Objective:

To characterize the transcriptomic profile of focal cortical dysplasia (FCD) type IIa and explore the interplay between metabolic, neuroinflammatory, and vascular pathways contributing to intrinsic epileptogenicity.

Background:

FCDIIa is a developmental malformation characterized by cortical lamination defects and dysmorphic neurons, and represents a leading cause of drug-resistant epilepsy. Inflammatory mechanisms have been proposed to contribute to epileptogenesis, but the molecular landscape of histologically pure FCD IIa remains poorly defined.

Design/Methods:

Bulk RNA-seq counts (GSE213488) from surgically resected human FCD IIa and control gray-matter cortex were analyzed using iDEP2. Low-abundance genes were filtered (CPM > 0.5 in ≥1 sample) and normalized (log₂-CPM). Differential expression was performed using DESeq2 (FDR < 0.05, |log₂FC| ≥ 1). Functional interpretation was conducted through over-representation analysis (ORA) of significant DEGs and preranked gene set enrichment analysis (fgsea) across Gene Ontology, Hallmark, KEGG, and Curated.Reactome databases (FDR < 0.05).

Results:

Differential expression identified 85 upregulated and 130 downregulated genes defining a distinctive molecular polarity. Upregulated genes converged on oxidative phosphorylation, cholesterol biosynthesis, and synaptic vesicle cycling, indicating heightened neuronal and astrocytic metabolic drive. Conversely, downregulated programs encompassed interferon and IL-6–JAK–STAT3 signaling, complement cascade, endothelial adhesion, and angiogenesis, suggesting suppression of immune–vascular communication. GSEA corroborated these patterns, showing strong enrichment of Oxidative Phosphorylation and Synaptic Transmission (NES > 2.0, FDR < 0.01) alongside coordinated depletion of IL6–JAK–STAT3, Interferon-α/γ, Complement, and Angiogenic pathways (NES < –2.0, FDR < 0.01), together delineating an energetically active yet immunologically dormant cortical network.

Conclusions:

The transcriptomic signature of FCD IIa indicates a state of metabolic-immune polarity: metabolically active yet immunologically and vascularly subdued cortical state. This "metabolic isolation" may create a self-sustaining hyperexcitable circuit that evades normal homeostatic regulation, contributing to pharmacoresistance. These findings reframe epileptogenesis in FCD IIa as a disorder of metabolic–microenvironmental imbalance.