Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years

Franz Huschner, Jagoda Głowacka-Walas, James D. Mills, Katarzyna Klonowska, Kathryn Lasseter, John M. Asara, Romina Moavero, Christoph Hertzberg, Bernhard Weschke, Kate Riney, Martha Feucht, Theresa Scholl, Pavel Krsek, Rima Nabbout, Anna C. Jansen, Bořivoj Petrák, Jackelien Scheppingen, Josef Zamecnik, Anand Iyer, Jasper J. Anink, Angelika Mühlebner, Caroline Mijnsbergen, Lieven Lagae, Paolo Curatolo, Julita Borkowska, Krzysztof Sadowski, Dorota Domańska-Pakieła, Magdalena Blazejczyk, Floor E. Jansen, Stef Janson, Malgorzata Urbanska, Aleksandra Tempes, Bart Janssen, Kamil Sijko, Konrad Wojdan, Sergiusz Jozwiak, Katarzyna Kotulska, Karola Lehmann, Eleonora Aronica, Jacek Jaworski and David J. Kwiatkowski ()
Additional contact information
Franz Huschner: Proteome Factory AG
Jagoda Głowacka-Walas: Transition Technologies Science
James D. Mills: Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience
Katarzyna Klonowska: Brigham and Women’s Hospital
Kathryn Lasseter: Brigham and Women’s Hospital
John M. Asara: Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center
Romina Moavero: Tor Vergata University
Christoph Hertzberg: Vivantes-Klinikum Neukölln
Bernhard Weschke: Charité University Medicine Berlin
Kate Riney: Queensland Children’s Hospital
Martha Feucht: Medical University of Vienna, Member of ERN EpiCARE
Theresa Scholl: Medical University of Vienna, Member of ERN EpiCARE
Pavel Krsek: Department of Paediatric Neurology, Motol University Hospital, 2nd Medical Faculty, Charles University
Rima Nabbout: Université Paris cité, Imagine Institute
Anna C. Jansen: Vrije Universiteit Brussel
Bořivoj Petrák: Department of Paediatric Neurology, Motol University Hospital, 2nd Medical Faculty, Charles University
Jackelien Scheppingen: Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience
Josef Zamecnik: Motol University Hospital, 2nd Medical Faculty, Charles University
Anand Iyer: Department of Internal Medicine
Jasper J. Anink: Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience
Angelika Mühlebner: Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience
Caroline Mijnsbergen: Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience
Lieven Lagae: University Hospitals KU Leuven
Paolo Curatolo: Tor Vergata University
Julita Borkowska: The Children’s Memorial Health Institute
Krzysztof Sadowski: The Children’s Memorial Health Institute
Dorota Domańska-Pakieła: The Children’s Memorial Health Institute
Magdalena Blazejczyk: The Children’s Memorial Health Institute
Floor E. Jansen: Brain Center University Medical Center Utrecht
Stef Janson: GenomeScan
Malgorzata Urbanska: The Children’s Memorial Health Institute
Aleksandra Tempes: International Institute of Molecular and Cell Biology
Bart Janssen: GenomeScan
Kamil Sijko: Transition Technologies Science
Konrad Wojdan: Transition Technologies Science
Sergiusz Jozwiak: The Children’s Memorial Health Institute
Katarzyna Kotulska: The Children’s Memorial Health Institute
Karola Lehmann: Proteome Factory AG
Eleonora Aronica: Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience
Jacek Jaworski: International Institute of Molecular and Cell Biology
David J. Kwiatkowski: Brigham and Women’s Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

Date: 2023
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DOI: 10.1038/s41467-023-42855-6

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