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Genomic DNA methylation distinguishes human FCD subtypes

ABSTRACT: Focal Cortical Dysplasia (FCD) is a major cause of drug-resistant focal epilepsy in children and the clinico-pathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation based classification of human brain tumors we examined, whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtype

ORGANISM(S): Homo sapiens

PROVIDER: GSE128299 | GEO | 2019/05/13

REPOSITORIES: GEO

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Project description: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 850K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1A, 2A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or in 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., fibrotic scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 specifically mapped to biological pathways related to neurodegeneration, biogenesis of 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.

Project description:Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2011 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gay and white matters of surgical FCD type II specimens. Our aim was to contribute to pathophysiology and tissue characterization. We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation by means of digital analyses. We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. The top enriched cellular pathway in IIa and IIb gray matter was cholesterol biosynthesis, their genes HMGCS1, HMGCR and SQLE being upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed respectively compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Overall, our study contributed to the identification of cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to neuroprotective response to seizures. Moreover, specific analyses in either the gay or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.

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Genomic DNA methylation distinguishes human FCD subtypes

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