Dysregulated cell states revealed by single-cell multiomics in mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy

Mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a distinct form of focal epilepsy characterized by oligodendroglial clusters, heterotopic neurons, and hypomyelination in the white matter. While previous studies have implicated somatic mutations in the SLC35A2 gene, the cellular and molecular mechanisms underlying MOGHE pathogenesis remain largely unknown. In this study, we utilized multiomic single-nuclei sequencing to profile the gene expression and chromatin accessibility of MOGHE lesions at cellular resolution. Analysis of grey and white matter regions from two MOGHE patients revealed significant alterations in cellular composition, highlighting an expansion of oligodendrocytes and the presence of heterotopic neurons within the subcortical white matter. We identified a population of MOGHE-associated oligodendrocytes, which were enriched in genes involved in immune response, myelination disruption, and epilepsy-related pathways, and shared transcriptional similarities with pathological oligodendrocytes identified in other neurological disorders. Further analysis of heterotopic neurons in MOGHE revealed the upregulation of genes associated with neuronal migration and the Wnt signaling pathway, suggesting a potential mechanism underlying their atypical localization. Altogether, this high-resolution cellular characterization of MOGHE unveils the neuronal and glial subpopulations affected in the disease and provide novel insights into the pathophysiological mechanisms of MOGHE. Overall design: We obtained frozen cortical tissue specimens from two donors aged 22 and 57 years with a confirmed pathological diagnosis of MOGHE after epilepsy surgery. We isolated nuclei from the MOGHE grey matter (MOGHE-GM, n=2) and white matter regions (MOGHE-WM, n=2), and performed paired snRNA-seq and snATAC-seq on each nucleus using the Multiome ATAC + Gene Expression kit (10X Genomics) to measure chromatin accessibility and gene expression at nuclei resolution.