The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D

Wang DD, Katoch M, Jabari S, Blümcke I, Blumenthal DB, Lu DH, Coras R, Wang YJ, Shi J, Zhou WJ, Kobow K, Piao YS (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Acta Neuropathologica Communications BioMed Central

Book Volume: 11

Article Number: 129

Journal Issue: 1

DOI: 10.1186/s40478-023-01618-6

Abstract

Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850 K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1 A, 2 A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., glial scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 mapped explicitly to biological pathways related to neurodegeneration, biogenesis of the extracellular matrix (ECM) components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.

Authors with CRIS profile

Mitali Katoch Institute of Neuropathology Samir Jabari Institute of Neuropathology Ingmar Blümcke Lehrstuhl für Neuropathologie David Blumenthal Professur für Biomedical Network Science Roland Coras Institute of Neuropathology Katja Kobow Institute of Neuropathology

Additional Organisation(s)

Sonderforschungsbereich 1540: Erforschung der Mechanik des Gehirns (EBM): Verständnis, Engineering und Nutzung mechanischer Eigenschaften und Signale in der Entwicklung, Physiologie und Pathologie des zentralen Nervensystems

Involved external institutions

Capital University of Medical Sciences / 首都医科大学 CN China (CN) Tsinghua University CN China (CN)

How to cite

APA:

Wang, D.-D., Katoch, M., Jabari, S., Blümcke, I., Blumenthal, D.B., Lu, D.-H.,... Piao, Y.-S. (2023). The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D. Acta Neuropathologica Communications, 11(1). https://doi.org/10.1186/s40478-023-01618-6

MLA:

Wang, Dan-Dan, et al. "The specific DNA methylation landscape in focal cortical dysplasia ILAE type 3D." Acta Neuropathologica Communications 11.1 (2023).

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