Fire and Ice: Who's the Main Character in FCDII Pathogenesis?

Original Article Citation 1: Single-Cell Genotyping and Transcriptomic Profiling of Mosaic Focal Cortical Dysplasia Baldassari S, Klingler E, Teijeiro LG, Doladilhe M, Raoux C, Roig-Puiggros S, Bizzotto S, Couturier J, Gilbert A, Sami L, Ribierre T, Aronica E, Adle-Biassette H, Chipaux M, Jabaudon D, Baulac S. Nat Neurosci . 2025;28(5):964-972. doi:10.1038/s41593-025-01936-z Focal cortical dysplasia type II (FCDII) is a cortical malformation causing refractory epilepsy. FCDII arises from developmental somatic activating mutations in mTOR pathway genes, leading to focal cortical dyslamination and abnormal cytomegalic cells. Which cell types carry pathogenic mutations and how they affect cell-type-specific transcriptional programs remain unknown. In the present study, we combined several single-nucleus genotyping and transcriptomics approaches with spatial resolution in surgical cortical specimens from patients with genetically mosaic FCDII. Mutations were detected in distinct cell types, including glutamatergic neurons and astrocytes, and a small fraction of mutated cells exhibited cytomegalic features. Moreover, we identified cell-type-specific transcriptional dysregulations in both mutated and nonmutated FCDII cells, including synapse- and neurodevelopment-related pathways, that may account for epilepsy and dysregulation of mitochondrial metabolism pathways in cytomegalic cells. Together, these findings reveal cell-autonomous and non-cell-autonomous features of FCDII that may be leveraged for precision medicine. Original Article Citation 2: Transcriptomic and Morphologic Vascular Aberrations Underlying FCDIIb Etiology Fang C, Zhang X, Yang L, Sun L, Lu Y, Liu Y, Guo J, Wang M, Tan Y, Zhang J, Gao X, Zhu L, Liu G, Ren M, Xiao J, Zhang F, Ma S, Zhao R, Mei X, Qi D. Nat Commun . 2025;16(1):3320. doi:10.1038/s41467-025-58535-6 Focal cortical dysplasia type II (FCDII) is a major cause of drug-resistant epilepsy, but genetic factors explain only some cases, suggesting other mechanisms. In this study, we conduct a molecular analysis of brain lesions and adjacent areas in FCDIIb patients. By analyzing over 217,506 single-nucleus transcriptional profiles from 15 individuals, we find significant changes in smooth muscle cells (SMCs) and astrocytes. We identify abnormal vascular malformations and a unique type of SMC that we call “Firework cells”, which migrate from blood vessels into the brain parenchyma and associate with VIM+ cells. These abnormalities create localized ischemic–hypoxic (I/H) microenvironments, as confirmed by clinical data, further impairing astrocyte function, activating the HIF-1α/mTOR/S6 pathway, and causing neuronal loss. Using zebrafish models, we demonstrate that vascular abnormalities resulting in I/H environments promote seizures. Our results highlight vascular malformations as a factor in FCDIIb pathogenesis, suggesting potential therapeutic avenues.