EPG5 Mutations Link Autophagy Dysfunction to Neurodevelopmental and Neurodegenerative Disorders

Autophagy—cells’ built‑in waste disposal and recycling system—is essential for neural health, and its failure is increasingly implicated in both developmental and degenerative brain diseases. A new large-scale study of EPG5, a key autophagy tethering factor required for autophagosome–lysosome fusion, maps an expanded disease spectrum linking childhood neurodevelopmental syndromes to adolescent-onset parkinsonism and other neurodegenerative phenotypes.

Historically, EPG5 truncating variants have been causally linked to Vici syndrome, a severe early-onset multisystem disorder characterized by corpus callosum agenesis, cardiomyopathy, immunodeficiency, and neurodevelopmental delay. This work, through international collaboration, describes 211 individuals with biallelic EPG5 mutations—97 previously unreported—revealing a wider and age-dependent phenotypic continuum.

Clinical presentations ranged from antenatal lethality to milder, isolated neurodevelopmental delays. Crucially, a subset of individuals developed adolescent-onset parkinsonism marked by dystonia, spasticity, rapid cognitive decline, and imaging or biomarker evidence of nigrostriatal degeneration. These findings expand the concept of EPG5-related disease from a purely congenital syndrome to a lifelong neurological continuum. Genotype–phenotype associations further clarified the landscape: bi-truncating (loss-of-function) alleles predominated in classic Vici syndrome, while mixed or bi-missense variants were more frequent in milder and later-onset phenotypes. Median life expectancy varied sharply by variant class, ranging from approximately 28 months in those with biallelic truncations to 192 months in those with two missense alleles.

Neuroimaging reinforced the clinical continuum. Common features among patients included corpus callosum agenesis or thinning, cerebellar hypoplasia, and optic nerve atrophy. In those presenting with movement disorders, additional signs emerged: iron or micronutrient deposition in basal ganglia, the “ear of the lynx” periventricular hyperintensity, and pulvinar hypointensities—findings overlapping with NBIA syndromes such as PKAN or WDR45-related disease.

To test whether milder EPG5 variants could drive age-dependent neurological decline, researchers engineered a knock-in mouse bearing the human Q336R variant. These mice showed normal early development but developed motor deficits by 12 months, including impaired rotarod performance, reduced stride length, and diminished exploratory behavior. Autophagic defects were regionally selective—especially in the cerebellum and brainstem—with increased LC3-II and p62 accumulation consistent with impaired autophagy flux.

In parallel, patient-derived fibroblasts and corresponding mouse fibroblasts displayed defective mitophagy. When subjected to mitochondrial stress, these cells failed to clear damaged mitochondria via PINK1–Parkin pathways and showed accumulation of autophagosomes, along with increased α‑synuclein mRNA expression. Electron microscopy confirmed stalled mitophagosome–lysosome fusion and enlarged mitochondria. Functional assays demonstrated reduced ATP-linked respiration and impaired mitochondrial recovery after stress, underscoring a failure in cellular energy regulation. To confirm conservation across species, epg-5 was knocked down in C. elegans. The worms exhibited hypokinetic movement, mitophagosome accumulation, and altered respiratory parameters, closely mimicking the phenotypes seen in worms lacking rab-7, ccz-1, or pdr-1 (the ortholog of PRKN). These cross-species findings affirm that impaired autophagosome–lysosome fusion disrupts mitophagy and locomotor function through deeply conserved mechanisms.

Altogether, the findings support a model in which EPG5 mutations cause a lifelong continuum of disease. Severe, multisystem neurodevelopmental presentations lie at one end of the spectrum, and early-onset neurodegeneration, including adolescent parkinsonism, lies at the other. Defective autophagosome–lysosome tethering emerges as the common mechanism, impairing both bulk and selective autophagy, particularly mitophagy.

Missense variants allow residual EPG5 function and may permit survival into adolescence or adulthood, but also predispose individuals to delayed-onset neurodegeneration, especially under stress. These phenotypes mirror known genetic forms of parkinsonism caused by PINK1 or PRKN mutations and overlap with disorders like WDR45-related NBIA, suggesting that disrupted mitophagy is a shared path to neuronal dysfunction.

From a clinical perspective, this reframes EPG5 as a gene of interest not only in congenital syndromes, but also in the differential diagnosis of early-onset parkinsonism and dystonia. Subtle signs—such as callosal anomalies, optic atrophy, or mild dysmorphism—may provide diagnostic clues in affected adolescents or young adults.

Looking ahead, therapeutics that enhance autophagosome–lysosome fusion, boost lysosomal function, or promote mitochondrial clearance may offer new treatments across the EPG5 spectrum. Longitudinal monitoring, including dopaminergic imaging and biomarker assays, could help track progression and therapeutic responses. Genetic panels for movement disorders and neurodevelopmental delay should consider including EPG5, particularly in cases that straddle both domains. And with increasing recognition of shared mechanisms across autophagic disorders, there may be opportunities to repurpose or co-develop treatments targeting convergent pathways.

Ultimately, this work places EPG5 at the intersection of two major domains in neurology—neurodevelopment and neurodegeneration—and adds to the growing consensus that maintaining autophagic and mitophagic flux is essential for lifelong brain health.