EPG5 gene errors connect infant neurodevelopmental disorder to adult neurodegeneration
A surprising thread is emerging from recent research: errors in the EPG5 gene, already known to cause the severe infant condition Vici syndrome, may also contribute to the development of Parkinson’s disease and related dementias in adolescence and adulthood. The large, international study, published in the Annals of Neurology, expands our understanding of how a single gene can influence brain health across the lifespan.
What is EPG5 and why does it matter?
The EPG5 gene plays a crucial role in autophagy, a cellular housekeeping process that disposes of damaged proteins and organelles. The protein produced by EPG5 orchestrates the final steps of this cleanup, ensuring defective components are properly tagged for disposal. When EPG5 malfunctions, cells struggle to clear damaged material, risking the buildup of proteins linked to neurodegenerative disease, including Parkinson’s.
The study: broadening the clinical spectrum of EPG5
Researchers led by teams at King’s College London, University College London (UCL), the University of Cologne and the Max Planck Institute for Biology of Ageing analyzed genetic and clinical data from 211 individuals worldwide with EPG5 errors. The findings show that EPG5-related pathology is more variable than previously thought: some babies present with classic, life-limiting Vici syndrome, while others exhibit milder developmental delays in movement, speech and learning skills.
Crucially, several participants developed neurodegenerative features in adolescence or early adulthood, including Parkinson’s disease and dementia. Brain imaging in some cases revealed iron deposition, a hallmark seen in other neurodevelopmental and neurodegenerative conditions. These observations indicate a potential lifelong continuum of brain disorder tied to EPG5 dysfunction, rather than a strict separation between childhood and adult disease.
Implications for understanding brain disease and therapy
The study provides evidence that rare paediatric brain disorders can illuminate common adult-onset conditions. By showing that autophagy defects in EPG5 can lead to both early developmental challenges and later neuronal degeneration, the research highlights a shared cellular mechanism that may underlie multiple diseases across the lifespan.
As Dr. Reza Maroofian of UCL notes, this work underscores the value of cross-disciplinary collaboration between basic scientists and clinicians. “Understanding the causes of these devastating diseases is essential for developing therapies and offers hope for patients and families,” he said. The team’s approach—combining patient-derived cells with model organisms like mice and C. elegans—allowed them to observe how EPG5 errors disrupt cellular clearance and drive pathogenic protein accumulation characteristic of Parkinson’s disease.
A pathway toward future treatments
By clarifying how autophagy dysfunction can contribute to a spectrum of neurological disorders, the study opens avenues for therapeutic strategies that target shared disease drivers. Interventions that enhance or correct autophagic processes could potentially benefit individuals with EPG5-related conditions at different life stages, from infancy through adulthood.
What this means for patients and families
For families affected by Vici syndrome or EPG5-related conditions, the findings bring a measure of precision to prognosis and future research directions. While still rare, EPG5-related disorders are now seen as a broader, lifelong risk factor for neurodegenerative processes, underscoring the importance of ongoing monitoring and research participation. As the authors emphasize, increasing our understanding of these mechanisms is key to developing targeted therapies that could change outcomes across the lifespan.
Authors and collaboration
Lead researchers include the team at King’s College London, with contributions from UCL, the University of Cologne and the Max Planck Institute for Biology of Ageing. The study was supported by patient organizations, reflecting a growing partnership between scientific discovery and patient communities.
Future directions
Ongoing work will aim to map the full spectrum of EPG5-related phenotypes and to identify biomarkers that predict which individuals are at greater risk of neurodegeneration. Additional research into autophagy-modulating therapies could offer new options for preventing or delaying the onset of Parkinson’s disease and related conditions in people with EPG5 mutations.
