Brain disease in children and Parkinson's disease in adults are linked

Gene defect causes developmental disorder and dementia

To the point

• Cellular Process: The EPG5 gene is crucial for autophagy, a process where cells remove damaged components. Disruptions in this gene impair the cell's ability to clear these components, contributing to neurological diseases.
• Gene Link: Errors in the EPG5 gene cause a rare neurodevelopmental disorder in infants and are also linked to Parkinson's disease in later life. The study highlights connections between pediatric and age-related neurodegenerative disorders.
• Broader Implications: Understanding Vici syndrome may offer insights into common conditions like Parkinson's and dementia, demonstrating the importance of researching rare disorders for public health benefits.

The study looked at a gene called EPG5. Errors in this gene are already known to cause Vici syndrome – a rare and severe inherited neurodevelopmental condition that presents early in life and affects multiple organ systems. Fewer than 10 children are currently known to have the condition in the UK.

Now researchers at King’s College London, University College London, the University of Cologne and the Max Planck Institute for Biology of Ageing have found that errors in the same gene are linked to changes in nerve cells that lead to more common age-related conditions like Parkinson’s disease and dementia. Heinz Jungbluth, Professor of Paediatric Neurology at King’s College London and lead and co-senior author of the study, said: “Our work shows that research into (ultra)rare conditions such as Vici syndrome may provide vital insights into much more common disorders and have substantial public health benefits.  Understanding the causes of these devastating and often life-limiting diseases is essential for therapy development and thus offers hope for patients and their families.”  “We are excited about this work because it shows that Vici syndrome EPG5 deficiency can trigger early onset Parkinison's-like disease, linking pediatric and age-related neurodegenerative pathology,” adds Adam Antebi, director at the Max Planck Institute for Biology of Ageing.

Individuals from across the world with rare errors in EPG5

In the largest study of its kind to date, the team of scientists analysed clinical and genetic data from 211 individuals from across the world with rare errors in EPG5. They found that the effects of these genetic errors are broader and more variable than previously known – while some individuals had life-limiting forms of Vici syndrome identified before or shortly after birth, others showed much milder symptoms, including delay in movement, speech, and learning.

The researchers also discovered that some of the patients included in the study went on to develop a breakdown of nerve cells in adolescence or early adulthood that led to Parkinson's disease and dementia. The brain scans analysed in some cases showed additional iron build-up in the brain, a feature of other, closely linked neurodevelopmental disorders. Reza Maroofian, co-first author of the study from the UCL Queen Square Institute of Neurology, said: “Our findings link EPG5 dysfunction to Parkinson’s disease, highlighting how neurodevelopmental and neurodegenerative disorders can be mechanistically interconnected and add to a growing list of such conditions. This study underscores how insights from rare paediatric brain disorders can inform our understanding of more common adult-onset neurodegenerative diseases, such as Parkinson’s and dementia.”

Involved in autophagy

The EPG5 gene is involved in an important cellular process called autophagy, where the cell breaks down unwanted or damaged components and either recycles them into new parts or disposes of them. The protein made by EPG5 is involved in the last stage of this process – attaching the parts for disposal to the cell’s waste disposal unit for removal from the cell.

To explore the biology underpinning their findings, the researchers used patient-derived cells and model organisms, including mice and the tiny roundworm C. elegans, and introduced errors into EPG5. These experiments showed that genetic errors in the gene disrupt the cell’s ability to clear damaged components from the cell, leading to the build-up of proteins closely associated with Parkinson’s disease. “We have learned a lot from families of patients with this monogenic disease, especially in regards to the role of EPG5 in neuronal health during ageing,” says Hormos Dafsari, co-first author of the study and guest scientist at the Max Planck Institute for Biology of Ageing.

Jungbluth, who is also a Consultant Paediatric Neurologist at Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, said: "Using the example of EPG5, our findings suggest a life-time continuum of early-onset neurodevelopmental and late-onset neurodegenerative disorders, and more specifically an intriguing link between aberrant nerve development and degeneration linked in the same fundamental cellular mechanism preserved throughout different species." Manolis Fanto, Reader in Functional Genomics at King’s College London and co-senior author of the study, added: "This project highlights the importance of collaboration between basic and clinical neuroscientists to unravel the complex mechanistic consequences of inherited genetic conditions throughout all life stages.”