VARIJANTE U GATOR1 GENIMA U FOKALNOJ EPILEPSIJI

Maša Kovačević; Ivana Novaković; Nikola Vojvodić

doi:10.5937/mp75-45140

Maša Kovačević Klinika za neurologiju, Univerzitetski klinički centar Srbije
Ivana Novaković Medicinski fakultet Univerziteta u Beogradu
Nikola Vojvodić Klinika za neuorologiju, Univerzitetski klinički centar Srbije

DOI: https://doi.org/10.5937/mp75-45140

Ključne reči: fokalna epilepsija, genetska epilepsija, DEPDC5, NPRL2, NPRL3, GATOR1

Sažetak

Iako je hereditarna priroda pojedinih epileptičkih sindroma odavno poznata, značaj genetskih faktora u etiopatogenezi fokalnih epilepsija je tek nedavno otkriven. Tako je na primer, 2013. godine opisana značajna uloga gena DEPDC5 u retkom sindromu familijarne fokalne epilepsije, što je nakon tri godine praćeno opisivanjem varijanti u genima NPRL2 i NPR3 kod pacijenata sa sličnom kliničkom slikom. Ovi geni kodiraju tri subjedinice GATOR1 (eng. GTPase-activating protein (GAP) activity towards Rags 1) kompleksa, negativnog regulatora mTORC1 (eng. mechanistic target of rapamycin (mTOR) complex 1). Gubitak funkcije GATOR1 dovodi do konstitutivne mTORC1 aktivacije koja je povezana sa različitim malformacijama kortikalnog razvoja (MKR) od kojih je najpoznatija fokalna kortikalna displazija (FKD), ali je takođe povezana sa epilepsijom bez vidljivih MKD. Varijante u GATOR1 genima su detektovane u familijama sa više obolelih članova obolelih od familijarnih sindroma fokalne epilepsije koje sa nasleđuju po autozomno dominantnom obrascu sa redukovanom penetrantnošću. U novijim studijama je definisana i njihova velika uloga u nestečenoj fokalnoj epilepsiji u kojoj su detektovane kod 3% sa familijarnom i 0,2% slučajeva sa sporadičnom epilepsijom, dok su posebno česte kod familijarne epilepsije povezane sa FKD gde su do 11% obolelih nosioci GATOR1 varijanti. Kliničke karakteristike nosioca obuhvataju sklonost ka noćnim napadima, slab odgovor na antiepileptičke lekove, kao i povećan rizik od naprasne neočekivane smrti u epilepsiji, zbog čega su ispitivane i druge forme lečenja, uključujući hirurgiju epilepsije nakon koje nosioci varijanti u GATOR1 genima imaju slične ishode kao drugi pacijenti sa fokalnom epilepsijom. Posebno obećavajuća mogućnost je upotreba mTOR inhibitora, poput everolimusa, u lečenju epilepsije, ali je neophodno dalje istraživanje ove opcije.

Biografije autora

Ivana Novaković, Medicinski fakultet Univerziteta u Beogradu

Redovni profesor na Katedri za humanu genetiku Medicinskog fakulteta Univerziteta u Beogradu

Nikola Vojvodić, Klinika za neuorologiju, Univerzitetski klinički centar Srbije

Specijalista neurologije, Odeljenje za epilepsiju i poremećaje spavanja, Klinika za neurologiju, Univerzitetski klinički centar Srbije

Vanredni profesor na Katedri za neurologiju Medicinskog fakulteta Univerziteta u Beogradu

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