Summary: Researchers have found that mutations in the EPG5 gene—previously identified as the cause of the rare childhood disorder Vici syndrome—also raise the risk of Parkinson’s disease and dementia later in life. EPG5 is essential for autophagy, the cellular process that clears damaged proteins and organelles. When this pathway fails, toxic proteins accumulate and progressively damage neurons. The new study draws a clear biological connection between early neurodevelopmental disorders and later-life neurodegeneration, pointing to shared targets for future therapies.
Autophagy disruption is increasingly recognized as a common mechanism underlying many neurological conditions. This research shows that defects in the same gene can produce a spectrum of outcomes—from severe, early-onset multisystem disease in infants to adolescent or adult-onset Parkinsonism and dementia—depending on the nature and severity of the genetic change.
Key Facts:
- Shared mechanism: Mutations in EPG5 impair autophagy, linking rare pediatric disorders with adult neurodegenerative diseases.
- Wide-ranging effects: EPG5 variants produce a continuum of clinical outcomes, from life-limiting Vici syndrome to milder developmental delays and later-onset Parkinsonism or dementia.
- Implications for therapy: Studying ultra-rare genetic conditions like Vici syndrome can reveal molecular pathways relevant to common neurological illnesses and guide new treatment approaches.
Source: King’s College London
Errors in a gene already linked to a severe infant neurodevelopmental disorder are now shown to be associated with Parkinson’s disease and dementia in later life, according to newly published research.
The study, appearing in the Annals of Neurology, examined mutations in the gene EPG5. Pathogenic variants in EPG5 cause Vici syndrome, a rare inherited condition that affects multiple organ systems and typically appears early in life. The international research team—from King’s College London, University College London, the University of Cologne and the Max Planck Institute for Biology of Ageing—showed that EPG5 defects can also trigger cellular changes that lead to more common neurodegenerative disorders.
Professor Heinz Jungbluth, Professor of Paediatric Neurology at King’s College London and co-senior author, explained that this work was motivated by observations suggesting an elevated Parkinson’s risk among relatives of children with Vici syndrome. He emphasized that studying very rare conditions, even when they affect only a handful of patients nationally, can provide crucial insights into widespread neurological diseases and yield public health benefits.
In the largest cohort study of its kind, researchers analyzed clinical and genetic data from 211 people worldwide with recessive EPG5 variants. The findings reveal a far broader and more variable impact of these mutations than previously recognized. Some individuals displayed the classical, severe Vici syndrome identified before or shortly after birth, while others experienced milder developmental issues such as delayed motor skills, speech, or learning. Crucially, a subset developed adolescent- or early-adult-onset neurodegeneration manifesting as Parkinsonism, cognitive decline, and other movement disorders. Imaging in several cases also showed increased iron accumulation in the brain, a feature sometimes seen in related neurodevelopmental conditions.
Dr Reza Maroofian of UCL’s Queen Square Institute of Neurology, co-first author, noted that the study connects EPG5 dysfunction to Parkinson’s disease and highlights mechanistic links between neurodevelopmental and neurodegenerative disorders. These results add to growing evidence that errors in cellular maintenance pathways during development can predispose to degeneration decades later.
EPG5 encodes a protein that functions at the final stage of autophagy, helping attach cellular cargo destined for lysosomal degradation. To probe how EPG5 variants cause disease, the team used patient-derived cells and model organisms—including mice and the roundworm C. elegans—introducing EPG5 defects to study their effects. Across models, impaired EPG5 reduced the cell’s capacity to clear damaged components, leading to accumulation of proteins known to be linked with Parkinson’s disease.
Professor Jungbluth, who is also a Consultant Paediatric Neurologist at Evelina London Children’s Hospital, said the findings support the concept of a lifelong neurological disease continuum driven by a single cellular mechanism—defective autophagy—across species. Dr Manolis Fanto, Reader in Functional Genomics at King’s College London and co-senior author, underscored the value of close collaboration between basic scientists and clinicians to uncover how inherited genetic defects affect health from childhood to adulthood.
Overall, this work advances understanding of how autophagy failure can underlie a range of persistent neurological conditions and suggests that therapies aimed at restoring cellular clearance pathways could benefit both rare pediatric disorders and common adult-onset neurodegenerative diseases.
Key Questions Answered:
A: Vici syndrome is a rare, inherited neurodevelopmental disorder caused by mutations in the EPG5 gene. It affects multiple organs—brain, muscle, heart and immune system—and typically leads to severe developmental delays and complications that appear early in life.
A: The study found that EPG5 mutations, previously associated with Vici syndrome in infants, are also linked to Parkinson’s disease and dementia appearing in adolescence or adulthood, expanding the known disease spectrum for this gene.
A: EPG5 is essential for autophagy—the process by which cells remove damaged components. When EPG5 is defective, damaged proteins and organelles accumulate, harming neurons and promoting neurodegeneration.
A: By linking rare pediatric conditions to common adult neurodegenerative diseases through a shared biological pathway, the research identifies potential molecular targets for therapies that could address disorders across the lifespan.
About this Parkinson’s disease, Vici syndrome, and genetics research news
Author: Joanna Dungate
Source: King’s College London
Contact: Joanna Dungate – King’s College London
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism” by Heinz Jungbluth et al. Annals of Neurology
Abstract
Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism
Objective
Autophagy is a core cellular pathway that maintains intracellular balance by directing defective cargoes—including damaged mitochondria—to lysosomes for recycling and disposal. Recessive truncating variants in EPG5 are known to cause Vici syndrome, a severe early-onset neurodevelopmental disorder with multisystem involvement. This study aimed to define the extended, age-dependent disease spectrum associated with EPG5 variants.
Methods
The investigators assembled the largest cohort of EPG5-related patients described to date and analyzed their clinical, radiological and molecular features. Experimental work used patient fibroblasts and animal models, including a knock-in mouse and Caenorhabditis elegans, to study the cellular consequences of EPG5 defects.
Results
The international collaboration identified 211 patients, 97 of whom had not been reported before, with recessive EPG5 variants. Clinical presentations ranged from antenatal lethality to milder isolated neurodevelopmental disorders. A novel knock-in mouse carrying a recurrent missense EPG5 variant showed motor problems and impaired autophagy in brain regions relevant to the observed neurological features. New age-dependent manifestations in the human cohort included adolescent-onset parkinsonism, dystonia with cognitive decline, and myoclonus. Neuroimaging suggested overlap with disorders of brain iron accumulation. Patient fibroblasts exhibited impaired PINK1-Parkin mitophagy and elevated alpha-synuclein, offering a cellular explanation for the neurodegenerative phenotypes. In C. elegans, EPG5 knockdown produced motor deficits, defective mitophagy and changes in mitochondrial respiration similar to knockdown of parkinsonism-related genes.
Interpretation
These findings support a lifetime continuum of neurological disease related to pathogenic EPG5 variants, linking early neurodevelopmental and later neurodegenerative disorders through a common defect in autophagy. Understanding this shared mechanism may guide therapies that target cellular clearance pathways across diverse neurological conditions.