Do idiopathic generalized epilepsies share a common susceptibility gene? D. Janz, MD; G. Beck Mannagetta, MD; and. Sander, MD ‘Sie relalinen ud suey ‘Peps (a poral abeene and evened eplepses UMS) aatable subtypes arses ay fel of fay sic date sow tht five ICE syndromes hve a enimen sence cin. Likge is bella gn eect Crono Op that pers «up ofa Me ene poy, ander ‘thar aren reging fre ody uate he critics mooted ith iret vation of GE "NEUROLOGY 10asdiupp 4885 Molecular genetic research in pilepay has three principal goals. The fret is t define the genic rctors tht predispae to the development of ar cous forms of epilopey. This might improve genetic sunseling by Permiing more accurate estimates Stak, The notand ie to produce» new casrifcs tion of genetically determined lorms af eplepey 0 the bass of defied molecular Quarters The third ‘goals to describe the pathogenetic mechanism of Epilepsy resulting fom the gence defect (tho pin lp of rverse genetics). This would promote ratio- ‘tl Gevelopment of therapeti strates, Epileptic syndromes suitable for genetic analy: se, Bplloptieeypdrumes are ciniealy and eile ‘ally Rotrogenedus, but research an the mee {enetr factors disposing to epllapay se necessarily {ke most promising in homageneode, geneteslly ‘letermined forms of eplopoy. This implies « pheno {ype genotype stratogy that requires sclecton of Ihomageneoue elope syndromes identified on the Dasie of an unequivocal eisieal presentation, Mendelian tracamisvion with similar clinical ‘apresson in lee alaives, and suficenly large Suimber falta frais Lacaliation related epilepsies are not the most appropriate syndromes for this. {ope of research, They ate, however, quite conmnon fd have been reported ia the majerty af eases In Sere published ndings. Setzares occur more oten Inthe ales of patente with fea epilepsies than Jn control groups." Ottmann ot alt have reported that the ineidence ofeplepey inthe faniies af eins ih al epee reat tha tat io families of patients with generalized epilepsy although our own data do not support these fad Inga able "The decisive factors that render foal epilepsies unsuitele as models for gentle analyse are thet heterogeneous symplams and etologren, Analysis tf epileptic disorders i the fomilien of patients Wh simple and complex fecal epilepein reveals ‘ery inconsistent picture in term of age at onset, types, and combinations of seizures (D.danz, Unpublished data, 1001. Ta addition, heteroge neous feetre—such as early onge of disease hist 1 of febrile convulsions, and polypike waves on the slectrooncophalogrars—corelta with eplepie seinures in relatives of patients with complex fea Seiures* The exception to this rales benign hl hood epilepry with centrotemporal spike, which ‘resents with an clocwooncephalographie patars That ig probably trencmittod as an autosomal dom nant disorder with age-dependent penetrance” Generalized epilepsies. Idiopathic generalized Spilepsies(IGES) have eqosnea linia eharae erate, and the various cea sbiypes have di ferent agee of net Bvdence fr the genetic eo 17 of IGE inclads the inereased fami snedence ‘with frequent homophenic transmission, the eculte of studies tm twins, and the absence of apparent exogenous causes Cede and Tatarall™ examined 45 pair of twine with IGE end reported ‘SGocordance sm 947% of 19 moncrygour paite and {Hu of diaygous pairs. The high rate of concor ‘dance in moneaygoua twine suggests Chat genet fhctors ght be deiaive inthe elogy of IGE, The Felatively law eae of concordance in izygovs wine Evcompatble with move complex mode of ier ince Berkovie ct al fund that all concordant Shonosygous twins in their study shered the samme {plop syndrome ex the co-twin, This observation {hplles thas the IGE subtype ts sleo genetically determined “The empire risk of developing epilepey ie to of for elon relatives of patente with IGE." ‘This order of aki too low for spl Saberted ‘nonogenie diorder. Segregation analjas of sub tppes of IGE has provided evidence against simple ‘Monogente inheritance and favors plygenic trane inissten.* Combinations of different types of oizares in a given individual (ebsences and ‘myodanl jerks, for example) and fama assoc “Table 1, Rsk of epllepey in offeprng in relation to penental epliepey Pistauthor —Epllepey in Otprng affected Seyear pleas PS ‘ion of diferent IGE subtypes, such as absonce tpilepey ond JME, are mare compatible with we Terug model or more complex tral of inheritance We have used m phonstype-genstype strategy to tsoalyae the pedigrees af al indet patienta with ‘sbforms of IGE in an stomp to identify duease entities that might be attrbatable to genetic foc- “Te principal difficulty in relating a uniform phenotype to's single genotype is genetic hetero- Benetyr i the possibilty that multiple genes fight be responsible for the phenotype. This ‘ecamse apparent in genti tds of benign far Jat neonatal convulsions an IGE subeyndreme with fn autocemal dominant pattern of inberitance. Leppert ota usd linkage nals to deny 2 DNA locus on chromosome 0, which was ass ‘sted with benign fami neonatal sonrusions in {i individonis four generations of ails Ta- |y, Subsequent studies, however, have documented tridenee for cinical and genetic heterogenelty ia {his spperenly homogeneou linia syndrome.” (Genetic heterogeneity is even more Ikaly Ip the seneralied eilepaics found in ited in the International Classification under ‘ames tht imply ciaaderable cinialheteogene [y. The search for appropriate models for genetic Shudies becomes less daunting, however, when tenign myecloni epiepay in infancy, an eplopey ‘ith grand smal canes on awakening, are pov ‘analy eliminated ftom consideration. ‘The fret of {these two subtypes of 1GE wil not be discusced, ‘oeszo itis rae and ite causation je tll the subject of controversy Epilepey on awakening wilinot be considered, beesuee pure menifstations Eee poo ee a ee ee ee sword | | mygtonc | | “Soewen’ | | sues ‘econ eke cSnwiaine | | “plagey’ | | Seepey | | Seopny "oer seg ‘igre 1. lly ponaalied pps hin Terenas of ee and Bee Symon=< = Fire 8 Sys of IGE os of oet™ ya Fir 8 Satins of 1GBncdees of pcan rs Dibner rome of this disrdee without absences or myuclonc jerks fre wery rare when thorough history is taken and ‘lecrosncephalograms during sleep deprivation “End vaotape recordings are avalale™" ‘The most appropriate types of eplepry for genet- teaaiyee are relatively common anes that demon nt &finy igh frail incldance ad homoge ‘nos linia presentations. Ascording to thi an tld: sbeoncaeplepies and IME wonld spear to be'the most sustable subtypes of IGE for genetic analysis alized epilep forms of abwence epilepsies and JMIE ae sn {at ney are linost exlosively iopathle disor ‘tvs with datned ager of onast and charactorstle {hl and iatercta EBC findings variants of the ‘Mister synchronous spike-wave pater, They are bhten asabeiated with generalized tonic-clone felaures on awakening snd respond tothe same ‘dications. A few minor differences distinguish Figaro 1B of abn ond ‘onky myoelonic jerks in JME." Be ba “Table 2, Syndrome-related occurrence of spike and pilepsy——_“Spand-mave duchares in Tindlose — Zitase nSabae bse Poly them, howaver. For exemele, they differ in age of ‘onset. Pynopsy, or hudhood absence epilepsy, haracteristically beging at 8 to 10, javenile ele 12 18 years of go (igure 2). Some dogres of overlap ietween forms might occur during the clinical ‘ouree(igures $ and) All three types might be limited to minor etzares but combinations with {grand mal aacks are more common, ad eombine fons of the various epileptic syndromes or sub types do oesur, Myocani seiraen acer a appeos ately & of patiente with childhood absence lepoy and in U6 of thoe with juvenile absence Shilepey, while absences are abuteved In 20% of patients wath IME “Al dvee subtypes have a high ineidonce of bia eral synchronous spike waves (table 2), which ‘Teubol and Christian found in one adaitianal form of epilepay: pure iiopatieeplepy on awa ning. Therefore, withthe exception of the slow Sarlant, bilateral synchronous spike-wave ds ‘anges can be considered relatively specific mark fs the group of juvenile 1GEs with their age of ‘hac in ehldhood and sdolsconce, etal patarne are elativly specif forthe vari cous syndromes, Myodani jerks are always noc sted with polyepke waves, and absonces usually ‘Hh opike waver a the lass” Meguency of 25 to 3'ohee although more ropid variants are boerved caatnaly. Te casi Bequency i most common Selo sbsenes eplopey and the more Tapia asa i juvenile absence epilepsy (able 2) Dots cur eapeetations, polypize waves an fore rapid patterns donot predominate in TME- ‘They ave fund approsimatly an oten as th eae fe patie The tow variant dove not eearn JME Sal dscrved in bth type of sbnenc epee, ‘hough never ax tho sale patterns” A fairy cba Aeterlticdltribution af fequoncies te seen in {hes ayndromon, but these ndings are nether Specie no well for diacriminating ton te Familial incidence of afebrile epileptic Sclruros. The three pes of IGE do ot appear to ‘Titer eonetially, at least in terme of incidence tong close relatives of patients with these syn- tomes (table 2) The prevatonce of epileptic saures song the parents, slings, and ehildren tines paenta ranges trom 45 to 8%. The di flrences are noe satstealy significant and aver tye 3. for absence epilepsies snd 5.9% for JMB, ‘ihe analyoce ov ied to parenta and siblings {Tis proportion doesnot sppear tobe vory high To develop an acrarate picture of the true fell Incidence of eplepay, however, ti asefal to can- ‘er the eumaletive snedence of epilepsy in the general pepelation—1.8% wp to the age of 40 Fears determined by Huser and Annegers* ‘Tab, Cumulative incidence of epllepy in fest ‘Teftc aatives of probands with lope cheralsed cploplerynaromes interes eatin frame es) Forty percnt of thes ese, of 0.7% jn the general population; valve IGE. Assuring thatthe cum {nlve inedence of fla) epilepsy most probably Increases to 3% by the age of 40 and that most tases of eplepy among relatives of patients with Gh involve the same type of epilepay, the sym ddrume fe actually 10 mes moro common in am lee f tis group ofeplepay patients Chain the general population "The cumulative sak of developing epilepsy in rolatives of pationta withthe to infantile sya Tromes ef generalized epilopay Soot significantly ‘hiforen fn the ak i eltives of patents with oven syndromses, the female of pabents with ‘yomptomatie cplepaies are excluded (able 4). This Sunomhatsurpeaing, nce the conventional wis flom uouelly makes 8 sharp distinction betwoen {atuatie and juvenile IGE. Calculating ineidence fbr the pereste siblings, and children of index putents separtaly preferable, bees consider Etions of familial incidence in the West and Lennox iataut syndromes must e limited tothe patents sn ilings a the patient, ance physical ind sual anenps result reduced forty sa those severely il patonta (able 8) The fact that {he incidence of eplepay among their parents i Sly tv to tres ces the expected rate might be stipbutable oehanee abe incroesed incidence of disease among si “Table 4 Cumulative incidence of epilepsy In irs Steeles fpr ith fee, ttm Baan“Tabi 6 Syndromes of eilepy in frst degree relatives of probands with diferent syndromes af oc pepe = [Mlopat generalized cpicpe West and Lennar Avene smyacanic ‘oun yadromes opie spine linge were not due to genetic transmission, then tne would bo forced to seoume that Seis eaused by Sivironmental factors acing az determinants oF nfactors inthe pathogenesis ofthe disorder. Scietien of Sopa ease, however, eliminates ‘xogenous factors by definition, which implies = entie ute afte opatieifene syndromes, EFTGE, aswell. Tncreagod rink to the sblings of Dalen withthe infantile or ave syndromes i Spat with yf the tres mero rei {amomissin: dominant, recessive, oF polyzenie: Tereased sak to the parents and bildran of index Dalene with Juvenile symdromes i mot probably [rsociated wi sutoeomal dominant or polyzenie "Comparison of the disease phenotype of index palienl and their aflected lve relatives reveals Felther random dtrbuton nor abooute spe {Gbte 6) Ir the incdence of he varios syaromes forresponded exactly fo expectations derved fom ‘pemiloge data then fea epilopies weld be and in approximately half ll snaromee. Tis however not the ate Is sen sorpraing thal Benign Ehildhoodepilepey with eentratemporal Soe wichita ert de at ‘ot found among the faalies of patients with gene {elled plop in our cohort although num ero invetgators have reported relatively high ewGvVvuveee SS incidence ofthis disease, These syndromes must have another genetic enue "The eplopic syndromes in close relatives of sndex patients with 108 ae amon al comparable ‘lsordera A hgh degree of similarity is oboerved, {hc thee area numero different lhoagh relat- clink presentations. "fo interpret the dat, i e wef to know that asmumplions based on epidemiologic data would ‘eel ln Cmtined ates of epoxies forthe vo abeence eplepeiet, approximately 1 for JME, nod apprenimetely 6% forthe wo ‘uni geet upp peranes Pre fran mal eplepies aro certainly hetrogencoas ‘roms. iden, somes thete patients Rave peo awaken, wile some ave oni oe fn cosnderng the relatively high proportion of grand mal seizures it important to relae that ‘a ofthe data were ebainel rm ecards provided {by ther hopin If there ad been an operant {Berane and eborve te patents fia very lel) that alwences and mgcelonie seizures would have been deaced nore en. ‘hcefre, ip reagonae to cantde thatthe proportion af rand mal ele ‘Ses among rolotvor of patents fs tetually much ‘Sualer and de proportion of abwens eplepses and [IME much anger a detected in hs survey. Figo & Mosnars [DD acres wand petro, ‘Thief aertnce war orumed oe dominant or Peete the aflesednse ti” omy ‘Mears th AE cbmc pp, ep th Piatced tect este OPES onl =the ‘pends saan cue fry members ih TM tno py opp ih QTCS nt amd ‘ie ah nro pike wes ony ‘Table 7 demonstrates that JME i times more goon and absence eplepsiesaPP7 ‘iy twice as common ae would bo expected vad ove relatives of index patents with JME. TriaSiie with aboene epilepsies, abeence eile Teusttre fund three tines more often and JME Spratly tice aa often au expected. A se SENG eppromnately the same iereased incl ‘Bence ot sbsence epilepsies Sa found in famies of Satients with the various subtypes of IGE, while Elsressed incidence of the West and Lenaox ‘Gana syndromes is more pronounced among the Stistives of patente with these disorders, and SME ‘fitioch more common in famies with JME. The ‘art and Lonnix-Gataut syndromes are 90 more omen in the famies of patients with absence Gpllepsies or IME than would be predicted by ‘hance, The same ie tru of JME inthe famosa coarse with the West and Lennox-Gastaut sy Uromes. five wo six Is there a common susceptibility gene for Visshathie generalized epilepsy? The results of Tepes chow Unt the Sve epndromes of IGE. ‘ern ngcnie generalized eplepey have a common mr Sale igin, which is evident because of the Feettaned incidence of sbeenee eplepes amon ‘Sige elatives of pliencs with theo eyndromes. In Shildon, there ina tendency toward familial ‘pression of speci ayndromes that is partelar ‘moored in the more “extreme” syndromes. As 0 Soot smite tyndsomes seeur more often than ‘Expecled in the families of index patients, while ‘GEG syndromes occur with the expected ine dence among clot relatives. If this tendency is genetic in origin, then one must assume both a sensi lspotion to IGE and an edison po Siten ‘io spect syndromes, This assumption He Suppurted ‘by high eencerdance rates and anzghenic expression of IGE subtype i onery ‘eigado Bseueta otal” and Greenberg etal cod Boke analysis in famalis with epilep=y Seduaing un inves patient with JME to dome. Ste am autosomal dominant gono defect located he clint of the HLA rgio of chromosome 6p, ‘Shich predisposed to JN and astocated elec Woeneephalographie changes. We have confirmed tie’ dings in fae of patients with JME in es involving lings a eatves with eplepey ‘ver several generations Tn addition, we Rave ‘Semonerated hat the gene defect on chromosome Gpiwedpone wo a group af IGE comprising JM b.znce epilepeiss, and epllopsies with generalized foment saurer™ igaro 8) enue of Une above factors, the defect om ches ‘mosomo Gp pevbably represents 9 common redis. Tsing faner inva complex suede of inheritance a remus thaw thre subtypes of IGE: The eet TGE subtypes might be determined by em inatons of aadienal gence factors, We intend a oaeipete this pouty with the help of bakage Nigel using eertrieton fragment lenat poly sree mee ef the HEA-DQ leew mal Flop nd mltigenerstonal families of patients ith absence epilepsies. To identify the involved Junedl'on chromosome 6p more exactly, we will sere ulin anmgss techie with Sani [DNA murkert in mlploe and muligeserstional Pies of patients with IME. Additional linkage aes wit integane DNA markers of candidate seat help to elie other gene defects that secapode tothe varios IGE cubiypes with com Plex modes otinberanc, “Landidase genes ar those whose products are {ovale tn the development ofthe brain and te HNulation of its electrieal activity (table 8) ‘Bibi stadios have exchaded an etitloge oe of {Es benign familia neonatal convalsion locus on Chrome 204 and te GABAveL-eretar eh SAE pone on chromosome 5g in our JME fri.” "iter tat gene defocs Have been identi on ninasmta Op and 20g i wil be possible to Ue Sonotype phenotype atrategy to investigate sabes Rc dace ve responsible for pedis soe a NMOL ee 8postion to other forms of epilepsy. On the other Rand. 9 phenotype-genotype strateny would be "pproprinte for tvestigetns of the peal ole AP genetic presispontion in eile convalions ond hitocontsvty Febnie convulsions appear tobe Tore common in children of patients th absence {plopten aad less common fn farses with JME. GasPwould otherwise be expected * Photo Sensitivity permite diesrimisation between ‘aliens with shaenees or eilepey on awakening Eid thowe with JME Ti und fn 7.8% of patents wrth childhood absence eplepay. compared to So. of pints with IME, and thie incense to Sv n female wih this syadvome™® A search for {he gene locus of thewe two disrtminant variables vllstart with nage analyse, employing the {rere acd in JAE snd big fala neonatal ‘onvulsions, but It will probably be mecesary to proved isa ptemati pestigain of the ome wit morphisms: The idea Ema large fanies with eplepry patients nae tral generation would be very Relpfal in this Shueraking “Although we now know mare about genetic pre diapentions TG, we must sevuine tht he mane ifeltation of thoes disorders ix not datermined ‘lunvely ty genet factors ea well known Ghat Se elagves of patients with eplepay are chat [Sly healthy and foe of seizures, even with pea Signs of epltepey onthe electroencaphalogram, ‘Bltoroa inven suchas stress and seep dep atjon, ere major factors contribting ta the Und eibeequest seloures, especially te 1GE® The ‘Variety of dineal manifestations might reat fom “hvironmental infueness or addonal genetic Tac “Sur current interpretation of Us multifactor pathogenic mechanism sugges that environmen EXiafsences have a majoreifct on the extant and severiy of the clinical expression of 1GE—detar ‘ining whether «disorder remaineTatent with nly subline spe andiwave discharges or pre= Ente with petit mal or grand mal selzuree—for ‘imple, wile oneic Stars determine the var Sty of tho neal presentation (as myetonie stat {Deeiaures in infancy, pokaoleptie absences in ‘hiltnood, nonpyknsepiejvente absenery, oF {naM yoda Jers io adnlescone). This also Implies chat madfieation of environmental in fences might be an effective mode of treatment, ‘Among the environmental factors, habits and Istle ace smportant snd strongly related oie patients egns and social ene. The role of eave Fenmental factors in manieting ellie dacaces ‘Should be atudiad withthe same serutny a Ut of Acknowledgments Eibaricpinrepemnetbedatabeanae Reforenes siege Bre Sree 1073 98 vs Wbsteact) Byilepess 1990,31838, Soe eae Selene of he pein New Yr: Kae, STSSRSA Siasactes Attar Doe me Cee eae Sn area + Bornean tens baton Extrema ee niche Wamemimeri eas SECT ret yes ney ewer ‘fener ett abe sp OATS » RES Sais racine Sree sa. Delos Ft Sow yee peer chara af» Ss hacia nme atest in ‘ah apt gmat epic i,t cise say oh paint: eri: Beant 0 Jag Daze hr edrne ey eid pg a pe ce ‘Rite ipepae ts Wate. Siowemde sense tate ‘Wasa Dara Map, tl Contain ot hae tere vee mac pny iSonic an Me ee 9182098, Lae ighepar poate ean? EE cen te te Senin reser bea ae Rae ee tase namo tat ieonorrb tie steae ac ‘Buttgnre Tome 868, lg od To et a OLDE ip BH