1976;  8 270-279
• 28 Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.  Am J Hum Genet. 2001;  68 (6) 1327-1332
• 29 Marini C, Scheffer I E, Nabbout R et al.. The genetics of Dravet syndrome.  Epilepsia. 2011;  52 (Suppl 2) 24-29
• 30 Scheffer I E, Zhang Y-H, Jansen F E, Dibbens L. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus?.  Brain Dev. 2009;  31 (5) 394-400
• 31 Marini C, Scheffer I E, Nabbout R et al.. SCN1A duplications and deletions detected in Dravet syndrome: implications for molecular diagnosis.  Epilepsia. 2009;  50 (7) 1670-1678
• 32 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 (11) 2690-2698
• 33 Yu F H, Mantegazza M, Westenbroek R E et al.. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy.  Nat Neurosci. 2006;  9 (9) 1142-1149
• 34 Martin M S, Dutt K, Papale L A 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 (13) 9823-9834
• 35 Madia F, Gennaro E, Cecconi M et al.. No evidence of GABRG2 mutations in severe myoclonic epilepsy of infancy.  Epilepsy Res. 2003;  53 (3) 196-200
• 36 Kelley S A, Kossoff E H. Doose syndrome (myoclonic-astatic epilepsy): 40 years of progress.  Dev Med Child Neurol. 2010;  52 (11) 988-993
• 37 Kossoff E H. Infantile spasms.  Neurologist. 2010;  16 (2) 69-75
• 38 Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology.  Hum Mutat. 2010;  31 (8) 889-900
• 39 Kato M, Saitoh S, Kamei A et al.. A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).  Am J Hum Genet. 2007;  81 (2) 361-366
• 40 Castrén M, Gaily E, Tengström C et al.. Epilepsy caused by CDKL5 mutations.  Eur J Paediatr Neurol. 2011;  15 (1) 65-69
• 41 Saitsu H, Kato M, Mizuguchi T et al.. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.  Nat Genet. 2008;  40 (6) 782-788
• 42 Mignot C, Moutard M L, Trouillard O et al.. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients.  Epilepsia. 2011;  52 (10) 1820-1827
• 43 Saitsu H, Kato M, Okada I et al.. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.  Epilepsia. 2010;  51 (12) 2397-2405
• 44 Kurian M A, Meyer E, Vassallo G et al.. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy.  Brain. 2010;  133 (10) 2964-2970
• 45 Kim D, Jun K S, Lee S B et al.. Phospholipase C isozymes selectively couple to specific neurotransmitter receptors.  Nature. 1997;  389 (6648) 290-293
• 46 Hannan A J, Blakemore C, Katsnelson A et al.. PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex.  Nat Neurosci. 2001;  4 (3) 282-288
• 47 Böhm D, Schwegler H, Kotthaus L et al.. Disruption of PLC-beta 1-mediated signal transduction in mutant mice causes age-dependent hippocampal mossy fiber sprouting and neurodegeneration.  Mol Cell Neurosci. 2002;  21 (4) 584-601
• 48 Mulley J C, Heron S E, Dibbens L M. Proposed genetic classification of the “benign” familial neonatal and infantile epilepsies.  Epilepsia. 2011;  52 (3) 649-650
• 49 Yamamoto H, Okumura A, Fukuda M. Epilepsies and epileptic syndromes starting in the neonatal period.  Brain Dev. 2011;  33 (3) 213-220
• 50 Singh N A, Westenskow P, Charlier C BFNC Physician Consortium et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum.  Brain. 2003;  126 (Pt 12) 2726-2737
• 51 Volkers L, Rook M B, Das JHG et al.. Functional analysis of novel KCNQ2 mutations found in patients with benign familial neonatal convulsions.  Neurosci Lett. 2009;  462 (1) 24-29
• 52 Soldovieri M V, Cilio M R, Miceli F et al.. Atypical gating of M-type potassium channels conferred by mutations in uncharged residues in the S4 region of KCNQ2 causing benign familial neonatal convulsions.  J Neurosci. 2007;  27 (18) 4919-4928
• 53 Tzingounis A V, Nicoll R A. Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents.  Proc Natl Acad Sci U S A. 2008;  105 (50) 19974-19979
• 54 Kanaumi T, Takashima S, Iwasaki H et al.. Developmental changes in KCNQ2 and KCNQ3 expression in human brain: possible contribution to the age-dependent etiology of benign familial neonatal convulsions.  Brain Dev. 2008;  30 (5) 362-369
• 55 Heron S E, Crossland K M, Andermann E et al.. Sodium-channel defects in benign familial neonatal-infantile seizures.  Lancet. 2002;  360 (9336) 851-852
• 56 Liao Y, Anttonen A-K, Liukkonen E et al.. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.  Neurology. 2010;  75 (16) 1454-1458
• 57 Guipponi M, Rivier F, Vigevano F et al.. Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q.  Hum Mol Genet. 1997;  6 (3) 473-477
• 58 Swoboda K J, Soong B, McKenna C et al.. Paroxysmal kinesigenic dyskinesia and infantile convulsions: clinical and linkage studies.  Neurology. 2000;  55 (2) 224-230
• 59 Vanmolkot KRJ, Kors E E, Hottenga J-J et al.. Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.  Ann Neurol. 2003;  54 (3) 360-366
• 60 Falace A, Filipello F, La Padula V et al.. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy.  Am J Hum Genet. 2010;  87 (3) 365-370
• 61 Pan X, Eathiraj S, Munson M, Lambright D G. TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism.  Nature. 2006;  442 (7100) 303-306
• 62 Frittoli E, Palamidessi A, Pizzigoni A et al.. The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway.  Mol Biol Cell. 2008;  19 (4) 1304-1316
• 63 Jaworski J. ARF6 in the nervous system.  Eur J Cell Biol. 2007;  86 (9) 513-524
• 64 Corbett M A, Bahlo M, Jolly L et al.. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24.  Am J Hum Genet. 2010;  87 (3) 371-375
• 65 Suzuki T, Delgado-Escueta A V, Aguan K et al.. Mutations in EFHC1 cause juvenile myoclonic epilepsy.  Nat Genet. 2004;  36 (8) 842-849
• 66 Ma S, Blair M A, Abou-Khalil B et al.. Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy.  Epilepsy Res. 2006;  71 (2-3) 129-134
• 67 Léon C, de Nijs L, Chanas G et al.. Distribution of EFHC1 or myoclonin 1 in mouse neural structures.  Epilepsy Res. 2010;  88 (2-3) 196-207
• 68 Suzuki T, Inoue I, Yamagata T et al.. Sequential expression of Efhc1/myoclonin1 in choroid plexus and ependymal cell cilia.  Biochem Biophys Res Commun. 2008;  367 (1) 226-233
• 69 Kamp M A, Krieger A, Henry M et al.. Presynaptic ‘Ca2.3-containing’ E-type Ca channels share dual roles during neurotransmitter release.  Eur J Neurosci. 2005;  21 (6) 1617-1625
• 70 de Nijs L, Léon C, Nguyen L et al.. EFHC1 interacts with microtubules to regulate cell division and cortical development.  Nat Neurosci. 2009;  12 (10) 1266-1274
• 71 Betting L E, Mory S B, Lopes-Cendes I et al.. MRI reveals structural abnormalities in patients with idiopathic generalized epilepsy.  Neurology. 2006;  67 (5) 848-852
• 72 Betting L E, Mory S B, Li L M et al.. Voxel-based morphometry in patients with idiopathic generalized epilepsies.  Neuroimage. 2006;  32 (2) 498-502
• 73 Tae W S, Kim S H, Joo E Y et al.. Cortical thickness abnormality in juvenile myoclonic epilepsy.  J Neurol. 2008;  255 (4) 561-566
• 74 Cossette P, Liu L, Brisebois K et al.. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy.  Nat Genet. 2002;  31 (2) 184-189
• 75 Escayg A, De Waard M, Lee D D et al.. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.  Am J Hum Genet. 2000;  66 (5) 1531-1539
• 76 Haug K, Warnstedt M, Alekov A K et al.. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.  Nat Genet. 2003;  33 (4) 527-532
• 77 Kleefuss-Lie A, Friedl W, Cichon S et al.. CLCN2 variants in idiopathic generalized epilepsy.  Nat Genet. 2009;  41 (9) 954-955
• 78 Niemeyer M I, Cid L P, Sepúlveda F V, Blanz J, Auberson M, Jentsch T J. No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy.  Nat Genet. 2010;  42 (1) 3
• 79 Sander T, Schulz H, Saar K et al.. Genome search for susceptibility loci of common idiopathic generalised epilepsies.  Hum Mol Genet. 2000;  9 (10) 1465-1472
• 80 D'Agostino D, Bertelli M, Gallo S et al.. Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy.  Neurology. 2004;  63 (8) 1500-1502
• 81 Wallace R H, Marini C, Petrou S et al.. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.  Nat Genet. 2001;  28 (1) 49-52
• 82 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. 2010;  75 (5) 432-440
• 83 Suls A, Mullen S A, Weber Y G et al.. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1.  Ann Neurol. 2009;  66 (3) 415-419
• 84 Seidner G, Alvarez M G, Yeh J I et al.. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier.  Nat Genet. 1998;  18 (2) 188-191
• 85 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 (Pt 7) 1831-1844
• 86 Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome.  Brain Dev. 2009;  31 (7) 545-552
• 87 Steinlein O K, Mulley J C, Propping P et al.. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.  Nat Genet. 1995;  11 (2) 201-203
• 88 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 (2) 342-350
• 89 De Fusco M, Becchetti A, Patrignani A et al.. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy.  Nat Genet. 2000;  26 (3) 275-276
• 90 Combi R, Dalprà L, Malcovati M et al.. Evidence for a fourth locus for autosomal dominant nocturnal frontal lobe epilepsy.  Brain Res Bull. 2004;  63 (5) 353-359
• 91 Klaassen A, Glykys J, Maguire J et al.. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.  Proc Natl Acad Sci U S A. 2006;  103 (50) 19152-19157
• 92 Crompton D E, Scheffer I E, Taylor I et al.. Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance.  Brain. 2010;  133 (11) 3221-3231
• 93 Kalachikov S, Evgrafov O, Ross B et al.. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.  Nat Genet. 2002;  30 (3) 335-341
• 94 Scheel H, Tomiuk S, Hofmann K. A common protein interaction domain links two recently identified epilepsy genes.  Hum Mol Genet. 2002;  11 (15) 1757-1762
• 95 Sirerol-Piquer M S, Ayerdi-Izquierdo A, Morante-Redolat J M et al.. The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface.  Hum Mol Genet. 2006;  15 (23) 3436-3445
• 96 Ribeiro PAO, Sbragia L, Gilioli R et al.. Expression profile of Lgi1 gene in mouse brain during development.  J Mol Neurosci. 2008;  35 (3) 323-329
• 97 Owuor K, Harel N Y, Englot D J et al.. LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology.  Mol Cell Neurosci. 2009;  42 (4) 448-457
• 98 Fukata Y, Lovero K L, Iwanaga T et al.. Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy.  Proc Natl Acad Sci U S A. 2010;  107 (8) 3799-3804
• 99 Yu Y E, Wen L, Silva J et al.. Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability.  Hum Mol Genet. 2010;  19 (9) 1702-1711
• 100 Lai M, Huijbers MGM, Lancaster E et al.. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.  Lancet Neurol. 2010;  9 (8) 776-785
• 101 Irani S R, Alexander S, Waters P et al.. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.  Brain. 2010;  133 (9) 2734-2748
• 102 Berkovic S F, McIntosh A, Howell R A et al.. Familial temporal lobe epilepsy: a common disorder identified in twins.  Ann Neurol. 1996;  40 (2) 227-235
• 103 Hedera P, Blair M A, Andermann E et al.. Familial mesial temporal lobe epilepsy maps to chromosome 4q13.2-q21.3  Neurology. 2007;  68 (24) 2107-2112
• 104 Baulac S, Picard F, Herman A et al.. Evidence for digenic inheritance in a family with both febrile convulsions and temporal lobe epilepsy implicating chromosomes 18qter and 1q25-q31.  Ann Neurol. 2001;  49 (6) 786-792
• 105 Claes L, Audenaert D, Deprez L et al.. Novel locus on chromosome 12q22-q23.3 responsible for familial temporal lobe epilepsy associated with febrile seizures.  J Med Genet. 2004;  41 (9) 710-714
• 106 Xiong L, Labuda M, Li D S et al.. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12.  Am J Hum Genet. 1999;  65 (6) 1698-1710
• 107 Berkovic S F, Serratosa J M, Phillips H A et al.. Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12.  Epilepsia. 2004;  45 (9) 1054-1060
• 108 Manzini M C, Walsh C. What disorders of cortical development tell us about the cortex: one plus one does not always make two.  Curr Opin Genet Dev. 2011;  21 (3) 333-339
• 109 Pal D K, Pong A W, Chung W K. Genetic evaluation and counseling for epilepsy.  Nat Rev Neurol. 2010;  16 (8) 445-453
• 110 Altshuler D, Daly M J, Lander E S. Genetic mapping in human disease.  Science. 2008;  322 (5903) 881-888
• 111 Shields R. Common disease: are causative alleles common or rare?.  PLoS Biol. 2011;  9 (1) e1001009
• 112 Chen Y, Lu J, Pan H et al.. Association between genetic variation of CACNA1H and childhood absence epilepsy.  Ann Neurol. 2003;  54 (2) 239-243
• 113 Chioza B, Everett K, Aschauer H et al.. Evaluation of CACNA1H in European patients with childhood absence epilepsy.  Epilepsy Res. 2006;  69 (2) 177-181
• 114 Liang J, Zhang Y, Chen Y et al.. Common polymorphisms in the CACNA1H gene associated with childhood absence epilepsy in Chinese Han population.  Ann Hum Genet. 2007;  71 (Pt 3) 325-335
• 115 Pal D K, Evgrafov O V, Tabares P et al.. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy.  Am J Hum Genet. 2003;  73 (2) 261-270
• 116 Greenberg D A, Cayanis E, Strug L et al.. Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.  Am J Hum Genet. 2005;  76 (1) 139-146
• 117 Cavalleri G L, Weale M E, Shianna K V et al.. Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.  Lancet Neurol. 2007;  6 (11) 970-980
• 118 Lenzen K P, Heils A, Lorenz S, Hempelmann A, Sander T. Association analysis of malic enzyme 2 gene polymorphisms with idiopathic generalized epilepsy.  Epilepsia. 2005;  46 (10) 1637-1641
• 119 Cavalleri G L, Weale M E, Shianna K V et al.. Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.  Lancet Neurol. 2007;  6 (11) 970-980
• 120 Mulley J C, Mefford H C. Epilepsy and the new cytogenetics.  Epilepsia. 2011;  52 (3) 423-432
• 121 Helbig I, Mefford H C, Sharp A J et al.. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.  Nat Genet. 2009;  41 (2) 160-162
• 122 Mefford H C, 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 (5) e1000962
• 123 Heinzen E L, Radtke R A, Urban T J et al.. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.  Am J Hum Genet. 2010;  86 (5) 707-718
• 124 Kasperaviciūte D, Catarino C B, Heinzen E L et al.. Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.  Brain. 2010;  133 (Pt 7) 2136-2147
• 125 Depondt C. Pharmacogenetics in neuropsychiatric diseases: epilepsy as a model.  Acta Neurol Belg. 2006;  106 (4) 157-167
• 126 Löscher W, Klotz U, Zimprich F, Schmidt D. The clinical impact of pharmacogenetics on the treatment of epilepsy.  Epilepsia. 2009;  50 (1) 1-23
• 127 Siddiqui A, Kerb R, Weale M E et al.. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1.  N Engl J Med. 2003;  348 (15) 1442-1448
• 128 Löscher W, Delanty N. MDR1/ABCB1 polymorphisms and multidrug resistance in epilepsy: in and out of fashion.  Pharmacogenomics. 2009;  10 (5) 711-713
• 129 Anderson G D. Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs.  Ther Drug Monit. 2008;  30 (2) 173-180
• 130 Depondt C, Godard P, Espel R S, Da Cruz A L, Lienard P, Pandolfo M. A candidate gene study of antiepileptic drug tolerability and efficacy identifies an association of CYP2C9 variants with phenytoin toxicity.  Eur J Neurol. 2011;  18 (9) 1159-1164
• 131 Tate S K, Singh R, Hung C-C et al.. A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.  Pharmacogenet Genomics. 2006;  16 (10) 721-726
• 132 Abe T, Seo T, Ishitsu T, Nakagawa T, Hori M, Nakagawa K. Association between SCN1A polymorphism and carbamazepine-resistant epilepsy.  Br J Clin Pharmacol. 2008;  66 (2) 304-307
• 133 Manna I, Gambardella A, Bianchi A et al.. A functional polymorphism in the SCN1A gene does not influence antiepileptic drug responsiveness in Italian patients with focal epilepsy.  Epilepsia. 2011;  52 (5) e40-e44
• 134 Pirmohamed M, Lin K, Chadwick D, Park B K. TNFalpha promoter region gene polymorphisms in carbamazepine-hypersensitive patients.  Neurology. 2001;  56 (7) 890-896
• 135 Chung W-H, Hung S-I, Hong H-S et al.. Medical genetics: a marker for Stevens-Johnson syndrome.  Nature. 2004;  428 (6982) 486
• 136 Chen P, Lin J-J, Lu C-S Taiwan SJS Consortium et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.  N Engl J Med. 2011;  364 (12) 1126-1133
• 137 Ozeki T, Mushiroda T, Yowang A et al.. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population.  Hum Mol Genet. 2011;  20 (5) 1034-1041
• 138 McCormack M, Alfirevic A, Bourgeois S et al.. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.  N Engl J Med. 2011;  364 (12) 1134-1143
• 139 Lee H Y, Huang Y, Bruneau N et al.. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions.  Cell Reports. 2012;  1 1-11

Truncating mutations involving the gene PRRT2 have been identified in the vast majority of well-characterized families with Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions. PRRT2 encodes a proline-rich transmembrane protein of unknown function that has been reported to interact with the synaptic proteins.[139]