Unraveling the Polygenic Architecture of Developmental and Epileptic Encephalopathies

• Applicant: Privatdozent Dr. Stefan Wolking
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456794357

• Final Report Year: 2025

Final Report Abstract

Epilepsy is one of the most common neurological disorders, affecting millions of people worldwide. While some cases of epilepsy are caused by rare genetic mutations, others arise from a complex combination of genetic factors. This research project aimed to better understand the genetic causes of epilepsy, particularly severe forms known as developmental and epileptic encephalopathies (DEEs). DEEs are often associated with rare genetic variants. However, in many cases, such variants cannot be detected through genetic testing, and symptoms can vary significantly between individuals. In the first part of this study, we explored whether more complex genetic influences, known as polygenic factors, could explain these differences. Our findings revealed that polygenic factors do indeed play a role in DEEs. Interestingly, their contribution was similar regardless of whether a known disease-causing rare variant was present. Additionally, our study identified a genetic link between epilepsy and mental health conditions such as depression, ADHD, and schizophrenia. Currently, we are investigating how polygenic factors influence specific symptoms (e.g., seizure types, cognitive impairments) and contribute to drug resistance in epilepsy. In the second part of this project, we focused on a specific form of DEE associated with the gene AP2M1. To better understand the underlying molecular mechanisms, we used genetically modified Drosophila melanogaster (fruit flies). Our experiments showed that deficits in AP2M1 led to changes in the structure of nerve cells in Drosophila and caused paralysis when exposed to heat. Surprisingly, however, flies with AP2M1 deficiencies were more resistant to seizures. This suggests that epilepsy in individuals with AP2M1 mutations may not arise from direct dysfunctions at nerve endings (synapses) but rather from disturbances during neuronal development. We also tested several anti-seizure medications (ASMs) on Drosophila lines exhibiting seizure-like behavior and observed distinct response patterns for specific ASMs. This highlights the potential of Drosophila as a screening tool for new epilepsy treatments, which could accelerate drug development. Currently, we are conducting follow-up studies using Drosophila to investigate other types of DEEs, with the goal of developing more targeted therapeutic strategies.

Publications

• Assessment of burden and segregation profiles of CNVs in patients with epilepsy. Annals of Clinical and Translational Neurology, 9(7), 1050-1058.
  Moreau, Claudia; Tremblay, Frédérique; Wolking, Stefan; Girard, Alexandre; Laprise, Catherine; Hamdan, Fadi F.; Michaud, Jacques L.; Minassian, Berge A.; Cossette, Patrick & Girard, Simon L.
  
• Genetic testing before epilepsy surgery – An exploratory survey and case collection from German epilepsy centers. Seizure, 95, 4-10.
  Boßelmann, Christian Malte; San Antonio-Arce, Victoria; Schulze-Bonhage, Andreas; Fauser, Susanne; Zacher, Pia; Mayer, Thomas; Aparicio, Javier; Albers, Kristina; Cloppenborg, Thomas; Kunz, Wolfram; Surges, Rainer; Syrbe, Steffen; Weber, Yvonne & Wolking, Stefan
  
• The role of common genetic variation in presumed monogenic epilepsies. eBioMedicine, 81, 104098.
  Campbell, Ciarán; Leu, Costin; Feng, Yen-Chen Anne; Wolking, Stefan; Moreau, Claudia; Ellis, Colin; Ganesan, Shiva; Martins, Helena; Oliver, Karen; Boothman, Isabelle; Benson, Katherine; Molloy, Anne; Brody, Lawrence; Michaud, Jacques L.; Hamdan, Fadi F.; Minassian, Berge A.; Lerche, Holger; Scheffer, Ingrid E.; Sisodiya, Sanjay ... & Cavalleri, Gianpiero L.
  
• Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview. Frontiers in Molecular Neuroscience, 16.
  Fischer, Florian P.; Karge, Robin A.; Weber, Yvonne G.; Koch, Henner; Wolking, Stefan & Voigt, Aaron
  
• Genetic variation supports a causal role for valproate in prevention of ischemic stroke. International Journal of Stroke, 19(1), 84-93.
  Mayerhofer, Ernst; Parodi, Livia; Narasimhalu, Kaavya; Wolking, Stefan; Harloff, Andreas; Georgakis, Marios K.; Rosand, Jonathan & Anderson, Christopher D.
  
• Genetics of nonlesional focal epilepsy in adults and surgical implications. Clinical Epileptology, 36(2), 91-97.
  Karge, R.; Knopp, C.; Weber, Y. & Wolking, S.
  
• Polygenic risk score analysis reveals shared genetic burden between epilepsy and psychiatric comorbidities. openRxiv.
  Campbell, C.; Lewis-Smith, D.; Leu, C.; Martins, H.; Wolking, S.; Krause, R.; O.’Brien, T.; Sill, G.; Zara, F.; Koeleman, B.; Depondt, C.; Marson, A.; Stefánnson, H.; Stefánnson, K.; Craig, J.; Johnson, MR.; Striano, P.; Jorgensen, A.; Lerche, H. ... & Cavalleri, G. L.
  
• Big data in genetics: PRS and HPO in epilepsy research. Clinical Neurophysiology, 159, e8-e9.
  Karge, R.; Lewis-Smith, D.; Bosselmann, C.; Lal, D.; Leu, C. & Wolking, S.
  
• Brain malformations and seizures by impaired chaperonin function of TRiC. Science, 386(6721), 516-525.
  Kraft, Florian; Rodriguez-Aliaga, Piere; Yuan, Weimin; Franken, Lena; Zajt, Kamil; Hasan, Dimah; Lee, Ting-Ting; Flex, Elisabetta; Hentschel, Andreas; Innes, A. Micheil; Zheng, Bixia; Julia Suh, Dong Sun; Knopp, Cordula; Lausberg, Eva; Krause, Jeremias; Zhang, Xiaomeng; Trapane, Pamela; Carroll, Riley; McClatchey, Martin ... & Kurth, Ingo
  
• The fruit fly Drosophila melanogaster as a screening model for antiseizure medications. Frontiers in Pharmacology, 15.
  Fischer, Florian P.; Karge, Robin A.; Koch, Henner; Voigt, Aaron; Weber, Yvonne G. & Wolking, Stefan