The Expanding Phenotypical Spectrum of Congenital Disorders of Autophagy Due To Recessive Mutations In Epg5

Introduction: Autophagy is a fundamental, highly-conserved biological pathway with important roles in intracellular quality control and homeostasis, and involves the engulfment of intracellular targets by double-membraned structures, autophagosomes, and their delivery to the lysosome for digestion and recycling. We previously identified recessive mutations in EPG5, encoding Ectopic P Granules protein 5 with a crucial role in autophagosome-lysosome fusion, in Vici syndrome, the paradigmatic disorder of defective autophagy characterized by callosal agenesis, cataracts, cardiomyopathy, hypopigmentation and immunodeficiency. Here we report the largest cohort of EPG5-mutated patients to date, complemented by experimental data from Caenorhabditis elegans, Drosophila melanogaster and murine models of EPG5 deficiency. Results: We identified almost 200 EPG5-mutated patients, nearly half of them previously unpublished. Presentations ranged from antenatally lethal fetal akinesia to classical Vici syndrome as well as non-specific milder neurodevelopmental phenotypes. Movement disorders (including dystonia, spastic paraparesis and Parkinsonism) of later onset and variable progression were the main presenting feature in some. Genotype-phenotype studies suggested tentative correlations between predicted residual EPG5 expression and clinical severity. Various organismic models replicated relevant neurodevelopmental, neurodegenerative and neurological features. Conclusions: Our findings expand the spectrum of EPG5-related disorders and suggest a lifetime continuum of neurodevelopmental and neurodegenerative disorders linked in defective autophagy. Organismic models of EPG5 deficiency give insights into the intricate relationship between autophagy and other vital intracellular pathways, and may provide an effective therapy development platform. Mutations in EPG5 and other autophagy genes should be considered in unresolved cases of primary dystonia, hereditary spastic paraparesis and early-onset Parkinsonism.