| 描述信息 |
Focal cortical dysplasia type II (FCDII), common in drug-resistant epilepsy, has genetic factors accounting for only a subset of cases, suggesting the involvement of other mechanisms. This study presents a comprehensive molecular atlas of lesions and adjacent neocortex in FCDIIb patients, analyzing 217,506 high-quality single-nucleus transcriptional profiles from 15 individuals. Our analysis revealed significant alterations in smooth muscle cells (SMCs) and astrocytes associated with the disease. Pathological examination and immunofluorescence staining uncovered pronounced vascular malformations in the lesion neocortex, alongside a unique type of abnormal SMCs that migrate from blood vessels into the brain parenchyma. These cells, characterized by extensive, fluffy processes and surrounded by FCDII-associated VIM+ cells, are termed "Firework cells". Additionally, ASL perfusion and PET-CT/MRI indicated that vascular malformations impair vessel function, creating localized ischemic-hypoxic (I/H) microenvironments. Within these I/H microenvironments, the HIF-1α/mTOR/S6 pathway was activated, which was accompanied by disrupted astrocyte activity and neuronal loss. Using zebrafish models of vascular malformation and I/H, we confirmed that vascular abnormalities resulting in I/H microenvironments can promote seizure occurrence. These findings reveal vascular malformation-mediated pathogenesis in FCDIIb and suggest potential therapeutic strategies, underscoring vascular malformations as both a clinical feature and a pathogenic factor. |
