Hindawi Publishing Corporation Neurology Research International Volume 2012, Article ID 876234, 18 pages doi:10.1155/2012/876234 Review Article From Genetics to Genomics of Epilepsy Silvio Garofalo, Marisa Cornacchione, and Alfonso Di Costanzo Dipartimento di Medicina e Scienze per la Salute (Me.S.pe.S.), Universita` del Molise, Via De Sanctis snc, 86100 Campobasso, Italy Correspondence should be addressed to Silvio Garofalo, [email protected] Received 13 December 2011; Accepted 17 February 2012 Academic Editor: Alexander Rotenberg Copyright © 2012 Silvio Garofalo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The introduction of DNA microarrays and DNA sequencing technologies in medical genetics and diagnostics has been a challenge that has significantly transformed medical practice and patient management. Because of the great advancements in molecular genetics and the development of simple laboratory technology to identify the mutations in the causative genes, also the diagnostic approach to epilepsy has significantly changed. However, the clinical use of molecular cytogenetics and high-throughput DNA sequencing technologies, which are able to test an entire genome for genetic variants that are associated with the disease, is preparing a further revolution in the near future. Molecular Karyotype and Next-Generation Sequencing have the potential to identify causative genes or loci also in sporadic or non-familial epilepsy cases and may well represent the transition from a genetic to a genomic approach to epilepsy. 1. Introduction these discoveries have been great advances in the field; how- ever, their impact on the management of epileptic patients In the last decades a large number of gene discoveries have was limited because of the failure to collect significant gen- changed our views of idiopathic and symptomatic epilepsy etic information from each patient to distinguish the large [1]. Indeed, idiopathic epilepsy has the considerable genetic number of genetic defects that can lead to the disease. There- advantage to be found very often in informative autosomal fore, genetic testing was possible only for few or selected fam- dominant families that have been of great relevance to map ily cases. and to positional clone the causative gene, opening insight Technical improvements in human chromosomes recog- into the biology and molecular pathology of this condition nition and better definition of chromosome regions realized [2, 3]. by increasing the number of detectable chromosome bands The search of epilepsy genes has allowed the identifi- have provided higher resolution of normal and pathological cation of several genes in idiopathic generalized epilepsy karyotype. It is today well established an association between epileptic seizures and chromosome abnormalities recognized (Table 1), the vast majority of which are channelopathies [4, by high-resolution chromosome banding [14, 15]. However, 5]oraffect the activity of excitatory or inhibitory neurotrans- the type and the size of the chromosome defects are not mitters in central nervous system [6]. It is possible that the always easy to detect even by the highest-resolution cytoge- dominant nature of these genes due to the multisubunit com- netic techniques available for light microscopes. position of the molecules have greatly overestimated the role The identification of the specific genetic defect in a pa- of their mutations in the disease. tient with epilepsy may clarify the diagnosis (diagnostic test- Other important insights came from the discoveries of ing), suggest the prognosis, assist with treatment and mana- causative genes of syndromic epilepsy (Table 2)[7] and other gement (e.g., the use of a ketogenic diet in glucose transpor- disorders where epilepsy is associated with encephalopathies ter type 1 deficiency syndrome or the avoidance of lamotrig- (Table 3)[8], mental retardation with brain malformation ine, phenytoin, and carbamazepine in Dravet syndrome), (Table 4)[9, 10], other neurologic conditions including neu- elucidate the risk of a disease in family members and fu- ronal migration disorders (Table 5)[11], and inborn errors ture children, and save the patient from further diagnostic of metabolism (Tables 6 and 7)[12, 13]. Without any doubt, evaluation and potentially invasive testing. 2 Neurology Research International Table 1: Disease genes identified in generalized myoclonic epilepsy, febrile seizures, absences (37 genes). Gene Symbol Gene name and description ALDH7A1 Aldehyde dehydrogenase 7 family, member A1 BRD2 Bromodomain containing 2 CACNA1A Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit CACNA1H Calcium channel, voltage-dependent, T type, alpha 1H subunit CACNB4 Calcium channel, voltage-dependent, beta 4 subunit CASR Calcium-sensing receptor CHRNA2 Cholinergic receptor, nicotinic, alpha 2 (neuronal) CHRNA4 Cholinergic receptor, nicotinic, alpha 4 CHRNB2 Cholinergic receptor, nicotinic, beta 2 (neuronal) CLCN2 Chloride channel 2 CSTB Cystatin B (stefin B) EFHC1 EF-hand domain (C-terminal) containing 1 EPM2A Epilepsy, progressive myoclonus type 2A, Lafora disease (laforin) GABRA1 Gamma-aminobutyric acid (GABA) A receptor, alpha 1 GABRB3 Gamma-aminobutyric acid (GABA) A receptor, beta 3 GABRD Gamma-aminobutyric acid (GABA) A receptor, delta GABRG2 Gamma-aminobutyric acid (GABA) A receptor, gamma 2 GPR98 G protein-coupled receptor 98 GRIN2A Glutamate receptor, ionotropic, N-methyl D-aspartate 2A GRIN2B Glutamate receptor, ionotropic, N-methyl D-aspartate 2B KCNMA1 Potassium large conductance calcium-activated channel, subfamily M, alpha member 1 KCNQ2 Potassium voltage-gated channel, KQT-like subfamily, member 2 KCNQ3 Potassium voltage-gated channel, KQT-like subfamily, member 3 KCTD7 Potassium channel tetramerisation domain containing 7 MBD5 Methyl-CpG-binding domain protein 5 ME2 Malic enzyme 2, NAD(+)-dependent, mitochondrial NHLRC1 NHL repeat containing 1 PCDH19 Protocadherin 19 PRICKLE1 Prickle homolog 1 (Drosophila) PRICKLE2 Prickle homolog 2 (Drosophila) SCARB2 Scavenger receptor class B, member 2 SCN1A Sodium channel, voltage-gated, type I, alpha subunit SCN1B Sodium channel, voltage-gated, type I, beta subunit SCN2A Sodium channel, voltage-gated, type II, alpha subunit SCN9A Sodium channel, voltage-gated, type IX, alpha subunit SLC2A1 Solute carrier family 2 (facilitated glucose transporter), member 1 TBC1D24 TBC1 domain family, member 24 In asymptomatic subjects with increased risk of seizures The International League Against Epilepsy (ILAE) Genet- because of a family history, genetic test may predict onset of ic Commission presented a tool in the approach to specific epilepsy (predictive testing) [16, 17]. Despite such potential tests for epilepsy [16]. According to ILAE report, the diag- benefits, genetic testing has also potential harms, such as nostic genetic testing is “very useful” in individual affected its ethical, legal, and social implications, and the potential by early-onset spasms, X-linked infantile spasms, Dravet and for stigma, distress, adverse labeling, and nonconfidentiality related syndromes, Ohtahara syndrome, epilepsy and mental that exists in the setting of inadequate safeguards against retardation limited to females, early-onset absence epilepsy, discrimination [18]. Considering that our understanding of autosomal dominant nocturnal frontal lobe epilepsy, and the epidemiology and clinical utility of genetic testing in the epilepsy with paroxysmal exercise-induced dyskinesia; the epilepsies is incomplete, the assessment of these potential be- predictive testing is “very useful” in unaffected relatives of in- nefits and harms is particularly complex and is closely linked dividuals affected by Dravet syndrome and epilepsy and to the clinical scenario. mental retardation limited to females [16]. Considering Neurology Research International Table 2: Disease genes identified in syndromic epilepsy (47 genes). Gene symbol Gene name and description Syndrome ARFGEF2 ADP-ribosylation factor GEF2 Periventricular heterotopia ARHGEF9 Cdc42 GEF 9 Hyperekplexia with epilepsy A2BP1 Ataxin 2-binding protein 1 (RNA binding protein fox-1 homolog 1) Mental retardation and epilepsy ASPA Aspartoacylase Canavan syndrome ATP1A2 ATPase, Na/K transporting, alpha 2 polypeptide Familial hemiplegic migraine ATP2A2 ATPase, Ca transporting, cardiac muscle, slow twitch 2 Darier-White syndrome ATP6V0A2 ATPase, H+ transporting, lysosomal V0 subunit a2 Cutis laxa with epilepsy and mental retardation CACNA1A Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit Familial hemiplegic migraine CCDC88C Coiled-coil domain containing 88C Hydrocephalus with medial diverticulum CLCNKA Chloride channel Ka Bartter syndrome CLCNKB Chloride channel Kb Bartter syndrome COH1 Cohen syndrome protein 1—vacuolar protein sorting 13 homolog B Cohen syndrome DLGAP2 Discs, large (Drosophila) homolog-associated protein 2 Progressive epilepsy with mental retardation GFAP Glial fibrillary acidic protein Alexander disease GLI3 GLI family zinc finger 3 Pallister-hall syndrome GLRA1 Glycine receptor, alpha 1 Hyperekplexia GLRB Glycine receptor, beta Hyperekplexia GPHN Gephyrin Hyperekplexia KCNA1 Potassium voltage-gated channel, shaker-related Episodic ataxia KCNJ1 Potassium inwardly rectifying channel, subfamily J, member 1 Bartter syndrome KCNJ10 Potassium inwardly rectifying channel, subfamily