Neuropediatrics 2025; 56(S 01): S1-S24
DOI: 10.1055/s-0045-1812133
Epilepsy

Epg5 Links Proteotoxic Stress Due to Defective Autophagic Clearance and Epileptogenesis in Drosophila and Vici Syndrome Patients

Authors

  • H. S. Dafsari

    1   Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
    2   Max-Planck-Institute for Biology of Ageing, Cologne, Germany
    3   King's College London, Randall Division of Cell and Molecular Biophysics, Muscle Signaling Section, London, United Kingdom

  • C. Deneubourg

    4   Department of Basic and Clinical Neuroscience, King's College London, London, United Kingdom
    • EPG5 epilepsy working group,

  • H. Jungbluth

    3   King's College London, Randall Division of Cell and Molecular Biophysics, Muscle Signaling Section, London, United Kingdom
    5   Department of Paediatric Neurology, Evelina's Children Hospital, London, United Kingdom

  • M. Fanto

    4   Department of Basic and Clinical Neuroscience, King's College London, London, United Kingdom
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Background/Purpose: Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism that has been linked to epileptogenesis when impaired. The precise molecular mechanisms underlying this association remain uncertain. Vici Syndrome is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the EPG5 gene, encoding ectopic P-granules autophagy tethering factor 5, with a crucial role in effective autophagic clearance. Vici syndrome is characterized by a wide range of neurodevelopmental, neurodegenerative, and neurological features, including epilepsy. The role of neuronal loss in epileptogenesis in Vici syndrome remains unclear to this date.

Methods: We investigated a transgenic epg5-deficient Drosophila melanogaster model to study the role of EPG5 in development, ageing, and epileptogenesis. We also provide complementary clinical data from EPG5-mutated patients.

Results: Our data indicate that seizures occur as a direct consequence of proteotoxic stress from autophagy defects and age-dependent neurodegenerative progression with dopaminergic loss in epg5 mutants, in the absence of evident neurodevelopmental abnormalities. Moreover, the seizure phenotype in EPG5-deficient Drosophila melanogaster appears to be amenable to fasting. We provide complementary evidence from EPG5-mutated patients, demonstrating progression of seizure activity and EEG abnormalities over time consistent with predictions from animal models. These observations provide insights into the intricate relationship between primary autophagy defects and epileptogenesis, and suggest autophagy-stimulating diets as a potential therapeutic approach to alleviate EPG5-related seizures.

Conclusion: These findings expand the clinical, genetic, and pathophysiological understanding of EPG5-related epilepsy and grant insights into age-dependent pathomechanisms in congenital disorders of autophagy.



Publikationsverlauf

Artikel online veröffentlicht:
26. September 2025

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