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Review ArticleGenetics and EpilepsyThe completion of the human genome project and thefurther availability of increasingly detailed data onhuman chromosomes 1 promise much for our understandingof the genetic basis of human health and disease.The entire human genome contains some 30,000 genes,more than half of which are expressed at some stage in thebrain. Genetic influences on brain function and diseases aretherefore pervasive. In the outbred human species, epilepsyis obviously not a constitutive phenotype: there are certaingenetic variants that either directly cause or contribute toepilepsy phenotypes. Epilepsy is a heterogeneous group ofconditions, and thus genetic influences on different types ofepilepsy are likely to vary widely. However, whilst genesencode every protein, many proteins undergo additionalmodulation by factors ranging from the post-transcriptionalto the macroenvironmental, so that we, and our diseases,are generally not products of a rigid genetic determinism.However, genetic factors are perhaps now morereadily determined than environmental factors, so thatgenetic studies in epilepsy hold promise for a better understandingand more rational treatment than that which currentlyexists.Genes could influence seizures, epileptogenesis andepilepsy at multiple levels. Genetic variation could affectthe aetiology, susceptibility, mechanisms, syndrome, treatmentresponse, prognosis and consequences of the epilepsiesto varying degrees in different individuals. Part of thepromise of genetics lies in its power to relate these facets ofthe overall clinical presentation to the individual patient.There has been considerable recent progress, though thishas focused largely on aetiology, susceptibility and treatmentresponse.More and more genetic mutations are being identifiedthat cause epilepsy. These mutations usually cause conditionsthat are inherited in a classical Mendelian fashion:autosomal dominant, autosomal recessive, X-linked orthrough mitochondrial inheritance. Mutations are rareand, even collectively, mutational causes of conditions inwhich epilepsy is the sole or main manifestation accountfor only a small proportion of cases of epilepsy. Perhapsunsurprisingly given the central position of neuronalexcitability in epilepsy, most mutations so far uncoveredthat lead to epilepsy occur in genes encoding ion channels. 2Sodium, potassium, calcium and chloride channelopathieshave all been described, and there are likely to be others tocome (Table 1). It is worth noting, in passing, that acquiredepileptogenic channelopathies also exist. 3 Mutations thatcause monogenic epilepsies fall into two other major categories:those that lead to structural brain malformationsone clinical manifestation of which is epilepsy; 4 and thosethat produce the progressive myoclonic epilepsies (PMEs). 5The latter are themselves a diverse group of conditions distinguishedby particular natural histories, pathophysiologiesand investigational findings, but which broadly sharethe common characteristics of myoclonic jerks, otherseizure types and progressive cognitive decline: many PMEscan now be defined and dissected genetically (Table 2).Only a few other genetic mutations are known to lead toepilepsy as their major consequence. These include LGI1,mutations which cause a familial focal epilepsy. 6 There areof course a large number of Mendelian conditions withknown underlying gene mutations that cause multisystemicconditions in which seizures are part of a broaderphenotype: the number of these also continues to grow, butagain account for only a small proportion of the epilepsies.This progress in the genetic aetiology of the epilepsiesis remarkable, and as yet unmatched by developments inthe genetics of other aspects of disease biology, such assusceptibility or treatment response, reflecting partly thefocus of researchers so far, but also the tractability of therelevant issues.Genetic variation influencing susceptibility to non-Mendelian epilepsies has been the other major focus ofresearch. Most epilepsies are complex traits and probablyarise in individuals as a result of gene-gene and gene-environmentinteractions. The numbers of genes involved areunknown, and may be few or many. The resulting patternsof inheritance in the majority of cases are thus more complicatedand subtle: such inheritance falls outside theMendelian patterns to which we have become accustomed.As a corollary, large cohorts of patients are needed to extractthe risks attributable to particular common genetic variants.Many positive associations between particular gene variantsand defined epilepsy syndromes have been found; it is likelythat many more negative results have not made it to theeditor’s in-tray. However, no common genetic variants areyet accepted as genuinely increasing the risk of any particularepilepsy type or syndrome. 7 Numerous problems ofmethodology dog this area of research. Perhaps the mostimportant is that any one research centre is unlikely to beable to recruit sufficient numbers of patients with an appropriatelyhomogeneous phenotype to have adequate powerto detect individual gene effects which are in practice likelyto be minor: a parallel with international clinical trialsrecruiting thousands to show minor benefits from a newtreatment regime may be drawn. However, as our understandingof the genome and its vagaries improves, and withincreased experience and international collaboration, itseems likely that common genetic variants driving commondisease processes will emerge.The genetics of drug response may prove to be moreamenable to analysis than other aspects of genetics inepilepsy, because the proteins that are drug targets, drugtransporters and drug metabolisers are to varying extentsalready known. Their encoding genes do not need to bepicked, at random or otherwise, from 30,000 genes, 8 andmany have been thoroughly characterised. 9 For example, itis well established that individuals who possess certain allelesof the CYP2C9 gene, that encodes the major metabolisingenzyme of phenytoin, have significantly reduced ratesof metabolism of phenytoin, necessitating lower maintenancedoses, 10 although prospective genotyping is not yetundertaken in practice. Whether variants in the ABCB1gene, that encodes the broad-spectrum multidrug transporterP-glycoprotein, influence resistance to antiepilepticdrugs or not remains a hotly-debated point. 11,12 Gene variantsinfluencing the sensitivity of targets to antiepilepticdrugs are also being uncovered: for example, a splice sitevariation in the SCN1A gene that encodes the cerebral neuronaltarget of many antiepileptic drugs, has been associatedwith dosing of these drugs. 10 Such pharmacogeneticadvances, if substantiated by further studies and proven instructured trials to be clinically significant, may permitcloser modelling of treatment to the individual patient.The genetics of most other biological facets of epilepsyhave not yet even been considered in any detail, but itremains possible that genetic variation will also have animpact of clinical relevance in these other areas (eg biologicalconsequences of epilepsy in an individual patient).Much is still expected of genetic research: careful evaluationin the clinical setting will remain critical to establishing thepractical utility of such research. Close collaborationbetween epilepsy clinical centres, and between clinical andlaboratory scientists, and accurate definition of phenotypes,will be the key to bringing epilepsy genetics to theclinic for the benefit of patients and society.Dr Sisodiya works in the Departmentof Clinical and ExperimentalEpilepsy, Institute of Neurology,UCL, London. His clinical andresearch interests are in the neurogenetic,neuropathological anddevelopmental biological aspectsof epilepsy, recently focusing ongenetic variation, disease susceptibilityand treatment response.Correspondence to:SM Sisodiya MA, PhD, FRCP,Reader in Neurology,Department of Clinical andExperimental Epilepsy,National Hospital for Neurologyand Neurosurgery, Box 29,Queen Square, London WC1N 3BG.Tel: 020 7837 3611,Fax: 020 7837 3941,Email: sisodiya@ion.ucl.ac.uk10 I ACNR • VOLUME 5 NUMBER 6 • JANUARY/FEBRUARY 2006