Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism

Hormos Salimi Dafsari^{1

2

3

4}, Celine Deneubourg⁵, Kritarth Singh⁶, Reza Maroofian⁷, Zita Suprenant⁸, Ay Lin Kho⁴, Neil J Ingham⁹, Karen P Steel⁹, Preethi Sheshadri⁶, Franciska Baur^{1

2}, Lea Hentrich^{1

2}, Birgit Gerisch², Mina Zamani^{7

10

11}, Cesar Alves¹², Ata Siddiqui¹³, Haidar S Dafsari¹⁴, Mehri Salari¹⁵, Anthony E Lang¹⁶, Michael Harris⁸, Alice Abdelaleem^{17

18}, Saeid Sadeghian¹⁹, Reza Azizimalamiri¹⁹, Hamid Galehdari¹⁰, Gholamreza Shariati^{10

20}, Alireza Sedaghat^{10

21}, Jawaher Zeighami¹⁵, Daniel Calame²², Dana Marafi²², Ruizhi Duan²³, Adrian Boehnke²², Gary D Clark²², Jill A Rosenfeld^{23

24}, Carrie A Mohila²⁵, Dora Steel²⁶, Saurabh Chopra²⁷, Suvasini Sharma²⁸, Nicolai Kohlschmidt^{29

30}, Steffi Patzer³¹, Afshin Saffari³², Darius Ebrahimi-Fakhari³³, Büşra Eser Çavdartepe³⁴, Irene J Chang³⁵, Erika Beckman³⁶, Renate Peters³⁷, Andrew Paul Fennell^{38

39}, Bernice Lo⁴⁰, Luisa Averdunk⁴¹, Felix Distelmaier⁴¹, Martina Baethmann⁴², Frances Elmslie⁴³, Kairit Joost⁴⁴, Sheela Nampoothiri⁴⁵, Dhanya Yesodharan⁴⁶, Hanna Mandel⁴⁶, Amy Kimball⁴⁷, Antonie D Kline⁴⁷, Cyril Mignot⁴⁸, Boris Keren⁴⁸, Vincent Laugel⁴⁹, Katrin Õunap⁵⁰, Kalpana Devadathan⁵¹, Frederique M C van Berkestijn⁵², Arpana Silwal⁵³, Saskia Koene⁵⁴, Sumit Verma⁵⁵, Mohammed Yousuf Karim⁵⁶, Chahynez Boubidi⁵⁷, Majid Aziz⁵⁸, Gehad ElGhazali⁵⁹, Lauren Mattas⁶⁰, Mohammad Miryounesi^{61

62}, Farzad Hashemi-Gorji⁶², Shahryar Alavi⁶³, Nayereh Nouri⁶⁴, Mehrdad Noruzinia⁶⁵, Saeideh Kavousi⁶⁶, Arveen Kamath⁶⁷, Sandeep Jayawant⁶⁸, Russell Saneto⁶⁹, Nourelhoda A Haridy⁷⁰, Pinar Ozkan Kart⁷¹, Ali Cansu⁷², Madeleine Joubert⁷², Claire Beneteau⁷², Kyra E Stuurman⁷³, Martina Wilke⁷³, Tahsin Stefan Barakat⁷³, Homa Tajsharghi⁷⁴, Annarita Scardamaglia⁷, Sadeq Vallian⁷⁵, Semra Hız⁷⁶, Ali Shoeibi⁷⁷, Reza Boostani⁷⁷, Narges Hashemi^{78

79}, Meisam Babaei⁸⁰, Norah Saleh Alsaleh⁸¹, Julie Porter⁸², Tania Attié-Bitach⁸³, Pauline Marzin⁸³, Dorota Wicher⁸⁴, Jessica I Gold⁸⁵, Elisabeth Schuler³², Amna Kashgari⁸⁶, Rakan F Alanazi⁸⁶, Wafaa Eyaid⁸⁶, Marc Engelen⁸⁷, Mirjam Langeveld⁸⁸, Burkhard Stüve⁸⁹, Yun Li⁹⁰, Gökhan Yigit^{90

91}, Bernd Wollnik^{90

91

92}, Mariana H G Monje⁹³, Dimitri Krainc⁹³, Niccolò E Mencacci⁹³, Somayeh Bakhtiari⁹⁴, Michael Kruer⁹⁴, Emanuela Argilli⁹⁵, Elliott Sherr⁹⁵, Yalda Jamshidi⁹⁶, Ehsan Ghayoor Karimiani⁹⁶, Yiu Wing Sunny Cheung⁹⁷, Ivan Karin⁹⁸, Giovanni Zifarelli⁹⁹, Peter Bauer⁹⁹, Wendy K Chung¹⁰⁰, James R Lupski^{22

23}, Manju A Kurian²⁶, Jörg Dötsch¹, Jürgen-Christoph von Kleist-Retzow¹, Thomas Klopstock^{98

101

102}, Matias Wagner¹⁰³, Calvin Yip⁹⁷, Andreas Roos^{104

105

106}, Rita Carsetti¹⁰⁷, Carlo Dionisi-Vici¹⁰⁸, Mathias Gautel⁴, Michael R Duchen⁶, Adam Antebi², Henry Houlden⁷, Manolis Fanto⁵, Heinz Jungbluth^{3

4}

Affiliations

¹ Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
² Max Planck Institute for Biology of Aging and Cologne Excellence Cluster for Aging-associated Diseases, Cologne, Germany.
³ Department of Pediatric Neurology, Evelina London Children's Hospital, Guy's & St Thomas NHS Foundation Trust, London, UK.
⁴ Randall Center for Cell and Molecular Biophysics, Muscle Signaling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, UK.
⁵ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁶ UCL Consortium for Mitochondrial Research and Department of Cell and Developmental Biology, University College London, London, UK.
⁷ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁸ Vici Syndrome Foundation, Inc, Silver Spring, Maryland, USA.
⁹ Wolfson Sensory Pain and Regeneration Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁰ Narges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz, Iran.
¹¹ Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
¹² Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
¹³ Department of Radiology, Guy's and Saint Thomas' Hospitals NHS Trust, London, UK.
¹⁴ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁵ Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁶ Edmond J Safra Program in Parkinson's Disease, Krembil Brain Institute, University Health Network and the Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Neurology, Weill Cornell Medicine Qatar, Education City, Doha, Qatar.
¹⁸ Medical Molecular Genetics, Institute Human Genetics and Genome Research, National Research Centre, Dokki, Egypt.
¹⁹ Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
²⁰ Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
²¹ Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
²² Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
²³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁴ Baylor Genetics Laboratories, Houston, TX, USA.
²⁵ Department of Pathology, Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
²⁶ Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL GOS-Institute of Child Health, London, UK.
²⁷ Indraprastha Apollo Hospital, New Delhi, India.
²⁸ Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India.
²⁹ Institute for Clinical Genetics and Tumour Genetics, Bonn, Germany.
³⁰ Laboratoire national de santé, National Center of Genetics, Dudelange, Luxembourg.
³¹ Department of Pediatrics, Krankenhaus St. Elisabeth und St. Barbara, Halle (Saale), Germany.
³² Division of Child Neurology and Metabolic Medicine, Department of Pediatrics I, Center for Pediatrics and Adolescent Medicine, Medical Faculty Heidelberg, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
³³ Movement Disorders Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³⁴ Department of Medical Genetics, Konya City Hospital, Konya, Turkey.
³⁵ Department of Pediatrics, Division of Medical Genetics, University of California at San Francisco, San Francisco, CA, USA.
³⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
³⁷ Christliches Kinderhospital Osnabrück, Osnabrück, Germany.
³⁸ Monash Genetics, Monash Health, Melbourne, Vic, Australia.
³⁹ Department of Paediatrics, Monash University, Melbourne, Vic, Australia.
⁴⁰ Research Branch, Sidra Medicine, Doha; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁴¹ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁴² Department of Pediatrics, Hospital Dritter Orden, Munich, Germany.
⁴³ St George's University Hospitals NHS Foundation Trust, London, UK.
⁴⁴ Faculty of Medicine, University of Tartu, Tartu, Estonia.
⁴⁵ Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Center, Cochin, India.
⁴⁶ Department of Metabolic and Genetic Disorders, Ziv, Medical Center, Safed, Israel.
⁴⁷ Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, USA.
⁴⁸ APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC Déficience Intellectuelle et Autisme, Paris, France.
⁴⁹ Service de Pédiatrie, Centre Hospitalier Universitaire (CHU) de Strasbourg-Hautepierre, Strasbourg, France.
⁵⁰ Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁵¹ Department of Pediatric Neurology, Government Medical College, Thiruvananthapuram, India.
⁵² Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵³ St Bart's Health NHS Trust, London, UK.
⁵⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁵⁵ Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.
⁵⁶ Department of Pathology, Sidra Medicine, College of Medicine, Qatar University, Doha, Qatar.
⁵⁷ Department of Pediatrics A, Hussein Dey University Hospital Center, University of Algiers 1, Algiers, Algeria.
⁵⁸ Department of Pediatric Neurology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
⁵⁹ Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
⁶⁰ Stanford Children's Hospital, Palo Alto, CA, USA.
⁶¹ Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁶² Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁶³ Palindrome, Isfahan, Iran.
⁶⁴ Karyogen Lab, Isfahan, Iran.
⁶⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
⁶⁶ Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
⁶⁷ Cardiff and Vale UHB-AWMGS, Cardiff, UK.
⁶⁸ Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁶⁹ Neuroscience Institute, Center for Integrated Brain Research, Department of Neurology/Division of Pediatric Neurology, Seattle Children's Hospital, Seattle, WA, USA.
⁷⁰ Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.
⁷¹ Department of Pediatrics Neurology, Karadeniz Technical University, Trabzon, Turkey.
⁷² Genetics Department, Nantes University Hospital, Nantes, France.
⁷³ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁷⁴ School of Health Science, Division Biomedicine and Translational Medicine, University of Skovde, Skovde, Sweden.
⁷⁵ Department of Cell and Molecular Biology & Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran.
⁷⁶ Faculty of Medicine, Pediatric Neurology Department, Dokuz Eylül University, Izmir, Turkey.
⁷⁷ Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷⁸ Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷⁹ Rare Pediatric Neurological Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸⁰ Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
⁸¹ Department of Genetics and Precision Medicine, King Abdullah Specialized Children's Hospital, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
⁸² Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
⁸³ Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Paris, France.
⁸⁴ Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
⁸⁵ Division of Medical Genetics, Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, NY, USA.
⁸⁶ Department of Clinical Genetics and Precision Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
⁸⁷ Amsterdam Leukodystrophy Center, Department of Pediatric Neurology, Emma Children's Hospital, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸⁸ Department of Endocrinology and Metabolism, Amsterdam UMC, Research Institute Gastroenterology, Endocrinology & Metabolism (AGEM), University of Amsterdam, Amsterdam, the Netherlands.
⁸⁹ Department for Neuropediatrics, DRK Children's Hospital Siegen, Siegen, Germany.
⁹⁰ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
⁹¹ DZHK (German Center for Cardiovascular Research), Partner Site Lower Saxony, Göttingen, Germany.
⁹² Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines To Networks of Excitable Cells" (MBExC), University of Göttingen; German Center for Child and Adolescent Health (DZKJ), Partner Site Göttingen, Göttingen, Germany.
⁹³ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁹⁴ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
⁹⁵ Department of Neurology, University of California San Francisco Division of Hospital Medicine, San Francisco, CA, USA.
⁹⁶ Molecular and Clinical Sciences Institute, St. George's University of London, London, UK.
⁹⁷ Life Sciences Institute, Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada.
⁹⁸ Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
⁹⁹ CENTOGENE GmbH, Rostock, Germany.
¹⁰⁰ Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
¹⁰² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁰³ Institute of Human Genetics, School of Medicine and Health, Technische Universität München, Munich, Germany.
¹⁰⁴ Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany.
¹⁰⁵ Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
¹⁰⁶ Brain and Mind Research Institute, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹⁰⁷ Immunology Research Area, B Cell Unit, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
¹⁰⁸ Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

PMID: 41053928
DOI: 10.1002/ana.78013

Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism

Hormos Salimi Dafsari et al. Ann Neurol. 2025.

. 2025 Oct 6.

doi: 10.1002/ana.78013. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
² Max Planck Institute for Biology of Aging and Cologne Excellence Cluster for Aging-associated Diseases, Cologne, Germany.
³ Department of Pediatric Neurology, Evelina London Children's Hospital, Guy's & St Thomas NHS Foundation Trust, London, UK.
⁴ Randall Center for Cell and Molecular Biophysics, Muscle Signaling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, UK.
⁵ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
⁶ UCL Consortium for Mitochondrial Research and Department of Cell and Developmental Biology, University College London, London, UK.
⁷ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁸ Vici Syndrome Foundation, Inc, Silver Spring, Maryland, USA.
⁹ Wolfson Sensory Pain and Regeneration Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
¹⁰ Narges Medical Genetics and Prenatal Diagnosis Laboratory, Ahvaz, Iran.
¹¹ Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
¹² Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
¹³ Department of Radiology, Guy's and Saint Thomas' Hospitals NHS Trust, London, UK.
¹⁴ Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁵ Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
¹⁶ Edmond J Safra Program in Parkinson's Disease, Krembil Brain Institute, University Health Network and the Department of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁷ Department of Neurology, Weill Cornell Medicine Qatar, Education City, Doha, Qatar.
¹⁸ Medical Molecular Genetics, Institute Human Genetics and Genome Research, National Research Centre, Dokki, Egypt.
¹⁹ Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USA.
²⁰ Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
²¹ Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
²² Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
²³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁴ Baylor Genetics Laboratories, Houston, TX, USA.
²⁵ Department of Pathology, Department of Pathology and Immunology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
²⁶ Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL GOS-Institute of Child Health, London, UK.
²⁷ Indraprastha Apollo Hospital, New Delhi, India.
²⁸ Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India.
²⁹ Institute for Clinical Genetics and Tumour Genetics, Bonn, Germany.
³⁰ Laboratoire national de santé, National Center of Genetics, Dudelange, Luxembourg.
³¹ Department of Pediatrics, Krankenhaus St. Elisabeth und St. Barbara, Halle (Saale), Germany.
³² Division of Child Neurology and Metabolic Medicine, Department of Pediatrics I, Center for Pediatrics and Adolescent Medicine, Medical Faculty Heidelberg, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany.
³³ Movement Disorders Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³⁴ Department of Medical Genetics, Konya City Hospital, Konya, Turkey.
³⁵ Department of Pediatrics, Division of Medical Genetics, University of California at San Francisco, San Francisco, CA, USA.
³⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
³⁷ Christliches Kinderhospital Osnabrück, Osnabrück, Germany.
³⁸ Monash Genetics, Monash Health, Melbourne, Vic, Australia.
³⁹ Department of Paediatrics, Monash University, Melbourne, Vic, Australia.
⁴⁰ Research Branch, Sidra Medicine, Doha; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁴¹ Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁴² Department of Pediatrics, Hospital Dritter Orden, Munich, Germany.
⁴³ St George's University Hospitals NHS Foundation Trust, London, UK.
⁴⁴ Faculty of Medicine, University of Tartu, Tartu, Estonia.
⁴⁵ Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Center, Cochin, India.
⁴⁶ Department of Metabolic and Genetic Disorders, Ziv, Medical Center, Safed, Israel.
⁴⁷ Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD, USA.
⁴⁸ APHP, Hôpital Pitié-Salpêtrière, Département de Génétique, Centre de Reference Déficience Intellectuelle de Causes Rares, GRC UPMC Déficience Intellectuelle et Autisme, Paris, France.
⁴⁹ Service de Pédiatrie, Centre Hospitalier Universitaire (CHU) de Strasbourg-Hautepierre, Strasbourg, France.
⁵⁰ Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁵¹ Department of Pediatric Neurology, Government Medical College, Thiruvananthapuram, India.
⁵² Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵³ St Bart's Health NHS Trust, London, UK.
⁵⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁵⁵ Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA.
⁵⁶ Department of Pathology, Sidra Medicine, College of Medicine, Qatar University, Doha, Qatar.
⁵⁷ Department of Pediatrics A, Hussein Dey University Hospital Center, University of Algiers 1, Algiers, Algeria.
⁵⁸ Department of Pediatric Neurology, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates.
⁵⁹ Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
⁶⁰ Stanford Children's Hospital, Palo Alto, CA, USA.
⁶¹ Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁶² Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁶³ Palindrome, Isfahan, Iran.
⁶⁴ Karyogen Lab, Isfahan, Iran.
⁶⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
⁶⁶ Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
⁶⁷ Cardiff and Vale UHB-AWMGS, Cardiff, UK.
⁶⁸ Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁶⁹ Neuroscience Institute, Center for Integrated Brain Research, Department of Neurology/Division of Pediatric Neurology, Seattle Children's Hospital, Seattle, WA, USA.
⁷⁰ Department of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt.
⁷¹ Department of Pediatrics Neurology, Karadeniz Technical University, Trabzon, Turkey.
⁷² Genetics Department, Nantes University Hospital, Nantes, France.
⁷³ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁷⁴ School of Health Science, Division Biomedicine and Translational Medicine, University of Skovde, Skovde, Sweden.
⁷⁵ Department of Cell and Molecular Biology & Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran.
⁷⁶ Faculty of Medicine, Pediatric Neurology Department, Dokuz Eylül University, Izmir, Turkey.
⁷⁷ Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷⁸ Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷⁹ Rare Pediatric Neurological Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁸⁰ Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
⁸¹ Department of Genetics and Precision Medicine, King Abdullah Specialized Children's Hospital, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
⁸² Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
⁸³ Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Paris, France.
⁸⁴ Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
⁸⁵ Division of Medical Genetics, Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, NY, USA.
⁸⁶ Department of Clinical Genetics and Precision Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
⁸⁷ Amsterdam Leukodystrophy Center, Department of Pediatric Neurology, Emma Children's Hospital, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸⁸ Department of Endocrinology and Metabolism, Amsterdam UMC, Research Institute Gastroenterology, Endocrinology & Metabolism (AGEM), University of Amsterdam, Amsterdam, the Netherlands.
⁸⁹ Department for Neuropediatrics, DRK Children's Hospital Siegen, Siegen, Germany.
⁹⁰ Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
⁹¹ DZHK (German Center for Cardiovascular Research), Partner Site Lower Saxony, Göttingen, Germany.
⁹² Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines To Networks of Excitable Cells" (MBExC), University of Göttingen; German Center for Child and Adolescent Health (DZKJ), Partner Site Göttingen, Göttingen, Germany.
⁹³ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁹⁴ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
⁹⁵ Department of Neurology, University of California San Francisco Division of Hospital Medicine, San Francisco, CA, USA.
⁹⁶ Molecular and Clinical Sciences Institute, St. George's University of London, London, UK.
⁹⁷ Life Sciences Institute, Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada.
⁹⁸ Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
⁹⁹ CENTOGENE GmbH, Rostock, Germany.
¹⁰⁰ Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
¹⁰² Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
¹⁰³ Institute of Human Genetics, School of Medicine and Health, Technische Universität München, Munich, Germany.
¹⁰⁴ Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, Essen, Germany.
¹⁰⁵ Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
¹⁰⁶ Brain and Mind Research Institute, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹⁰⁷ Immunology Research Area, B Cell Unit, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
¹⁰⁸ Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

PMID: 41053928
DOI: 10.1002/ana.78013

Abstract

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 ANN NEUROL 2025.

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References

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Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism

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Mutations in the Key Autophagy Tethering Factor EPG5 Link Neurodevelopmental and Neurodegenerative Disorders Including Early-Onset Parkinsonism

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