Genetic biomarkers in drug-resistant focal epilepsies and their role in surgical outcome

Aim: To determine the incidence of mTOR pathway variants in surgical malformations of cortical development (MCDs) and negative histology cases. To assess the predictive value of genotype-histotype findings on the surgical outcome. Methods: We enrolled surgically treated patients from Niguarda and Bellaria Hospital. We retrospectively selected all cases operated on from 2013 to 2016 with type II focal cortical dysplasia (FCD) and unmatched formalin-fixed, paraffin-embedded (FFPE) brain tissues available. For the prospective phase, we selected patients with neuropathological diagnosis of MCDs or aspecific findings and fresh frozen brain tissues. We performed smMIPs analysis to target MTOR (retrospective cases) and 9 mTOR pathway genes (prospective cases). We performed genotype-histotype and surgical outcome statistical correlations. Results: Seven pathogenic MTOR somatic variants were found in FFPE brain tissues of 28 retrospective cases. We prospectively selected 63 MCDs and negative histology cases out of 184 cases. Six MTOR somatic variants and two DEPDC5, two TSC1 and one TSC2 germline variants were identified. Type IIb FCD was associated with MTOR genotype (P< 0.001). Any differences in surgical outcome between MTOR mutated-not mutated cases were found. A MTOR patient repeated surgeries up to hemispherectomy without seizure control and with a shift of the epileptogenic zone into the residual “normal” hemisphere. All patients carrying germline variants except one (TSC1) were seizure-free after surgery. Conclusion: a genetic aetiology is found in 18 patients: 13 brain somatic MTOR (14%), 2 DEPDC5 (3.2%), 2 TSC1 (3.2%) and 1 TSC2 (1.6%) germline variants. Somatic MTOR variants are found at low-level somatic mosaicism especially in type IIb FCDs. MTOR genotype does not represent a contraindication for epilepsy surgery. Nevertheless, the detection of MTOR somatic mutation and the failure in seizure control after the first surgery may represent a red flag for planning further surgical procedures.