Authors :
Presenting Author: Mathilde Chipaux, MD, PhD – Rothschild Hospital-Foundation
Emmanuel Raffo, MD, PhD – Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, EpiCARE member, F-75019 Paris, France; Homa Adle-Biassette, MD, PhD – Service d'Anatomie et de Cytologie Pathologiques, Hôpital Lariboisière, APHP, F-75010, Paris, France; Marc Polivka, MD – Service d'Anatomie et de Cytologie Pathologiques, Hôpital Lariboisière, APHP, F-75010, Paris, France; Christine Bulteau, MD, PhD – Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, EpiCARE member, F-75019 Paris, France; Rayann Chekri, MD – Institut du Cerveau-Paris Brain Institut-ICM, Sorbonne Université, INSERM, CNRS, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France.; Marie-Thérèse Dangles, MD – Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, EpiCARE member, F-75019 Paris, France; Sarah Rosenberg, MD, PhD – Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, EpiCARE member, F-75019 Paris, France; Sarah Ferrand-Sorbets, MD – Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, EpiCARE member, F-75019 Paris, France; Georg Dorfmuller, MD – Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, EpiCARE member, F-75019 Paris, France; Sara Baldassari, MD, PhD – Institut du Cerveau-Paris Brain Institut-ICM, Sorbonne Université, INSERM, CNRS, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France.; Stéphanie Baulac, MD, PhD – Institut du Cerveau-Paris Brain Institut-ICM, Sorbonne Université, INSERM, CNRS, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France.
Rationale:
Genetic malformations of cortical development such as foca cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies potentially accessible to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs).
Methods:
We provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical cases. We enrolled in a monocentric study 287 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of FCD 1 or 2. We performed targeted gene sequencing on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes in 204 patients.
Results:
We were able to elucidate 64.2% (131/204) of the patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in MOGHE. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found in FCD2/HME cases. Somatic mutations could also be detected from CSF and SEEG trace tissues. Phenotypic-genotypic correlations showed that PIK3CA mutation was responsible for neonatal epilepsy, but RHEB/AKT3 mutations led to a later onset in the first year of life. Cognitive delay and autistic features were more prominent in SLC35A2/PIK3CA/RHEB mutations. We provided extensive analysis of these phenotypic-genotypic correlations. At the end of the follow-up, 66.3% of the children were cured (Engel 1) after resective surgery.
Conclusions:
MOGHE and FCD2/HME were two distinct genetic entities; while all FCD2/HME are mosaic mTORopathies, MOGHE were not caused by mTOR-pathway-hyperactivating variants. Targeting mTOR pathway therapies might be encouraged in FCD2 related epilepsies. Phenotypic-genotypic correlations might lead to earlier diagnosis, especially since we were able to find the mutation on invasive EEG electrodes and in cerebrospinal fluid. Finally, the postsurgical outcome was similar whether a mutation was found or not and shouldn’t delay the surgery.
Funding: None