November 2025

NEUROSCIENCES

DUAL ROLE OF EPG5: CONNECTING EARLY-ONSET DISORDERS TO LATE-ONSET NEUROLOGICAL CONDITIONS

Scientists have uncovered that mutations in the EPG5 gene, previously associated with the rare childhood disorder Vici syndrome, also elevate the risk of developing Parkinson’s disease and dementia later in life.

When autophagy malfunctions, harmful proteins accumulate, leading to the gradual deterioration of nerve cells. A recent study published in Annals of Neurology, co-authored by three Northwestern Medicine Neurologists, reveals a significant biological connection between early neurodevelopmental disorders and later-onset neurodegenerative diseases, suggesting the potential for shared therapeutic strategies that could benefit both patient populations.

Methods
Researchers analyzed data from 211 individuals with recessive EPG5 variants, integrating clinical, radiological and genetic data with experiments using model organisms.

Results
  • The study identified a broad phenotypic spectrum associated with EPG5 mutations:
    • Severe, life-threatening conditions in early infancy
    • Milder neurodevelopmental issues emerging during adolescence
  • Key clinical observations:
    • Motor impairments, notably:
      • Parkinsonism
      • Dystonia
      • Cognitive decline
  • Development of a novel knock-in mouse model revealed:
    • Age-dependent neurological deficits
    • Defective autophagy
  • Patient fibroblast cells showed:
    • Impaired mitophagic clearance linked to PINK1-Parkin pathway defects, indicating mitochondrial dysfunction
  • Findings in C. elegans confirmed:
    • Motor impairment and mitophagic defects due to EPG5 dysfunction

Conclusion 
This research illustrates that EPG5 deficiency creates a continuous spectrum of neurological disorders, combining neurodevelopmental and neurodegenerative elements. The findings highlight the importance of autophagy in neuronal health and suggest that early signs of neurodegeneration in patients with prior developmental delays should prompt consideration of EPG5-related disorders.
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Defective autophagy resulting from EPG5 mutations is implicated in both early-onset neurodevelopmental diseases and later-life neurodegenerative conditions. The study enhances understanding of the varied clinical manifestations associated with EPG5 variants and underscores the necessity for further exploration of treatment strategies aimed at mitigating the impacts of these defects.
Niccolo Mencacci, MD, PhD, Assistant Professor of Neurology at Northwestern Medicine
​Dimitri Krainc, MD, PhD, the Aaron Montgomery Ward Professor, Chair of the Department of Neurology and Director of the Simpson Querrey Center for Neurogenetics at Northwestern Medicine
Mariana Hernandez Gonzalez-Monje, MD, Instructor of Neurology at Northwestern Medicine

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