Molecular Heterogeneity of WNT and mTOR Signaling Pathways in Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia and Epilepsy (MOGHE)

<title>Abstract</title> <p>Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia and Epilepsy (MOGHE) is a recently recognized developmental lesion associated with drug-resistant epilepsy. Although its clinical and neuropathological features are increasingly understood, the molecular mechanisms underlying MOGHE remain largely unknown. Given the roles of mTOR and WNT signaling in cortical development and epileptogenesis, we investigated the expression of selected genes from these pathways in surgically resected MOGHE tissue and explored their biological associations through computational network analysis. Cortical samples from 12 patients with histopathologically confirmed MOGHE were analyzed by quantitative real-time PCR. Gene expression levels were compared with control cortical tissue from patients with temporal lobe epilepsy associated with hippocampal sclerosis. Bioinformatic analyses included MalaCards-derived gene–disease associations, molecular network modeling, community detection, and heuristic disease-prioritization approaches. Gene expression analysis revealed marked molecular heterogeneity among MOGHE samples. Despite substantial interindividual variability, several genes showed a consistent reduced expression, including RICTOR, RPTOR, TSC2, LRP6, and WNT5A. Stratification by cortical location identified region-specific expression patterns, particularly for WNT5A, which was upregulated in right temporal lesions and markedly downregulated in frontal lesions. Network analyses identified two major functional modules: one centered on RICTOR, RPTOR, and TSC2, associated with epilepsy and neurodevelopmental disorders, and another centered on LRP6 and WNT5A. TSC2 occupied a central position connecting both modules, suggesting biological interaction between mTOR and WNT signaling. These findings indicate that MOGHE is a molecularly heterogeneous developmental disorder involving coordinated alterations in mTOR and WNT pathways, providing new insights into its pathogenesis and potential therapeutic targets.</p>