New Evidence Connects EPG5 Mutations Across the Lifespan
Researchers are uncovering a surprising link between a gene known for causing a severe infant disorder and neurodegenerative diseases that emerge much later in life. In a study published in the Annals of Neurology, scientists demonstrated that errors in the EPG5 gene, already associated with Vici syndrome, may also contribute to the development of Parkinson’s disease and related dementia in adolescence and adulthood. The work, conducted by teams from King’s College London (KCL), University College London (UCL), the University of Cologne, and the Max Planck Institute for Biology of Ageing, illuminates how a single genetic defect can influence distinct stages of the nervous system’s life course.
Vici Syndrome and the Broader Spectrum of EPG5-Related Effects
EPG5 plays a pivotal role in autophagy, a cellular process that recycles damaged components and maintains cellular health. Defects in EPG5 disrupt the final steps of autophagy, hindering the cell’s ability to clear waste and contributing to disease. Vici syndrome, the well-known pediatric manifestation of EPG5 mutations, is a rare, life-limiting neurodevelopmental disorder with multi-system involvement. The new findings reveal that the same genetic errors can produce a much broader clinical spectrum, ranging from milder developmental delays to severe, early-life illness, and, in some individuals, later-onset neurodegenerative symptoms.
The Life-Long Impact: From Early Development to Late-Life Neurodegeneration
In the largest study to date examining EPG5 mutations, researchers analyzed clinical and genetic data from 211 individuals worldwide who carried rare EPG5 errors. While some participants exhibited classic Vici syndrome features early in life, others displayed more subtle developmental delays in movement, speech, or learning. Crucially, a subset progressed to experience neurodegenerative outcomes in adolescence or adulthood, including Parkinson’s disease and dementia. Brain imaging in some cases showed iron accumulation, a hallmark shared with other neurodevelopmental and neurodegenerative conditions, further supporting a continuum of disease linked by autophagy dysfunction.
Shared Cellular Mechanisms Point to Unified Therapeutic Targets
The study reinforces a growing view that developmental and degenerative brain disorders can share underlying cellular mechanisms. By showing how EPG5 mutations disrupt autophagy and lead to accumulation of proteins associated with Parkinson’s disease, the researchers highlight potential targets for therapies aimed at the autophagy pathway. Dr. Reza Maroofian of UCL Queen Square Institute of Neurology described the findings as demonstrating a life-time continuum of neurodevelopmental and neurodegenerative disease tied to a single cellular process.
Implications for Research and Public Health
Despite Vici syndrome being extremely rare in the UK, with fewer than 10 known cases, the study suggests that insights from ultra-rare pediatric brain disorders can inform our understanding of more common adult diseases. As Dr. Manolis Fanto from King’s College London noted, the collaboration between basic science and clinical neuroscience is essential to unravel how inherited conditions affect individuals across life stages. The authors argue that studying these rare conditions could accelerate the development of therapies for Parkinson’s disease and dementia by targeting shared biological pathways such as autophagy.
Future Directions
Going forward, researchers aim to expand clinical datasets and perform more functional studies to validate autophagy-related targets in EPG5-related neurodegeneration. The ultimate aim is to translate these discoveries into interventions that can modulate autophagy, potentially delaying or preventing late-life neurodegenerative outcomes for people carrying EPG5 mutations. This work exemplifies how a rare pediatric disorder can illuminate mechanisms underlying common neurodegenerative diseases, offering hope to families and patients affected by a broader spectrum of conditions.
