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<p>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<sup>+</sup> 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.</p>

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Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月8日

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  • Chuantao Fang,
  • Xiaodan Zhang,
  • Lin Yang,
  • Licheng Sun,
  • Yujia Lu,
  • Yi Liu,
  • Jingjing Guo,
  • Min Wang,
  • Yanfeng Tan,
  • Jinsen Zhang,
  • Xin Gao,
  • Li Zhu,
  • Guoping Liu,
  • Maozhi Ren,
  • Jianbo Xiao,
  • Fayong Zhang,
  • Shaojie Ma,
  • Rui Zhao,
  • Xinyu Mei,
  • Dashi Qi

摘要

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.