RT Journal Article SR Electronic T1 Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder? JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e540 DO 10.1212/NXG.0000000000000540 VO 7 IS 1 A1 Guerrini, Renzo A1 Cavallin, Mara A1 Pippucci, Tommaso A1 Rosati, Anna A1 Bisulli, Francesca A1 Dimartino, Paola A1 Barba, Carmen A1 Garbelli, Rita A1 Buccoliero, Anna Maria A1 Tassi, Laura A1 Conti, Valerio YR 2021 UL http://ng.neurology.org/content/7/1/e540.abstract AB Objective To alert about the wide margin of unpredictability that distribution of somatic MTOR mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD).Methods Clinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic MTOR mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for AKT1 (patient 3).Results The strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) MTOR mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys AKT1 mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere.Conclusions Our understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic.AAF=alternative allele fraction; AED=antiepileptic drug; DMEG=dysplastic megalencephaly; FCDII=focal cortical dysplasia type II; HME=hemimegalencephaly; MCD=malformations of cortical development; MEG=megalencephaly; mTOR=mammalian target of rapamycin; OFC=occipital frontal circumference (head circumference); smMIP=single-molecule molecular inversion probe; WES=whole-exome sequencing