Answers to important questions:
Q: What is Vicky syndrome?
A: Vicky syndrome is a rare inherited neurodevelopmental disorder caused by mutations in the EPG5 gene. It affects multiple organ systems, including the brain, muscles, heart, and immune system, causing severe developmental delays and other complications that usually manifest in early childhood.
Question: What have researchers discovered about the EPG5 gene?
A: Defects in EPG5, which have long been known to cause Vici syndrome in infants, have also been linked to Parkinson’s disease and dementia in adulthood.
Question: How does EPG5 affect the brain?
A: The EPG5 protein controls how cells clear damaged material. When EPG5 function is impaired, the proteins accumulate and damage neurons, leading to neurodegeneration.
Question: Why is this study important?
A: It bridges the gap between rare brain diseases in children and widespread diseases in adults, revealing shared biological processes that could be targets for new treatments.
Summary: Scientists have discovered that mutations in the EPG5 gene — known to be a cause of Wicky syndrome, a rare childhood disorder — also increase the risk of developing Parkinson’s disease and dementia in adulthood. The gene plays a key role in autophagy, the process by which cells eliminate damaged material.
When this system fails, harmful proteins accumulate and eventually damage nerve cells. This study demonstrates a direct biological link between early neurodevelopmental disorders and late-onset neurodegenerative diseases, offering hope for identifying common therapeutic targets.
Key data:
- Shared mechanism: Mutations in the EPG5 gene alter autophagy, linking rare childhood diseases to neurodegeneration in adulthood.
- Wider implications: People with errors in EPG5 may develop Parkinson’s disease or dementia in adolescence or young adulthood.
- Treatment Perspective: The findings highlight how studying extremely rare diseases can inform treatments for common neurological disorders.
Source: King’s College London
New research suggests that errors in a gene that cause a severe neurodevelopmental disorder in infants are also linked to the development of Parkinson’s disease in adolescents and adults.
The study, published in the journal Annals of Neurology, focuses on a gene called EPG5 . Defects in this gene already cause Wicky syndrome, a rare and severe inherited neurodevelopmental disorder that manifests in early childhood and affects multiple organ systems.
Researchers from King’s College London, University College London (UCL), the University of Cologne, and the Max Planck Institute for Biology of Ageing have discovered that defects in a single gene are linked to changes in nerve cells that lead to more common age-related conditions, such as Parkinson’s disease and dementia.
Professor Heinz Jungbluth, Chair of Child Neurology at King’s College London and lead author and senior co-author of the study, said: “This research, which is supported by patient organisations, was inspired by our previous observation of an increased risk of Parkinson’s disease in relatives of children with Wickey syndrome, after a team from King’s EPG discovered the condition.
“Our work shows that, although research into (extremely) rare conditions such as Vici syndrome (which currently affects fewer than 10 children in the UK) is rarely considered a priority, it can provide important information about much more common conditions and offer significant public health benefits.
“Understanding the causes of these devastating and often fatal diseases is essential for the development of treatments and therefore provides hope to patients and their families.”
In the largest study of its kind to date, a team of scientists analyzed medical and genetic data from 211 people worldwide with rare defects in the EPG5 gene . They discovered that the effects of these genetic defects are much more widespread and diverse than previously thought. While some individuals were diagnosed with severe forms of Wick syndrome before or shortly after birth, others showed much milder symptoms, such as delays in movement, speech and learning.
The researchers also found that some of the patients in the study developed a degeneration of nerve cells in adolescence or early adulthood, which leads to Parkinson’s disease and dementia. In some cases, analysis of brain scans revealed excessive accumulation of iron in the brain, a characteristic of other closely related neurodevelopmental disorders.
Dr. Raza Maroof, a co-senior author of the study from the UCL Queen Square Institute of Neurology, stated that their research establishes a link between $EPG5$ gene dysfunction and Parkinson’s disease. He emphasized that this discovery highlights a mechanistic connection between neurodevelopmental and neurodegenerative disorders, thereby increasing the number of conditions known to share such underlying ties.
“This study highlights how insights gained from rare childhood brain disorders can improve our understanding of more common adult-onset neurodegenerative diseases, such as Parkinson’s disease and dementia.”
The EPG5 gene is involved in a crucial cellular process called autophagy, by which the cell breaks down unwanted or damaged components and reuses them into new components or eliminates them. The protein produced by EPG5 is involved in the final step of this process: attaching the components to the cell’s waste removal system, allowing them to be excreted.
To investigate the biology behind their findings, the researchers used patient-derived cells and model organisms, including mice and the tiny roundworm C. elegans, and introduced errors in EPG5.
These experiments showed that genetic defects in the gene alter the cell’s ability to eliminate damaged components, resulting in the accumulation of proteins closely associated with Parkinson’s disease.
Professor Jung Bluth, who is also a paediatric neurologist at Evelina Hospital for Children, Guys and St Thomas’ NHS Foundation Trust in London, noted that their findings, using the example of $EPG5$, indicate a significant link. Specifically, the research suggests that the cellular mechanism underlying the connection between early-onset neurodevelopmental disorders and late-onset neurological diseases (particularly neurodegenerative conditions) is conserved across different species. This conservation becomes more likely when the impairment of neural development and degeneration is more severe.
Dr Manolis Fanto, Associate Professor of Functional Genomics at King’s College London and co-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 disorders across the lifespan.”
The research offers new insights into how autophagy defects may affect various chronic neurological disorders. Furthermore, it may pave the way for future treatments targeting these common causes of disease.
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 StackZone Neuro
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 affecting , a key factor in the cellular process of autophagy, provide a mechanistic link between neurodevelopmental disorders (NDDs) and neurodegenerative disorders, specifically including forms of early-onset parkinsonism.
Purpose
Autophagy is a fundamental biological process that plays a critical role in intracellular homeostasis. During autophagy, defective cargo, including mitochondria, is transported to lysosomes for removal and recycling.
the autophagy gene EPG5 are associated with Wickey syndrome, a severe, early-onset neurodevelopmental disorder with widespread multisystem involvement. In this study, we aimed to describe the broad spectrum of EPG5-related diseases , which vary with age.
Methods
investigated the clinical, radiological, and molecular characteristics of the largest cohort of patients with EPG5- related disorders identified to date , complemented by experimental investigations of cellular and animal models of EPG5 defects.
Results
of the EPG5 gene , 97 of which had not been previously reported. The phenotypic spectrum ranges from lethal presentations in the prenatal stage to mild and isolated neurodevelopmental disorders.
EPG5 gene is frequently misfolded, showing motor deficits and impaired autophagy in brain areas particularly related to neurological disorders in mild manifestations.
In our cohort, new age-related neurodegenerative phenomena included adolescent-onset parkinsonism, dystonia with cognitive impairment, and myoclonus. Radiological features suggested an emerging continuum with brain iron storage disorders.
Fibroblasts from patients showed defects in PINK1-Parkin-dependent mitophage clearance and α-synuclein overexpression, suggesting a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans , EPG5 inhibition caused motor deficits, impaired mitophage clearance, and alterations in mitochondrial respiration, similar to observations in C. elegans where genes related to parkinsonism were inhibited.
Interpretation
of EPG5 illustrate the continuum of lifelong neurological disorders associated with the disease, linking neurodevelopmental disorders and neurodegenerative disorders through a common differential diagnosis of defective autophagy.
