Predictive Biomarkers of Drug-resistant Epilepsy in TSC Patients- results of the EPIMARKER Study
Abstract number :
3.213
Submission category :
2. Translational Research / 2C. Biomarkers
Year :
2024
Submission ID :
674
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Sergiusz Jóźwiak, MD, PhD – The Children's Memorial Health Institute, Warsaw, Poland
Katarzyna Kotulska, MD, PhD, – The Children's Memorial Health Institute, Warsaw, Poland
Aleksander Jamsheer, MD, PhD – Poznan University of Medical Sciences, Poznan, Poland
Wojciech Młynarski, MD, PhD – Medical University of Lodz, Lodz, Poland
Katarzyna Babol-Pokora, PhD – Medical University of Lodz, Lodz, Poland
Adria-Jaume Roura Canalda, PhD – Nencki Institute, Warsaw, Poland
Bartosz Wojtas, PhD – Nencki Institute, Warsaw,Poland
Bartlomiej Gielniewski, PhD – Nencki Institute, Warsaw, Poland
Bozena Kaminska, PhD – Nencki Institute, Warsaw, Poalnd
Bianka Swiderska, PhD – Department of Biophysics Polish Academy of Science, Warsaw, Poland
Ewa Sitkiewicz, PhD – Department of Biophysics Polish Academy of Science, Warsaw, Poland
Jacek Jaworski, PhD – International Institute of Molecular and Cell Biology, Warsaw, Poland,
Rationale:
Epilepsy affects 80-90% of patients with Tuberous Sclerosis Complex (TSC) leading to psychiatric and behavioral comorbidities, including developmental delay and autism spectrum disorder. In spite of multiple trials, no reliable biomarker of drug-resistant epilepsy development has been identified. EPIMARKER is a first project, carried out in humans, examining in prospective way clinical, electroencephalographic and molecular biomarkers to produce an integrative tool useful in prevention of drug-resistant epilepsy and its behavioural comorbidities as mental retardation and autism. The set of molecular biomarkers has been determined by quantitative transcriptomic and proteomic studies and validated in reprogrammed cellular models. We present the results of prospective analyses of mRNA markers of drug-resistant epilepsy development in children with TSC.
Methods: In the EPIMARKER study, 80 pediatric patients (up to one year of age) were included and received vigabatrin either preventively or immediately after the onset of seizures. Serial whole blood samples were collected before (30-150 days), at and 12 months after the seizure onset and RNA was isolated. RNA sequencing was done using NEB RNA library protocols and Illumina HiSeq1500 sequencer. The quality of RNA was verified by spectrophotometry (only samples with RNA Integrity number >7 were accepted. mRNA analysis was performed with own pipeline based on open-source solutions (mapping: STAR algorithm). Obtained RNAseq data was assessed and only samples with more than 10 M fragments assigned to exons and < 30% of optical duplicates were taken for further analysis.
Results:
We detect a large change in blood mRNA profile to be associated with epilepsy. Further analysis focused on finding genes whose expression profile predicts a good or bad response to the first drug. First non-gender-specific analysis did not show statistical differences. However, principal component analysis revealed a sex-dependent differential mRNA expression. Subsequent, sex specific analysis revealed significant changes between females with TSC with good or bad response to the first drug. These were genes encoding variable and constant lambda immunoglobulin chains: GLV1-40, IGVK4-1, IGLC7, IGLV3-19, IGHV4-34, IGKV1-39, IGHV6-1, IGHV1-3, IGHV3-53, IGKV3-15, IGHV5-51, IGKV1-16, IGLJ2 and some other genes: RRP7A, KTI12, HRAS, TNFRSF13B (10 padj < 0.05, 51 padj < 0.1). In girls, the expression of these genes was lower in those not responding to the drug. Altogether, we identified significant changes in 17 mRNAs in a whole blood as potential predictors of drug-resistant epilepsy in girls.
Conclusions:
Based on analysis of RNA isolated from a whole blood we identified significant decrease in abundance of 17 mRNAs that could be potentially predict of drug-resistant epilepsy in girls up to age of 2 years.
Funding: A grant of the CMHI financed by the Ministry of Education and Science (S196/2022) and grant EPIMARKER
of the Polish National Center for Research and Development (STRATEGMED3/306306/4/2016
).
Translational Research