Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism
Number of Authors: 1412025 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 98, no 5, p. 932-950Article in journal (Refereed) Published
Abstract [en]
OBJECTIVE: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.
METHODS: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.
RESULTS: Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes.
INTERPRETATION: Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy. ANN NEUROL 2025;98:932-950.
Place, publisher, year, edition, pages
John Wiley & Sons, 2025. Vol. 98, no 5, p. 932-950
Keywords [en]
Adolescent, Adult, Age of Onset, Animals, Autophagy, Autophagy-Related Proteins, Caenorhabditis elegans, Child, Child, Preschool, Cohort Studies, Disease Models, Animal, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Neurodevelopmental Disorders, Parkinsonian Disorders, Vesicular Transport Proteins, Young Adult, autophagy related protein, EPG5 protein, human, vesicular transport protein, animal, cohort analysis, degenerative disease, diagnostic imaging, disease model, genetics, human, mental disease, mouse, onset age, parkinsonism, preschool child
National Category
Neurosciences Neurology Medical Genetics and Genomics
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-25996DOI: 10.1002/ana.78013PubMedID: 41053928Scopus ID: 2-s2.0-105020614786OAI: oai:DiVA.org:his-25996DiVA, id: diva2:2013496
Funder
EU, Horizon Europe, 765912—DRIVE—H2020-MSCA-ITN-2017German Research Foundation (DFG), 413543196Max Planck SocietyNIH (National Institutes of Health), HG011758NIH (National Institutes of Health), NS105078NIH (National Institutes of Health), 1K08NS131581
Note
CC BY 4.0
© 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Address correspondence to Dr Jungbluth, Department of Pediatric Neurology, Neuromuscular Service, Evelina London Children’s Hospital, Guy’s & St. Thomas’ Hospital NHS Foundation Trust, London, UK; E-mail: Heinz.Jungbluth@nhs.net, Heinz.Jungbluth@kcl.ac.uk, heinz.jungbluth@gstt.nhs.uk
This work was supported by grants from the European Union Horizon 2020 Program (765912—DRIVE—H2020-MSCA-ITN-2017) to C.D., M.F., and H.J.; Action Medical Research (2446) to H.J. and M.F.; and Action Medical Research (GN2959) to K.S. and M.R.D.. H.J., M.F. and M.G. like to thank the Rare Genomics Institute for their support, and Taconic Biosciences for the generation of the EPG5 mouse model investigated in this study. H.S.D. was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (371/2021 and 243/2022), as well as the Cologne Clinician Scientist Program/Medical Faculty/University of Cologne and German Research Foundation (CCSP, DFG project No. 413543196). A.A. was supported by the Max Planck Gesellschaft. T.S.B. was supported by the Netherlands Organization for Scientific Research (ZonMw Vidi, grant 09150172110002), and acknowledges ongoing support from EpilepsieNL and CURE Epilepsy. K.Õ. is supported by an Estonian Research Council grant PRG2040. Funding bodies did not have any influence onstudy design, results, and data interpretation or final manuscript. Some of the authors of this publication are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). Also supported in part by US National Institutes of Health HG011758 and NS105078 to J.R.L. N.E.M. receives National Institutes of Health (NIH) funding (1K08NS131581) and is supported by the ASAP Global Parkinson’s Genetics Program (GP2). Biospecimens used in this article were obtained from the Northwestern Movement Disorders Center (MDC) Biorepository. As such, the investigators within the MDC Biorepository contributed to the design and implementation of the MDC Biorepository, and/or provided data and collected biospecimens, but did not participate in the analysis or writing of this report (Rizwan Akhtar, MD, PhD; Tanya Simuni, MD; Puneet Opal, MD, PhD; Monika Szela MHA; Joanna Blackburn, MD; and Lisa Kinsley, MS, CGC). We thank the Coriell Institute for Medical Research (Camden, NJ, USA) and Dr Fleur Vansenne (Groningen, the Netherlands) for their kind gift of EPG5-mutated patient fibroblasts. We thank Dr Susan Byrne (Dublin, Republic of Ireland) for her past work on EPG5-related Vici syndrome. This paper is dedicated to the memory of David Chanan Harris (2006-2025) and Kennedy Rose Bowen (2019-2021). Open Access funding enabled and organized by King's College London.
2025-11-132025-11-132025-11-14Bibliographically approved