EPG5 Mutations Reveal Lifespan-Spanning Link Between Neurodevelopmental Delay and Parkinsonism

A multinational team of researchers has uncovered a striking continuum between early-onset neurodevelopmental disorders and later-onset neurodegenerative diseases, all rooted in mutations of the same autophagy gene: EPG5. In what is now the largest study of its kind, data from 211 patients spanning 147 families identified biallelic pathogenic EPG5 variants that expand the phenotypic spectrum beyond the well-characterized Vici syndrome.

Traditionally, Vici syndrome—caused by loss-of-function mutations in EPG5—has been viewed as a rare, multisystem, pediatric neurodevelopmental disorder. Hallmark features include agenesis of the corpus callosum, cataracts, immunodeficiency, and profound developmental delay. But in this newly assembled cohort, researchers observed that EPG5-related disorders (EPG5-RDs) also manifest as adolescent-onset parkinsonism, dystonia, and progressive cognitive decline, particularly in patients with milder, missense mutations.

Clinical data revealed that among the 211 patients studied, approximately 80 exhibited movement disorders without a prior diagnosis of Vici syndrome. Of those, 16 developed adolescent-onset parkinsonism preceded by only mild developmental delay. In several of these cases, the neurodegenerative symptoms—rigidity, tremor, and bradykinesia—emerged rapidly and were accompanied by atypical features such as dystonia, spasticity, and early cognitive deterioration. Neuroimaging in these patients often showed brain atrophy and iron accumulation in basal ganglia structures, paralleling findings in disorders such as PKAN.

Genotype–phenotype analysis showed that bi-truncating variants were strongly associated with the classical Vici syndrome and markedly reduced life expectancy. By contrast, individuals with compound heterozygous or bi-missense mutations typically presented later in life and survived longer. Median life expectancy among patients with bi-truncating variants was 28 months, compared to 192 months for those with bi-missense mutations.

To probe the underlying mechanisms, the authors engineered a novel Epg5 knock-in mouse model carrying the Q331R mutation—orthologous to the human Q336R missense variant. These mice showed no early motor deficits but developed coordination impairments, reduced stride length, and balance issues by 12 months of age, corresponding to human adolescent-onset symptoms. Autophagic defects were localized to the brainstem and cerebellum—regions implicated in motor control—alongside evidence of mitochondrial dysfunction and impaired mitophagy.

Patient-derived fibroblast studies corroborated these findings, revealing defects in PINK1/Parkin-mediated mitophagy and accumulation of dysfunctional mitochondria. Notably, these cellular phenotypes were present not only in patients with parkinsonism but also in those with milder neurodevelopmental disorders. Further analysis showed elevated levels of α-synuclein mRNA in these cells, echoing molecular signatures observed in familial forms of Parkinson’s disease.

Using Caenorhabditis elegans, the team demonstrated that knockdown of epg-5 recapitulates mitophagy defects and movement abnormalities seen in other Parkinson’s disease models. These findings reinforce the role of EPG5 as a critical autophagy tethering factor whose dysfunction bridges early and late-onset neurological pathology.

The study suggests that EPG5 mutations may underlie a broader array of clinical syndromes than previously recognized, including unexplained adolescent-onset parkinsonism. The researchers propose that defective autophagosome–lysosome fusion, central to EPG5 function, leads to cumulative mitochondrial stress and proteostatic overload, ultimately driving neurodegeneration in susceptible individuals.

By illuminating the molecular basis and phenotypic breadth of EPG5-related disorders, this study paves the way for improved genetic diagnostics and potential therapeutic strategies targeting autophagy and mitochondrial quality control.