Investigating the use of steroids in children with Infantile Epileptic Spasms Syndrome: A multi-omics evaluation of gene and epigenetic regulation
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Open Access
Type
ThesisThesis type
Masters by ResearchAuthor/s
Innes, Emily AmyAbstract
Objectives: Infantile epileptic spasms syndrome (IESS) is a severe developmental and epileptic encephalopathy of infancy. High-dose oral prednisolone may induce epileptic spasm remission yet long-term outcomes remain poor and it remains unclear whether steroids are targeting disease ...
See moreObjectives: Infantile epileptic spasms syndrome (IESS) is a severe developmental and epileptic encephalopathy of infancy. High-dose oral prednisolone may induce epileptic spasm remission yet long-term outcomes remain poor and it remains unclear whether steroids are targeting disease mechanisms. We investigated the biological pathways underlying IESS and how prednisolone treatment exerts an effect in IESS. Methods: A multi-omics analyses compared blood samples from infants with IESS at baseline (n=11) to controls (n=11) and IESS pre-post prednisolone treatment (n=11). Analyses included bulk RNA sequencing, proteomics, phosphoproteomics and neuroinflammation panel testing. Pathway enrichment analysis using GSEA and ORA identified significantly enriched pathways based on FDR-adjusted p-values. Results: Infants with unknown aetiology had better developmental outcomes than infants with structural aetiologies. Prednisolone induced significant leukophilia, neutrophilia and lymphopenia (all adjusted p-value <0.05). BDNF was significantly elevated at baseline, and prednisolone caused significant increase in nerve growth factor, and significant decrease in the chemokine CCL2. Using RNA seq, prednisolone reversed baseline upregulated ribosomal and mitochondrial pathways, and reversed baseline downregulated immune and membrane transport pathways. Using concordance of quantitative RNA and protein to explore the effects of prednisolone, the most upregulated pathway was 'secretory granule membrane' and the most downregulated pathway was 'ribonucleoprotein complex biogenesis'. Phosphoproteomics revealed the most dysregulated pathway at baseline and after prednisolone was 'chromatin binding'. Significance: Altered gene and epigenetic regulation may be an aetiological mechanism underlying IESS. Prednisolone treatment may control epileptic spasms by altering gene expression through immune-mediated, ribosomal and chromatin pathways.
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See moreObjectives: Infantile epileptic spasms syndrome (IESS) is a severe developmental and epileptic encephalopathy of infancy. High-dose oral prednisolone may induce epileptic spasm remission yet long-term outcomes remain poor and it remains unclear whether steroids are targeting disease mechanisms. We investigated the biological pathways underlying IESS and how prednisolone treatment exerts an effect in IESS. Methods: A multi-omics analyses compared blood samples from infants with IESS at baseline (n=11) to controls (n=11) and IESS pre-post prednisolone treatment (n=11). Analyses included bulk RNA sequencing, proteomics, phosphoproteomics and neuroinflammation panel testing. Pathway enrichment analysis using GSEA and ORA identified significantly enriched pathways based on FDR-adjusted p-values. Results: Infants with unknown aetiology had better developmental outcomes than infants with structural aetiologies. Prednisolone induced significant leukophilia, neutrophilia and lymphopenia (all adjusted p-value <0.05). BDNF was significantly elevated at baseline, and prednisolone caused significant increase in nerve growth factor, and significant decrease in the chemokine CCL2. Using RNA seq, prednisolone reversed baseline upregulated ribosomal and mitochondrial pathways, and reversed baseline downregulated immune and membrane transport pathways. Using concordance of quantitative RNA and protein to explore the effects of prednisolone, the most upregulated pathway was 'secretory granule membrane' and the most downregulated pathway was 'ribonucleoprotein complex biogenesis'. Phosphoproteomics revealed the most dysregulated pathway at baseline and after prednisolone was 'chromatin binding'. Significance: Altered gene and epigenetic regulation may be an aetiological mechanism underlying IESS. Prednisolone treatment may control epileptic spasms by altering gene expression through immune-mediated, ribosomal and chromatin pathways.
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Date
2026Rights statement
The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.Faculty/School
Faculty of Medicine and Health, The Children's Hospital at Westmead Clinical SchoolAwarding institution
The University of SydneyShare