Cell type mapping of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy using single-nucleus multiomics

Objective

Mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) are brain lesions associated with focal epilepsy and characterized by increased oligodendroglial density, 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 elusive. To address this gap, this study aimed to systematically characterize the cell type composition and molecular alterations of MOGHE lesions at cellular resolution using single-nucleus multiomics profiling.

Methods

We performed single-nucleus multiomics sequencing to obtain paired gene expression and chromatin accessibility profiles of > 31,000 nuclei from gray matter and white matter regions of MOGHE lesions, and compared the results with publicly available neurotypical control datasets.

Results

The analysis of gray and white matter regions from two MOGHE patients revealed significant cellular composition alterations, including an oligodendrocyte expansion and heterotopic neurons within the subcortical white matter. We identified a distinct population of MOGHE-associated oligodendrocytes characterized by expressing genes related to immune response, myelination disruption, and epilepsy-related pathways. These oligodendrocytes shared a common transcriptional signature with oligodendrocytes in other neurological conditions involving white matter abnormalities. Further analysis of heterotopic neurons in MOGHE revealed the upregulation of genes associated with neuronal migration and the Wnt signaling pathway, suggesting a mechanism underlying their atypical localization.

Significance

This high-resolution cell type mapping of MOGHE lesions in clinical samples unveils neuronal and glial populations affected by the disease, and provides novel insights into the pathophysiological mechanisms of MOGHE.

Key Points

• We provide a multimodal cellular atlas of the human cortical and subcortical regions affected in MOGHE

• MOGHE-associated oligodendrocytes exhibit immune response and myelination dysfunction

• Neuronal migration and Wnt signaling are upregulated in heterotopic neurons