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

Acta Neuropathologica Communications

Research

David B. Blumenthal¹  Katja Kobow²  Roland Coras²  Ingmar Blumcke²  Samir Jabari²  Mitali Katoch²  Jie Shi³  Wen-Jing Zhou³  Yue-Shan Piao⁴  De-Hong Lu⁴  Yu-Jiao Wang⁴  Dan-Dan Wang⁴ 

[1] Biomedical Network Science Lab, Department of Artificial Intelligence in Biomedical Engineering, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;Department of Neuropathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;Department of Neurosurgery, Tsinghua University Yuquan Hospital, 100049, Beijing, China;Department of Pathology, Xuanwu Hospital, Capital Medical University, No. 45, Changchun Street, Xicheng District, 100053, Beijing, China;Clinical Research Center for Epilepsy, Capital Medical University, 100053, Beijing, China;National Center for Neurological Disorders, 100053, Beijing, China;

关键词: Epilepsy;    Malformation of cortical development;    Neuropathology;    Occipital lobe;    Epigenetic;   

DOI  :  10.1186/s40478-023-01618-6

 received in 2023-03-30, accepted in 2023-07-09,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

【 图 表 】

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