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. 2023 Oct;49(5):e12937.
doi: 10.1111/nan.12937.

Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies

Julie Lerond  1 , Bertrand Mathon  2 , Mélina Scopin  3 , Lucia Nichelli  4 , Justine Guégan  5 , Céline Bertholle  6 , Brigitte Izac  6 , Muriel Andrieu  6 , Thomas Gareau  5 , Florian Donneger  3 , Badreddine Mohand Oumoussa  7 , Franck Letourneur  6 , Suzanne Tran  8 , Mathilde Bertrand  5 , Isabelle Le Roux  1 , Mehdi Touat  9 , Sophie Dupont  10 , Jean Christophe Poncer  3 , Vincent Navarro  11 , Franck Bielle  8   12
Affiliations

Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies

Julie Lerond et al. Neuropathol Appl Neurobiol. 2023 Oct.

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.

Keywords: BRAF; CD34; HOPX; epilepsy; hippocampal sclerosis; methylation; senescence; somatic mosaicism.

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