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- Title
Hippocampal and neocortical BRAF mutant non‐expansive lesions in focal epilepsies.
- Authors
Lerond, Julie; Mathon, Bertrand; Scopin, Mélina; Nichelli, Lucia; Guégan, Justine; Bertholle, Céline; Izac, Brigitte; Andrieu, Muriel; Gareau, Thomas; Donneger, Florian; Mohand Oumoussa, Badreddine; Letourneur, Franck; Tran, Suzanne; Bertrand, Mathilde; Le Roux, Isabelle; Touat, Mehdi; Dupont, Sophie; Poncer, Jean Christophe; Navarro, Vincent; Bielle, Franck
- Abstract
Objective: Mesial Temporal Lobe Epilepsy‐associated Hippocampal Sclerosis (MTLE‐HS) is a syndrome associated with various aetiologies. We previously identified CD34‐positive extravascular stellate cells (CD34+ cells) possibly related to BRAFV600E oncogenic variant in a subset of MTLE‐HS. We aimed to identify the BRAFV600E oncogenic variants and characterise the CD34+ cells. Methods: We analysed BRAFV600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE‐HS samples (25 with CD34+ cells) and nine non‐expansive neocortical lesions resected during epilepsy surgery (five with CD34+ cells). Ex vivo multi‐electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAFwildtype MTLE‐HS and BRAFV600E mutant non‐expansive lesion of hippocampus and/or neocortex. Results: We identified a BRAFV600E oncogenic variant in five MTLE‐HS samples with CD34+ cells (19%) and in five neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAFV600E mutant samples. The co‐expression of the oncogene‐induced senescence marker p16INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in eight of the 10 patients with BRAF mutant lesions. Interpretation: BRAFV600E underlies a subset of MTLE‐HS and epileptogenic non‐expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and open perspectives for targeted therapies.
- Subjects
PARTIAL epilepsy; IMMUNOSENESCENCE; BRAF genes; HIPPOCAMPAL sclerosis; HIPPOCAMPUS (Brain); EPILEPSY surgery; OLIGODENDROGLIA
- Publication
Neuropathology & Applied Neurobiology, 2023, Vol 49, Issue 5, p1
- ISSN
0305-1846
- Publication type
Article
- DOI
10.1111/nan.12937