Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders...

Area of Science:

• Cellular Biology
• Genetics
• Neuroscience

Background:

• Autophagy is crucial for cellular homeostasis, clearing damaged components like mitochondria.
• Recessive variants in EPG5, an autophagy gene, are linked to Vici syndrome, a severe neurodevelopmental disorder.
• The full spectrum of EPG5-related disorders, particularly age-dependent manifestations, requires further delineation.

Purpose of the Study:

• To define the extended, age-dependent spectrum of diseases associated with pathogenic EPG5 variants.
• To investigate the cellular and animal model basis of EPG5-related neurological phenotypes.
• To explore the link between EPG5 defects, autophagy, and neurodevelopmental/neurodegenerative disorders.

Main Methods:

• Clinical, radiological, and molecular data from 211 EPG5 variant patients (97 new) were analyzed.
• Experimental models, including an Epg5 knock-in mouse and C. elegans knockdown, were used to study EPG5 function.
• Patient-derived fibroblasts were analyzed for autophagic and mitochondrial clearance defects.

Main Results:

• The EPG5-related phenotypic spectrum spans antenatally lethal conditions to milder neurodevelopmental disorders.
• Novel age-dependent neurodegenerative features included adolescent-onset parkinsonism, dystonia, cognitive decline, and myoclonus.
• Cellular models showed impaired mitophagy and α-synuclein overexpression, linking EPG5 defects to Parkinson's disease pathways.

Conclusions:

• Pathogenic EPG5 variants are associated with a lifetime neurological disease continuum.
• Defective autophagy is a common mechanism linking neurodevelopmental and neurodegenerative disorders in EPG5-related conditions.
• This study expands the understanding of EPG5-related diseases and their underlying autophagic defects.