6 . Guerrini R , Dravet CH . Severe epileptic encephalopathies of infancy . In: Engel J, Pe dley TA (eds) Epilepsy , pp. 2285 \200\223 302 . Philadelphia, PA: Lippincott-Raven , 1997 . 7 . Guerrini R , Striano P , Catarino C , Sisodiya SM . Neuroimaging and neuropathology of Dravet syndrome . Epilepsia 2011 ; 52 : 30 \200\223 4 . 8 . Catarino CB , Liu JY , Liagkouras I , Gibbons VS , Labrum RW , Ellis R , et al . Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology . Brain 2011 ; 134 : 2982 \200\223 3010 . 9 . Suls A , Claeys KG , Goossens D , Harding B , Van Luijk R , Scheers S , et al . Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients . Hum Mutat 2006 ; 27 : 914 \200\223 20 . 10 . Marini C , Scheffer IE , Nabbout R , Mei D , Cox K , Dibbens LM , et al . SCN1A duplic ations and deletions detected in Dravet syndrome: implications for molecular diagnosis . Ep ilepsia 2009 ; 50 : 1670 \200\223 8 . 11 . Macdonald RL , Kang JQ . Molecular pathology of genetic epilepsies associated with GABAA receptor subunit mutations . Epilepsy Curr 2009 ; 9 : 18 \200\223 23 . 12 . Depienne C , Arzimanoglou A , Trouillard O , Fedirko E , Baulac S , Saint-Martin C , e t al . Parental mosaicism can cause recurrent transmission of SCN1A mutations associated wi th severe myoclonic epilepsy of infancy . Hum Mutat 2006 ; 27 : 389 . 13 . Marini C , Mei D , Helen CJ , Guerrini R . Mosaic SCN1A mutation Future perspectives The next steps include identifying additional genes both in mono- genic epilepsies and epilepsies with complex inheritance, geno- type \200\223phenotype correlati ons, and functional studies of the abnormal proteins. These studies may have practical appl ications for diagnosis, genetic counseling, and possible treatment. Most of the epilepsy sy ndromes listed in this chapter are characterized by marked clinical and genetic heterogenei ty. This may be explained by pleiotropic expression of a single-gene mutation, modifying ge nes, or by several genes producing a similar phenotype, at times because they affect the sa me developmental or metabolic pathway. It is hoped that a constantly updated database will be established for all the known gene mutations and polymorphisms and their clinical correl ates, so that genotype \200\223phenotype correlations can be determined. This is the object ive of the Human Variome project ( 153 ). For example, over 600 mutations in SCN1A associat ed with Dravet syndrome have now been identi \201 ed and the severity of the related pheno type can be predicted early, with reasonable accuracy for those recurrent mutations in whic h suf \201 cient numbers of clini- cal observations are available. in familial severe myoclonic epilepsy of infancy . Epilepsia 2006 ; 47 : 1737 \200\223 40 . 14 . Guerrini R , Oguni H . Borderline Dravet syndrome: a useful diagnostic category? Epilepsia 2011 ; 52 : 10 \200\2231 2 . 15 . Fujiwara T , Sugawara T , Mazaki-Miyazaki E , Takahashi Y , Fukushima K , Watanabe M , et al . Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures . Brain 2006 ; 126 : 531 \200 \223 46 . 16 . Wallace RH , Scheffer IE , Barnett S , Richards M , Dibbens L , Desai RR , et al . Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febri le seizures plus . Am J Hum Genet 2001 ; 68 : 859 \200\223 65 . 17 . Harkin LA , McMahon JM , Iona X , Dibbens L , Pelekanos JT , Zuberi SM , et al . The s pectrum of SCN1A-related infantile epileptic encephalopathies . Brain 2007 ; 130 : 843 \200\223 52 . 18 . Scheffer IE , Berkovic SF . Generalized epilepsy with febrile seizures plus: a genetic disorder with heterogeneous clinical phenotypes . Brain 1997 ; 120 : 479 \200\223 90 . 19 . Wallace RH , Wang DW , Singh R , Scheffer IE , George AL Jr, Phillips HA , et al . Febrile seizures and generalized epilepsy associated with a mutation in the Na + channel beta1 subunit gene SCN1B . Nat Genet 1998 ; 19 : 366 \200\223 70 . 20 . Escayg A , MacDonald BT , Meisler MH , Baulac S , Huberfeld G , An-Gour \201 nkel I , et al . Mutations of SCN1A, encoding a neuronal sodium channel, in t wo families with GEFS + 2 . Nat Genet 2000 ; 24 : 343 \200\223 5 . References 1 . Greenberg DA , Delgado-Escueta AV , Widelitz H , Sparkes RS , 21 . Marini C , Mei D , Temudo T , Ferrari AR , Buti D , Dravet C , et al . Treiman L , Maldonado HM , et al . Juvenile myoclonic epilepsy (JME) may be linked to the B F and HLA loci on human chromosome 6 . Am J Med Genet 1988 ; 31 : 185 \200\223 92 . Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities . Epileps ia 2007 ; 48 : 1678 \200\223 85 . 22 . Wallace RH , Marini C , Petrou S , Harkin LA , Bowser DN , Panchal RG , et al . Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures . Nat G enet 2001 ; 28 : 49 \200\223 52 . 23 . Baulac S , Huberfeld G , Gour \201 nkel-An I , Mit ropoulou G , Beranger A , Prud \200\231homme JF , et al . First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene . Nat Genet 2001 ; 28 : 46 \200\223 8 . 2 . Steinlein OK , Mulley JC , Propping P , Wallace RH , Phillips HA , Sutherland GR , et al . A missense mutation in the neuronal nicotinic acetylcholine recepto r alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy . N at Genet 1995 ; 11:201 \200\223 3 . 3 . Heron SE , Scheffer IE , Berkovic SF , Dibbens LM , Mulley JC . Channelopathies in idiopathic epilepsy . Neurotherapeutics 2007 ; 4 : 295 \200\223 304 . 24 . Mantegazza M , Rusconi R , Scalmani P , Avanzini G , Franceschetti S . 4 . Martin MS , Tang B , Papale LA , Yu FH , Catterall WA , Escayg A . The voltage-gated so dium channel Scn8a is a genetic modi \201 er of severe myoclonic epilepsy of infancy . Hum Mol Genet 2007 ; 16 : 2892 \200\223 9 . Epileptogenic ion channel mutations: from bedside to bench and, hopefully, back again . Epi lepsy Res 2010 ; 92 : 1 \200\223 29 . 25 . Lerche H , Weber YG , Jurkat-Rott K , Lehmann-Horn F . Ion channel defects in idiopath ic epilepsies . Curr Pharm 2005 ; 11 : 2737 \200\223 52 . 5 . Gour \201 nkel-An I , Baulac S , Nabbout R , Ruberg M , Baulac M , Brice A , et al . Monogenic idiopathic epilepsies . Lancet Neurol 2004 ; 3 : 209 \200\223 18 . CHAPTER 2 neurogenetics of epilepsy 23 46 . Scheffer IE , Bhatia KP , Lopes-Cendes I , Fish DR , Marsden CD , 26 . Yu FH , Mantegazza M , Westenbroek RE , Robbins CA , Kalume F , Andermann E , et al . Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive cli nical disorder . Brain 1995 ; 118 : 61 \200\223 73 . 47 . Picard F , Baulac S , Kahane P , Hirsch E , Sebastianelli R , Thomas P , Burton KA , et al . Reduced sodium current in GABAergic interneurons in a mouse model of se vere myoclonic epilepsy in infancy . Nat Neurosci 2006 ; 9 : 1142 \200\223 9 . et al . Dominant partial epilepsies. A clinical, electrophysiological and genetic study of 19 European families . Brain 2000 ; 123 : 1247 \200\223 62 . 48 . Ryvlin P , Minotti L , D emarquay G , Hirsch E , Arzimanoglou A , 27 . Ogiwara I , Miyamoto H , Morita N , Atapour N , Mazaki E , Inoue I , et al . Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circ uit basis for epileptic seizures in mice carrying an Scn1a gene mutation . J Neurosci 2007 ; 27 : 5903 \200\223 14 . Hoffman D , et al . Nocturnal hypermotor seizures, suggesting frontal lobe epilepsy, can or iginate in the insula . Epilepsia 2006 ; 47 : 755 \200\223 65 . 28 . Plouin P , Anderson VE . Benign familial and non-familial neonatal seizures . In: Roge r J , Bureau M , Dravet C , Genton P , Tassinari CA , Wolf P (eds) Epileptic syndromes in i nfancy , childhood and adolescence , pp. 89 \200\223 113 . Mountrouge : John Libbey Eurote xt Ltd , 2005 . 49 . Steinlein OK . Genetic mechanisms that underlie epilepsy . Nat Rev Neurosci 2004 ; 5 : 443 \200\223 8 . 50 . Aridon P , Marini C , Di Resta C , Brilli E , De Fusco M , Politi F , et al . Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial ep ilepsy with nocturnal wandering and ictal fear . Am J Hum Genet 2006 ; 79 : 342 \200\223 5 0 . 29 . Steinlein OK , Conrad C , Weidner B . Benign familial neonatal convulsions: always ben ign? Epilepsy Res 2007 ; 73 : 245 \200\223 9 . 30 . Biervert C , Schroeder BC , Kubisch C , Berkovic SF , Propping P , 51 . Chen Y , Wu L , Fang Y , He Z , Peng B , Shen Y , et al . A novel mutation of the nico tinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy . Epil epsy Res 2009 ; 83 : 152 \200\223 6 . Jentsch TJ , et al . A potassium channel mutation in neonatal human epilepsy . Science 1998 ; 279 : 403 \200\223 6 . 31 . Singh NA , Charlier C , Stauffer D , DuPont BR , Leach RJ , Melis R , et al . 52 . Liu H , Lu C , Li Z , Zhou S , Zhou S , Li X , Ji L , et al . The identi \201 cation A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns . Na t Genet 1998 ; 18 : 25 \200\223 9 . of a novel mutation of nicotinic acetylcholine receptor gene CHRNB2 in a Chinese patient: I ts possible implication in non-familial nocturnal frontal lobe epilepsy . Epilepsy Res 2011 ; 95 : 94 \200\223 9 . 32 . Heron SE , Cox K , Grinton BE , Zuberi SM , Kivity S , Afawi Z , et al . Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures . J Med Genet 2007 ; 44 : 791 \200\223 6 . 53 . Ottman R , Risch N , Hauser WA , Pedley TA , Lee JH , Barker- Cummings C , et al . Localization of a gene for partial epilepsy to chromosome 10q . Nat Ge net 1995 ; 10 : 56 \200\223 60 . 33 . Singh NA , Westenskow P , Charlier C , Pappas C , Leslie J , Dillon J , et al . KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions:expansion of the functional and mutation spectrum . Brain 2003 ; 126 : 2726 \200\223 37 . 54 . Michelucci R , Poza JJ , So \201 a V , de Feo MR , Binelli S , Bisulli F , et al . Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, a nd genetic heterogeneity in seven European families . Epilepsia 2003 ; 44 : 1289 \200\223 97 . 34 . Delmas P , Brown DA . Pathways modulating neural KCNQ/M (Kv7) potassium channels . Nat Rev Neurosci 2005 ; 6 : 850 \200\223 62 . 55 . Kalachikov S , Evgrafov O , Ross B , Winawer M , Barker-Cummings C , Martinelli Bonesc hi F , et al . Mutations in LGI1 cause autosomal- dominant partial epilepsy with auditory f eatures . Nat Genet 2002 ; 30 : 335 \200\223 41 . 35 . Schroeder BC , Kubisch C , Stein V , Jentsch TJ . Moderate loss of function of cyclic-AMP-modulated KCNQ2 \201\204 KCNQ3 K + channels causes epilepsy . Natur e 1998 ; 396 : 687 \200\223 90 . 56 . Ottman R , Winawer MR , Kalachikov S , Barker-Cummings C , Gilliam TC , Pedley TA , et al . LGI1 mutations in autosomal dominant partial epilepsy with auditory features . Neurol ogy 2004 ; 62 : 1120 \200\223 6 . 36 . Weber YG , Lerche H . Genetic mechanisms in idiopathic epilepsies . Dev Med Child Neurol 2008 ; 50 : 648 \200\223 54 . 37 . Heron SE , Crossland KM , Andermann E , Phillips HA , Hall AJ , Bleasel A , et al . So dium-channel defects in benign familial neonatal-infantile seizures . Lancet 2002 ; 360 : 8 51 \200\223 2 . 57 . Chernova OB , Somerville RP , Cowell JK . A novel gene, LGI1, from 10q24 is rearranged and down-regulated in malignant brain tumors . Oncogene 1998 ; 17 : 287 3 \200\223 81 . 38 . Berkovic SF , Heron SE , Giordano L , Marini C , Guerrini R , Kaplan RE , et al . Benign familial neonatal infantile seizures: characterization of a new sodium chann elopathy . Ann Neurol 2004 ; 55 : 550 \200\223 7 . 58 . Scheel H , Tomiuk S , Hofmann K . A common protein interaction domain links two recently identi \201 ed epilepsy genes . Hum Mol Genet 2002 ; 11 : 1757 \200\223 62 . 39 . Herlenius E , Heron SE , Grinton BE , Keay D , Scheffer IE , Mulley JC , et al . SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypicspectrum . Epilep sia 2007 ; 48 : 1138 \200\223 42 . 40 . Vigevano F . Benign familial infantile seizures . Brain Dev 2005 ; 59 . Skradski SL , Clark AM , Jiang H , White HS , Fu YH , Pt cek LJ . A novel gene causing a mendelian audiogenic mouse epilepsy . Neuron 2001 ; 31 : 537 \200\223 44 . 27 : 172 \200\223 7 . 60 . Sadleir LG , Scheffer IE . Febrile seizures . Br Med J 2007 ; 334 : 307 \200\223 11 . 61 . Hauser WA , Annegers JF , Anderson VE , Kurland LT . The risk of 41 . Szepetowski P , Rochette J , Berquin P , Piussan C , Lathrop GM , Monaco AP . Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked t o the pericentromeric region of human chromosome 16 . Am J Hum Genet 1997 ; 61 : 889 \200 \223 98 . seizure disorders among relatives of children with febrile convulsions . Neurology 1985 ; 3 5 : 1268 \200\223 73 . 62 . Maher J , McLachlan RS . Febrile convulsions. Is seizure duration the most important p redictor of temporal lobe epilepsy? Brain 1995 ; 118 : 1521 \200\223 8 . 42 . Guipponi M , Rivier F , Vigevano F , Gastaldi M , Echenne B , Motte J , et al . Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q . Hum Mol Genet 1997 ; 6 : 473 \200\223 7 . 63 . Johnson WG , Kugler SL , Stenroos ES , Meulener MC , Rangwalla I , 43 . Vanmolko KR , Kors EE , Hottenga JJ , Terwindt GM , Haan J , Johnson TW , et al . Pedigree analysis in families with febrile seizures . Am J Med Genet 1 996 ; 61 : 345 \200\223 52 . Hoefnagels WA , et al . Novel mutations in the Na + , K + -ATPase pump gene ATP1A2 associat ed with familial hemiplegic migraine and benign familial infantile convulsions . Ann Neurol 2003 ; 54 : 360 \200\223 6 . 64 . Baulac S , Gour \201 nkel-An I , Nabbout R , Huberfeld G , Serratosa J , Leguern E , et al . Fever, genes, and epilepsy . Lancet Neurol 2004 ; 3 : 421 \200\223 30 . 44 . Zhou X , Ma A , Liu X , Huang C , Zhang Y , Shi R , et al . Infantile 65 . Dibbens LM , Tarpey PS , Hynes K , Bayly MA , Scheffer IE , Smith R , seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCN Q2 . Eur J Pediatr 2006 ; 165 : 691 \200\223 5 . et al . X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive imp airment . Nat Genet 2008 ; 40 : 776 \200\223 81 . 66 . Marini C , Mei D , Parmeggiani L , Norci V , Calado E , Ferrari A , et al . Protocadherin 19 mutations in girls with infantile onset epilepsy . Neurology 2010 ; 75 : 646 \200\223 53 . 45 . Striano P , Bordo L , Lispi ML , Specchio N , Minetti C , Vigevano F , et al . A novel SCN2A mutation in family with benign familial infantile seizures . Epilepsia 2006 ; 47 : 2 18 \200\223 20 . oxford textbook of epilepsy and epileptic seizures 24 87 . Ohtahara S , Yamatogi Y . Ohtahara syndrome: with special reference to its development al aspects for differentiating from early myoclonic encephalopathy . Epilepsy Res 2006 ; 70 : S58 \200\223 67 . 67 . Deprez L , Jansen A , De Jonghe P . Genetics of epilepsy syndromes starting in the \201 rst year of life . Neurology 2009 ; 72: 273 \200\223 81 . 68 . Depienne C , Bouteiller D , Keren B , Cheuret E , Poirier K , Trouillard O , et al . S poradic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet s yndrome but mainly affects females . PLoS Genet 2009 ; 5 :e1000381 . 88 . Mignot C , Moutard ML , Trouillard O , Gour \201 nkel-An I , Jacquette A , Arveiler B , et al . STXBP1-related encephalopathy presenting as infantile spasms and generalized tre mor in three patients . Epilepsia 2011 ; 52 : 1820 \200\223 7 . 69 . Ohira R , Zhang YH , Guo , Dipple K , Shih SL , Doerr J , et al . Human ARX gene: Geno mic characterization and expression . Mol Genet Metab 2002 ; 77 : 179 \200\223 88 . 89 . Milh M , Villeneuve N , Chouchane M , Kaminska A , Laroche C , Barthez MA , et al . Epileptic and nonepileptic features in patients with early onset epile ptic encephalopathy and STXBP1 mutations . Epilepsia 2011 ; 52 : 1828 \200\223 34 . 70 . G cz J , Cloosterman D , Partington M . ARX: A gene for all seasons . Curr Opin Genet Dev 2006 ; 16 : 308 \200\223 16 . 90 . Saitsu H , Kato M , Mizuguchi T , Hamada K , Osaka H , Tohyama J , 71 . Guerrini R , Moro F , Kato M , Barkovich AJ , Shiihara T , McShane MA , et al . Expans ion of the \201 rst PolyA tract of ARX causes infantile spasms and status dystonicus . Ne urology 2007 ; 69 : 427 \200\223 33 . et al . De novo mutations in the gene encoding STXBP1 (MUNC18 \200\2231) cause early infant ile epileptic encephalopathy . Nat Genet 2008 ; 40 : 782 \200\223 8 . 72 . Marsh E , Fulp C , Gomez E , Nasrallah I , Minarcik J , Sudi J , et al . 91 . Berkovic SF , Andermann F , Carpenter S , Wolfe LS . Progressive Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females . Brain 2009 ; 132 : 1563 \200\223 76 . myoclonus epilepsies: speci \201 c causes and diagnosis . N Engl J Med 1986 ; 315 : 296 \200\223 305 . 92 . Genton P , Malafosse A , Moulard B , Rogel-Ortiz FJ , Dravet C , Bureau M , et al . Pr ogressive myoclonus epilepsies . Roger J , Bureau M , Dravet C , Genton P , Tassinari CA , Wolf P (eds) Epileptic syndromes in infancy , childhood and adolescence (3rd edn), pp. 89 \200\223 113 . London : John Libbey , 2002 . 73 . Kato M , Das S , Petras K , Kitamura K , Morohashi K , Abuelo DN , et al . Mutations of ARX are associated with striking pleiotropy and consistent genotype \200\223ph enotype correlation . Hum Mutat 2004 ; 23 : 147 \200\223 59 . 74 . Stromme P , Mangelsdorf ME , Scheffer IE , Gecz J . Infantile spasms, 93 . Delgado-Escueta AV , Ganesh S , Yamakawa K . Advances in the dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX . Brain Dev 2002 ; 24 : 266 \200\223 8 . 75 . Wallerstein R , Sugalski R , CohnL , Jawetz R , Friez M . Expansion of the genetics of progressive myoclonus epilepsy . Am J Med Genet 2001 ; 106 : 129 \200\223 38 . 94 . Annegers JF , Hauser WA , Anderson VE , Kurland LT . The risk of ARX spectrum . Clin Neurol Neurosurg 2008 ; 110 : 631 \200\223 4 . seizure disorders among relatives of patients with childhood onset epilepsy . Neurology 198 2 ; 32 : 174 \200\223 79 . 76 . Shinozaki Y , Osawa M , Sakuma H , Komaki H , Nakagawa E , Sugai K , et al . Expansion of the \201 rst polyalanine tract of the ARX gene in a boy presenting with generalized d ystonia in the absence of infantile spasms . Brain Dev 2008 ; 31 : 469 \200\223 72 . 95 . Risch N . Linkage strategies for genetically complex traits. (1) Multilocus models . A m J Hum Genet 1990 ; 46 : 222 \200\223 8 . 96 . Berkovic SF , Howell RA , Hay DA , Hopper JL . Epilepsies in twins: genetics of the ma jor epilepsy syndromes . Ann Neurol 1998 ; 43 : 435 \200\223 45 . 77 . Kato M , Saitoh S , Kamei A , Shiraishi H , Ueda Y , Akasaka M , et al . A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic en cephalopathy with suppression-burst pattern (Ohtahara syndrome) . Am J Hum Genet 2007 ; 81 : 361 \200\223 6 . 97 . Berkovic SF , Scheffer IE . Genetics of the epilepsies . Epilepsia 2001 ; 42 : 16 \200\223 23 . 78 . Mari F , Azimonti S , Bertani I , Bolognese F , Colombo E , Caselli R , et al . CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset se izure variant of Rett syndrome . Hum Mol Genet 2005 ; 14 : 1935 \200\223 46 . 98 . Klassen T , Davis C , Goldman A , Burgess D , Chen T , Wheeler D , et al . Exome seque ncing of ion channel genes reveals complex pro \201 les confounding personal risk assessme nt in epilepsy . Cell 2011 ; 145 : 1036 \200\223 48 . 79 . Kalscheuer VM , Tao J , Donnelly A , Hollway G , Schwinger E , K bart S , et al . Dis ruption of the serine/threonine kinase 9 gene causes severe X-linked infantilespasms and me ntal retardation . Am J Hum Genet 2003 ; 72 : 1401 \200\223 11 . 99 . Sander T , Schulz H , Saar K , Gennaro E , Riggio MC , Bianchi A , et al . Genome sear ch for susceptibility loci of common generalized epilepsies . Hum Mol Genet 2000 ; 9 : 1465 \200\223 72 . 80 . Buoni S , Zannolli R , Colamaria V , Macucci F , di Bartolo RM , Corbini L , et al . M yoclonic encephalopathy in the CDKL5 gene mutation . Clin Neurophysiol 2006 ; 117 : 223 \200\223 7 . 100 . Durner M , Keddache MA , Tomasini L , Shinnar S , Resor SR , Cohen J , et al . Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modify ing genes in \202uencing the seizure type . Ann Neurol 2001 ; 49 : 328 \200\223 35 . 81 . Archer HL , Evans J , Edwards S , Spalletta A , Bottitta M , Calabrese G , et al . CDK L5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients . J Med Genet 2006 ; 43 : 729 \200\223 34 . 101 . Cossette P , Liu L , Brisebois K , Dong H , Lortie A , Vanasse M , et al . Mutation o f GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy . Nat Genet 2002 ; 31 : 184 \200\223 9 . 102 . D \200\231Agostino D , Bertelli M , Gallo S , Cecchin S , Albiero E , Garofalo PG , e t al . Mutations and polymorphisms of the CLCN2 gene in idiopathic epilepsy . Neurology 200 4 ; 63 : 1500 \200\223 2 . 82 . Elia M , Falco M , Ferri R , et al . CDKL5 mutations in boys with severe encephalo pat hy early-onset intractable epilepsy . Neurology 2008 ; 71 : 997 \200\223 9 . 103 . Chen Y , Lu J , Pan H , Wu H , Xu K , Liu X , et al . Association between genetic var iation of CACNA1H and childhood absence epilepsy . Ann Neurol 2003 ; 54 : 239 \200\223 43 . 83 . Weaving LS , Christodoulou J , Williamson SL , Friend KL , McKenzie OL , Archer H , et al . Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation . Am J Hum Genet 2004 ; 75 : 1079 \200\223 93 . 104 . Heron SE , Phillips HA , Mulley JC , Mazarib A , Neufeld MY , Berkovic SF , et al . Genetic variation of CACNA1H in idiopathic generalized epilepsy . Ann Neurol 2 004 ; 55 : 595 \200\223 6 . 84 . Melani F , Mei D , Pisano T , Savasta S , Franzoni E , Ferrari AR , et al . CDKL5 gene-related epileptic encephalopathy: electroclinical \201 ndings in the \201 rs t year of life . Dev Med Child Neurol 2011 ; 53 : 54 \200\223 60 . 85 . Mei D , Marini C , Novara F , Bernardina BD , Granata T , Fontana E , 105 . Dibbens LM , Feng HJ , Richards MC , Harkin LA , Hodgson BL , Scott D , et al . GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus f or generalized epilepsies . Hum Mol Genet 2004 ; 13 : 1315 \200\2231 9 . et al . Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epilept ic encephalopathy . Epilepsia 2010 ; 51 : 647 \200\223 54 . 106 . Greenberg DA , Cayanis E , Strug L , Marathe S , Durner M , Pal DK , 86 . Djukic A , Lado FA , Shinnar S , Moshe SL . Are early myoclonic et al . Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generaliz ed epilepsy . Am J Hum Genet 2003 ; 76 : 139 \200\223 46 . encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other? Epilepsy R es 2006 ; 70 : S68 \200\223 76 . CHAPTER 2 neurogenetics of epilepsy 25 128 . Sheen VL , Ganesh VS , Topcu M , Sebire G , Bodell A , Hill RS , et al . Mutations in ARFGEF2 implicate vesicle traf \201 cking in neural progenitor proliferation and migratio n in the human cerebral cortex . Nat Genet 2004 ; 36 : 69 \200\223 76 . 107 . Pal DK , Evgrafov OV , Tabares P , Zhang F , Durner M , Greenberg DA . BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy . Am J Hum Genet 2003 ; 73 : 261 \200\223 70 . 108 . Dibbens LM , Ekberg J , Taylor I , H odgson BL , Conroy SJ , Lensink IL , et al . NEDD4-2 as a potential candidate susceptibilit y gene for epileptic photosensitivity . Genes Brain Behav 2007 ; 6 : 750 \200\223 5 . 109 . Guerrini R , Carrozzo R . Epilepsy and genetic malformations of the 129 . Guerrini R , Parrini E . Neuronal migration disorders . Neurobiol Dis 2010 ; 38 : 154 \200\223 66 . 130 . Guerrini R , Dobyns W , Barkovich A . Abnormal development of the human cerebral cort ex: genetics, functional consequences and treatment options . Trends Neurosci 2008 ; 31 : 1 54 \200\223 62 . cerebral cortex . Am J Med Genet 2001 ; 106 : 160 \200\223 73 . 110 . Barkovich AJ , Kuzniecky RI , Jackson GD , Guerrini R , Dobyns WB . A developmental a nd genetic classi \201 cation for malformations of cortical development . Neurology 2005 ; 65 : 1873 \200\223 87 . 131 . Roll P , Rudolf G , Pereira S , Scheffer IE , Massacrier A , Valenti MP , et al . SRPX2 mutations in disorders of language cortex and cognition . Hum Mol Genet 2006 ; 15 : 1195 \200\223 207 . 111 . Friede RL . Developmental neuropathology. New York: Springer-Verlag , 132 . Robin NH , Taylor CJ , McDonald-McGinn DM , Zackai EH , Bingham 1989 . P , Collins KJ , et al . Polymicrogyria and deletion 22q11.2 syndrome: window to the etiolo gy of a common cortical malformation . Am J Med Genet A 2006 ; 140 : 2416 \200\223 25 . 112 . Guerrini R , Filippi T . Neuronal migration disorders, genetics, and epileptogenesis . J Child Neurol 2005 ; 20 : 287 \200\223 99 . 113 . Reiner O , Carrozzo R , Shen Y, Wehnert M, Faustinella F, Dobyns WB, et al . Isolatio n of a Miller \200\223Dieker lissencephaly gene containing G protein beta-subunit-like repe ats . Nature 1993 ; 364 : 717 \200\223 21 . 133 . Piao X , Hill RS , Bodell A , Chang BS , Basel-Vanagaite L , Straussberg R , et al . G protein-coupled receptor-dependent development of human frontal cortex . Science 2004 ; 303 : 2033 \200\223 6 . 114 . des Portes V , Francis Pinard JM , Desguerre I , Moutard ML , Snoeck I , et al . doub lecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH) . Hum Mo l Genet 1998 ; 7 : 1063 \200\223 70 . 115 . Gleeson JG , Allen KM , Fox JW , Lamperti ED , Berkovic S , Scheffer I , et al . Doublecortin, a brain-speci \201 c gene mutated in huma n X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein . Cell 1998 ; 92 : 63 \200\223 72 . 134 . Jaglin XH , Poirier K , Saillour Y , Buhler E , Tian G , Bahi-Buisson N , et al . Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria . N at Genet 2009 ; 41 : 746 \200\223 52 . 135 . Dobyns WB , Mirzaa G , Christian SL , Petras K , Roseberry J , Clark GD , et al . Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2 p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2 . Am J Med Genet A 2008 ; 146 : 1637 \200 \223 54 . 116 . Mei D , Lewis R , Parrini , Lazarou LP , Marini C , Pilz DT , et al . High frequency of genomic deletions and duplication in the LIS1 gene in lissencephaly: implications for mo lecular diagnosis . J Med Genet 2008 ; 45 : 355 \200\223 61 . 136 . Kolodny EH , Sathe S . Lysosomal disorders and Menkes syndrome . In: Shorvon SD , Andermann F , Guerrini R (eds) The Causes of Epilepsy: Common and Uncommon Cau ses in Adults and Children , pp. 206 \200\223 11 . New York : Cambridge University Press , 2011 . 117 . Matsumoto N , Leventer RJ , Kuc JA , Mewborn SK , Dudlicek LL , 137 . Donati MA , Gasperini S , Guerrini R . Organic acid, amino acids and Ramocki MB , et al . Mutation analysis of the DCX gene and genotype/ phenotype correlation in subcortical band heterotopia . Eur J Hum Genet 2001 ; 9 : 5 \200\223 12 . peroxisomal disorders . In: Shorvon SD , Andermann F , Guerrini R (eds) The Causes of Epile psy: Common and Uncommon Causes in Adults and Children , pp. 216 \200\223 30 . New York : Cambridge University Press , 2011 . 118 . Cardoso C , Leventer RJ , Dowling JJ , Ward HL , Chung J , Petras KS , et al . Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1) . Hum Mutat 2002 ; 19 : 4 \200\223 15 . 119 . Sicca F , Kelemen A , Genton , D as S , Mei D , Moro F , et al . Mosaic 138 . Plecko B , Paul K , Paschke E , Stoeckler-Ipsiroglu S , Struys E , Jakobs C , et al . Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene . Hum Mutat 2007 ; 28 : 19 \200 \223 26 . mutations of the LIS1 gene cause subcortical band heterotopia . Neurology 2003 ; 61 : 1042 \200\223 6 . 139 . Sadilkova K , Gospe SM Jr , Hahn SH . Simultanous determination of alpha-aminoadipic semialdehyde, piperideine-6-carboxylate and pipecolic acid by LC-MS/MS for pyridoxine-depen dent seizures and folinic acid-responsive seizures . J Neurosci Methods 2009 ; 184 : 136 \200\223 41 . 120 . Mei , D. , Parrini , E. , Pasqualetti , M , Tortorella G , Franzoni E , Giussani U , et al . Multiplex ligation-dependent probe ampli \201cation detects DCX gene deletions in band heterotopia . Neurology 2007 ; 68 : 446 \200\223 50 . 121 . Gleeson JG , Minnerath S , Kuzniecky RI , Dobyns WB , Young ID , Ross ME , et al . Somatic and germline mosaic mutat ions in the doublecortin gene are associated with variable phenotypes . Am J Hum Genet 2000 ; 67 : 574 \200\223 81 . 140 . Seidner G , Alvarez MG , Yeh JI , O \200\231Driscoll KR , Klepper J , Stump TS , et al . GLUT-1 de \201 ciency syndrome caused by haploinsuf \201 ciency of the blood \200 \223brain barrier hexose carrier . Nat Genet 1998 ; 18 : 188 \200\223 91 . 141 . De Vivo D C , Tri \201 letti RR , Jacobson RI , Ronen GM , Behmand RA , 122 . Poirier K , Keays DA , Francis , Saillour Y , Bahi N , Manouvrier S , et al . Large s pectrum of lissencephaly and pachygyria phenotypes resulting fromde novomissensemutations i n tubulin alpha 1A (TUBA1A) . Hum Mutat 2007 ; 28 : 1055 \200\223 64 . Harik SI . Defective glucose transportation across the blood \200\223brain barrier as a cau se of persistent hypoglycorrhachia, seizures, and developmental delay . N Engl J Med 1991 ; 325 : 703 \200\223 9 . 142 . Leary LD , Wang D , Nordli DR Jr , Engelstad K , De Vivo DC . Seizure characterizatio n and electroencephalographic features in Glut-1 de \201 ciency syndrome . Epilepsia 2003 ; 44 : 701 \200\223 7 . 123 . Hong SE , Shugart YY , Huang DT , Shahwan SA , Grant PE , Hourihane JO , et al . Auto somal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN muta tions . Nat Genet 2000 ; 26 : 93 \200\223 6 . 143 . Suls A , Dedeken P , Gof \201 n K , Van Esch H , Dupont P , Cassiman D , et al . Par oxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding th e glucose transporter GLUT1 . Brain 2008 ; 131 : 1831 \200\223 44 . 124 . Parrini E , Ramazzotti A , Dobyns WB , Guerrini R. Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations . Brain 2006 ; 129 : 1892 \200\223 906 . 125 . Sheen VL , Dixon PH , Fox JW , Hong SE , Kinton L , Sisodiya SM , et al . Mutations i n the X-linked \201 lamin 1 gene cause periventricular nodular heterotopia in males as we ll as in females . Hum Mol Genet 2001 ; 10 : 1775 \200\223 83 . 144 . Roulet-Perez E , Ballhausen D , Bonaf L , Cronel-Ohayon S , Maeder- Ingvar M . Glut -1 de \201 ciency syndrome masquerading as idiopathic generalize epilepsy . Epilepsia 2008 ; 49 : 1955 \200\223 8 . 145 . Suls A , Mullen SA , Weber YG , Verhaert K , Ceulemans B , Guerrini R , et al . Early -onset absence epilepsy caused by mutations in the glucose transporter GLUT1 . Ann Neurol 2 009 ; 66 : 415 \200\223 19 . 126 . Guerrini R , Mei D , Sisodiya S , Sicca F , Harding B , Takahashi Y , et al . Germlin e and mosaic mutations of FLN1 in men with periventricular heterotopia . Neurology 2004 ; 6 3 : 51 \200\223 6 . 146 . Mullen SA , Marini C , Suls A , Mei D , Della Giustina E , Buti D , et al . 127 . Parrini E , Rivas IL , Toral JF , Pucatti D , Giglio S , Mei D , et al . In-frame del etion in FLNA causing familial periventricular heterotopia with skeletal dysplasia in males . Am J Med Genet A 2011 ; 155A : 1140 \200\223 6 . Glucose transporter 1 de \201 ciency as a treatable cause of myoclonic astatic epilepsy . Arch Neurol 2011 ; 68 : 1152 \200\223 5 . oxford textbook of epilepsy and epileptic seizures 26 regions and genes in unexplained mental retardation . Neurology 2007 ; 68 : 721 \200\223 2 . 147 . Singh R , McKinlay Gardner RJ , Crossland KM , Scheffer IE , Berkovic SF . Chromosoma l abnormalities and epilepsy: a review for clinicians and gene hunters . Epilepsia 2002 ; 4 3 : 127 \200\223 40 . 151 . Kim HS , Yim SV , Jung KH , Zheng LT , Kim YH , Lee KH , et al . Altered DNA copy num ber in patients with different seizure disorder type: by array-CGH . Brain Devel 2007 ; 29 : 639 \200\223 43 . 148 . Guerrini R , Battaglia A , Carrozzo R , Gobbi G , Parrini E , Pramparo T , et al . Ch romosomal abnormalities . In: Engel J Jr . , Pedley TA (eds) Epilepsy: A Comprehensive Text book (2nd edn) , pp. 2589 \200\223 601 . Philadelphia, PA : Lippincott Williams and Wilkin s , 2008 . 149 . Ledbetter DH . Cytogenetic technology: genotype and phenotype . 152 . de Kovel CG , Trucks H , Helbig I , Mefford HC , Baker C , Leu C, et al . Recurrent m icrodeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies . Bra in 2010 ; 133 : 23 \200\223 32 . N Engl J Med 2008 ; 359 : 1728 \200\223 30 . 153 . Cotton RG , Auerbach AD , Axton M , Barash CI , Berkovic SF , Brookes AJ , et al . GE NETICS: the Human Variome Project . Science 2008 ; 322 : 861 \200\223 2 . 150 . Engels H , Brockschmidt A , Hoischen A , Landwehr C , Bosse K , Walldorf C , et al . DNA microarray analysis identi \201 es candidate CHAPTER 3 Neurochemistry of Epilepsy B. Keith Day, Lawrence Eisenman, and R. Edward Hogan Introduction Epileptic seizures emerge from complex biochemical processes in the human brai n. Physicians and scientists engaged in the study of this disease process have gained signi \201 cant knowledge about the neurochemical basis for epilepsy. The earliest studies at t he turn of the 20th century focused attention and subsequent theories on changes in chemica ls detected in the urine, serum, and cerebrospi- nal \202 uid, many of which we today rec ognize as non-speci \201 c associ- ated biochemical changes ( 1 ). However, with advances in studies of the human brain on cellular and molecular levels and the evolu- tion of the p harmacology of epilepsy, the early idea that excitatory and inhibitory in \202 uences in t he brain existed in balance that could be tipped toward excitation or away from inhibition to produce seizures was supported in numerous types of epilepsies and seizure-related condi tions. With this simple yet elegant view in mind, studies advancing our knowledge of the ne urochemistry of epilepsy continue to aid our understanding of the pathophysiology of epilep tic disorders as well as our approach to their diagnosis and treatment. Having reviewed the neurochemistry of the neurotransmitter sys- tems, we next turn to the n eurochemistry of antiepileptic drugs (AEDs). Finally, we conclude with a review of a clinic al trial of a drug speci \201 cally designed to modulate the GABA system that highlights s ome of the complexities of applying our knowledge of neurochemistry to patient care. GABA GABA is the major inhibitory molecule in the mammalian brain. GABA was recognized as a neurochemical in 1950 and as the amino acid in the inhibitory nerves of crustaceans by 196 3 ( 2 ). It was later accepted as satisfying criteria as a neurotransmitter in the mam- mal ian brain in 1973 ( 3 ). The idea that reduction of GABAergic inhibition results in epileps y while its potentiation is antiepileptic became known as the GABA hypothesis of epilepsy a nd continues to withstand experimental scrutiny ( 4 , 5 ). As discussed in more detail late r, its role in epilepsy became viewed as so important that designer drugs (including vigaba trin, tiagabine, and gabapentin) were created in hopes of mimicking the effects of GABA. The focus of this chapter will be on synaptic neurotransmission and its role in epilepsy. T he main excitatory and inhibitory neurochemicals in the human brain are glutamate and gamma -aminobutyric acid (GABA), respectively, which have gained wide acceptance as the major neu rochemical in \202 uences in epilepsy. However, other neu- rotransmitters such as aspartat e and glycine remain chemicals of interest as excitatory and inhibitory amino acids. Also, the roles of acetylcholine, serotonin, and the catecholamines (dopamine and noradrenaline) in epilepsy have been studied. We will review the basic chemistry of neurotransmission for the major neurotransmit- ters glutamate and GABA to provide a substrate for further discus- sion. Next, we brie \202 y consider the contribution of selective neuronal circuits to se izure generation. Animal models of seizures and epi- lepsy have been a critical source of k nowledge of the neurochemis- try of epilepsy, and we briefly review relevant data from seve ral such models with a focus on microdialysis experiments. We turn back to human studies, a gain focusing on microdialysis exper- iments. We also review magnetic resonance spectroscop y and the emerging technology of microelectrode arrays as newer methods that are complement ary to microdialysis. We then address potential contributions of the other neurotransmitter systems noted earlier. GABA is biochemically synthesized in presynaptic terminals with the removal of a carboxyl g roup from the alpha carbon of L-glutamate by the enzyme glutamic acid decarboxylase (GAD) ( 6 ). Depolarization of GABA-producing presynaptic terminals leads to voltage-gated calcium channel activation. Calcium entering the terminals facilitates vesicular docking and relea se of GABA into the extracellular space at the synaptic cleft where it is able to interact with two recognized receptor types, GABA A and GABA B . GABA A receptors are ligand-gated i on channels. When GABA binds GABA A receptors in the adult brain, a conformational change i n the shape of the receptor allows chloride to \202 ow along its concen- tration gradient into the postsynaptic cell increasing the negative membrane potential and hyperpolarizing the cell. GABA B recep- tors are metabotropic receptors that are coupled to G-proteins whic h activate adenylate cyclase leading to changes in cyclic adeno- sine monophosphate (cAMP) signaling to alter the conductance of a potassium channel. This, in turn, releases potassiu m from within the cell leading again to hyperpolarization. Both GABA receptor types make it more dif \201 cult for excitatory in \202 uences to depolarize the cell body to the poin t of creating new action poten- tials. GABA is actively removed from the extracellular spac e by oxford textbook of epilepsy and epileptic seizures 28 but reduce the activities of other excitatory and inhibitory ion channels. Overall, in addi tion to an important role in positive feed- back inhibiting further glutamate release, mGlu Rs modulate the postsynaptic cell \200\231s response to both excitatory and inhibitory in \202 u- ences ( 14 , 15 ).