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2005, vol. 133, br. 1-2, str. 7-13
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Generalizovana epilepsija sa febrilnim napadima plus - klinička i genetska analiza kod tri srpske porodice
Generalized epilepsy with febrile seizures plus: Clinical and genetic analysis of three Serbian families
Ristić Aleksandar J.a  , Janković Slavkoa, Annesi Grazziab, Carrideo Sarab, Annesi Ferdinandab, Gambardella Antonioc, Maksimović Gorand, Gnjatović Brankicae, Petrović Igora, Vojvodić Nikolaa, Sokić Dragoslava
aKlinički centar Srbije, Klinika za neurologiju, Beograd bInstitut neuroloških nauka, Nacionalni istraživački savet, Piano Lago di Mangone, Cosenza cInstitut za neurologiju, Univerzitet Magna Graecia, Catanzaro, Institut neuroloških nauka, Nacionalni istraživački savet, Piano Lago di Mangone, Cosenza dOpšta bolnica 'Sveti vrači', Bijeljina eOpšta bolnica, Prijedor
e-adresa: dsokic@sezampro.yu
Sažetak
Generalizovana epilepsija sa febrilnim napadima plus (GEFN+) je tipičan genetički epilepsijski sindrom s autozomno dominantnim tipom nasleđivanja i nepotpunom penetracijom. Fenotipska ekspresija GEFN+ obuhvata raznovrstan spektar kliničkih epilepsijskih fenotipova, koji uključuje febrilne napade i različite tipove afebrilnih, generalizovanih ili parcijalnih epilepsijskih napada. Do sada je opisano nekoliko tzv. point mutacija na četiri genska lokusa (SCN1A, SCN2A, SCN1B i GABRG2). Prikazujemo rezultate kliničke i genske analize kod tri srpske porodice sa fenotipskim odlikama GEFN+. Zabeležene su kliničke odlike, EEG, neurovizuelizacioni nalazi i učinjena je genska analiza (radi pronalaženja mutacija na SCN1A, SCN1B i GABRG2 genima) kod 20 obolelih članova tri srpske porodice koje nisu u srodstvu (MM, OM i KS), bez poznatog konsangviniteta, od ukupno 33 analizirana člana (77 živih kod sve tri porodice). Dva bolesnika u porodici MM su bolovala od epilepsije rezistentne na lekove u trenutku sprovođenja studije, a kod osam od 12 klinički ispitanih bolesnika (66,6%) tok epilepsije je bio povoljan. Kod dva bolesnika prognoza je bila neizvesna. Kod pet od 12 ispitanih članova iz porodice MM zabeleženi su i drugi tipovi napada osim generalizovanih toničko-kloničkih napada (GTKN). Dva člana porodice OM bolovala su od epilepsije rezistentne na lekove, čija su najčešća klinička manifestacija GTKN koji nisu provocirani febrilnošću, a u varijabilnoj frekvenciji se događaju i apsansni napadi. U porodici KS zabeleženi su febrilni i afebrilni GTKN, bez drugih tipova napada i sa pretpostavljenim bilinealnim nasleđem. Pojava anticipacije nije zabeležena. Ni kod jedne analizirane osobe, niti u jednom od egzona SCN1A, SCN1B i GABRG2 gena nisu pronađene dosad opisane odgovorne mutacije. GEFN+je vrlo heterogen klinički sindrom i njegovo prepoznavanje doprinosi njegovom detaljnijem sagledavanju, što bi trebalo da omogući njegovu potpunu integraciju u već definisane epilepsijske sindrome.
Abstract
The results of clinical and genetic analysis of three Serbian families (pedigrees) with autosomal dominant inheritance, incomplete penetrance and phenotypic features of GEFS+ are presented in this study. Mutation analysis of the SCN1A, SCN1B and GABRG2 genes was performed in all affected and some unaffected members of these three families. Twentysix exons of SCN1A, five exons of SCN1B and nine exons of GABRG2 were individually amplified using primers based on intronic sequence. PCR products were sequenced in both forward and reverse directions. Subsequently, the samples were run and analyzed using 377 DNA automated sequencer. No consanguinity was noticed. The MM and OM family members live in Republic of Srpska while KS family originates from the central Serbia. No mutations of the exons of SCN1A, SCN1B and GABRG2 genes were found in tested subjects. Obligate carriers in MM family (III-1, III-2, and III-4) exhibit variable expressivity or incomplete penetrance rather than proof of polygenetic inheritance. OM pedigree follows autosomal dominant pattern despite reduced penetrance. Bilinear transmission may assume the possibility of multigenetic mode of inheritance in KS family. The fact that all affected members in three Serbian families were negative for mutations in SCN1A, SCN1B and GABRG2 genes strongly supports the hypothesis of significant genetic heterogeneity of GEFS+. Recognizing GEFS+ on clinical grounds contributes to more precise integration of this syndrome into already existing classification of epileptic syndromes.
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