An international team of researchers has shown that mutations in the EPG5 gene – an important regulator of the body’s cellular recycling system, known as autophagy – can cause a range of neurological conditions that develop at different stages of life. The findings, published in Annals of Neurology, reveal how the same genetic defect can lead to both early childhood developmental disorders and later-onset neurodegenerative diseases such as parkinsonism.
The study analyzed 211 patients from 147 families with mutations in EPG5, including nearly 100 new cases. This makes it the largest group of patients with EPG5-related disease studied so far. The disorders ranged from Vici syndrome – a rare and severe condition affecting the brain, heart, eyes, and immune system – to milder cases involving developmental delay, movement problems, or adolescent-onset parkinsonism. The type of mutation appeared to influence disease severity: truncating mutations caused the most severe early disease, while milder missense variants were more likely to appear later in life.
Brain imaging showed characteristic abnormalities such as underdevelopment of the corpus callosum, cerebellum, and optic nerves. Some patients with later-onset symptoms also had iron accumulation in the basal ganglia, a feature that overlaps with other brain iron storage disorders.
Movement symptoms were common, including dystonia, muscle stiffness, and tremor. Sixteen patients developed adolescent-onset parkinsonism with cognitive decline, and imaging revealed loss of dopamine-producing neurons – similar to patterns seen in inherited forms of Parkinson’s disease caused by PINK1 or Parkin mutations.
To understand how these genetic changes affect cells, the researchers examined fibroblasts from affected patients. These cells showed defects in the PINK1–Parkin pathway, which normally removes damaged mitochondria through mitophagy. The cells also accumulated α-synuclein, a protein that builds up in Parkinson’s disease. In animal studies, mice carrying an Epg5 mutation developed movement problems and showed disrupted autophagy in the brain. Similar effects were seen in C. elegans worms with reduced EPG5 activity.
The results suggest that loss of EPG5 function prevents cells from effectively clearing damaged mitochondria and other waste products. This failure in cellular maintenance appears to link childhood neurodevelopmental disorders with later-life neurodegenerative disease.
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