Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16111
Title: EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy
Austin Authors: Byrne, Susan;Jansen, Lara;U-King-Im, Jean-Marie;Siddiqui, Ata;Lidov, Hart GW;Bodi, Istvan;Smith, Luke;Mein, Rachael;Cullup, Thomas;Dionsi-Vici, Carlo;Al-Gazali, Lihadh;Al-Owain, Mohammed;Bruwer, Zandre;Al Thihli, Khalid;El-Garhy, Rana;Flanigan, Kevin M;Manickam, Kandamurugu;Zmuda, Erik;Banks, Wesley;Gershoni-Baruch, Ruth;Mandel, Hanna;Dagan, Efrat;Raas-Rothschild, Annick;Barash, Hila;Filloux, Francis;Creel, Donnell;Harris, Michael;Hamosh, Ada;Kölker, Stefan;Ebrahimi-Fakhari, Darius;Hoffmann, Georg F;Manchester, David;Boyer, Philip J;Manzur, Adnan Y;Lourenco, Charles Marques;Pilz, Daniela T;Kamath, Arveen;Prabhakar, Prab;Rao, Vamshi K;Rogers, R Curtis;Ryan, Monique M;Brown, Natasha J;McLean, Catriona A;Said, Edith;Schara, Ulrike;Stein, Anja;Sewry, Caroline;Travan, Laura;Wijburg, Frits A;Zenker, Martin;Mohammed, Shehla;Fanto, Manolis;Gautel, Mathias;Jungbluth, Heinz
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK
Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK
Department of Neuroradiology, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
Department of Clinical Neuropathology, King's College Hospital, London, UK
Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK
Viapath, Guy's Hospital, London, UK
Regional Molecular Genetics Laboratory, Great Ormond Street Hospital, London, UK
Division of Metabolism, Department of Paediatric Medicine, Bambino Gesù Children's Research Hospital, Rome, Italy
Departments of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, UAE
Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman
Ain Shams University Hospital, Egypt, Cairo
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA
Center for Human and Molecular Genetics at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
Institute of Human Genetics, Rambam Health Care Campus and the Technion Faculty of Medicine, Haifa, Israel
Metabolic Disease Unit, Meyer Children's Hospital, Rambam Health Care Campus and the Technion Faculty of Medicine, Haifa, Israel
Department of Nursing, University of Haifa, Haifa, Israel
Institute of Rare Diseases, Institute of Genetics; Sheba Medical Centre, Tel Hashomer and the Sackler school of Medicine Tel Aviv University Ramat Aviv, Israel
Division of Pediatric Neurology, University of Utah School of Medicine and Primary Children's Medical Centre, Salt Lake City, Utah, USA
University of Utah School of Medicine, Moran Eye Centre, Salt Lake City, Utah, USA
Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington DC, USA
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA
Division of Child Neurology and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany
Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
Department of Pathology, East Carolina University, Brody School of Medicine, Brody Medical Sciences Building, Greenville, North Carolina, USA
Dubowitz Neuromuscular Centre, ICH, London, UK
Medical Genetics Unit, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
Department of Paediatric Neurology, Great Ormond Street Children's Hospital, London, UK
University of Nebraska Medical Center and Childrens Hospital and Medical Center, Omaha, Nebraska, USA
Greenwood Genetic Center, Greenville, South Carolina, USA
Department of Neurology, Royal Children's Hospital and Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Murdoch Childrens Research Institute, Parkville, Victoria, Australia
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
Department of Paediatrics, University of Melbourne, Parkville, Australia
Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
Department of Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia
Department of Anatomy and Cell Biology, University of Malta, Msida, Malta
Section of Medical Genetics, Mater dei Hospital, Msida, Malta
Pediatric Neurology, University Childrens Hospital, University of Duisburg-Essen University of Duisburg-Essen, Essen, Germany
Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, London, UK
Department of Neonatology, University Childrens Hospital, University of Duisburg-Essen, Essen, Germany
Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy
Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Institute of Human Genetics, University Hospital Magdeburg, Magdeberg, Germany
Department of Clinical Genetics, Guy's Hospital, London, UK
Issue Date: Mar-2016
metadata.dc.date: 2016-02-25
Publication information: Brain 2016; 139(3): 765-781
Abstract: Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16111
DOI: 10.1093/brain/awv393
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/26917586
Type: Journal Article
Subjects: EPG5
Vici syndrome
Callosal agenesis
Ectopic P granules autophagy protein 5
Neurodegeneration
Neurodevelopment
Appears in Collections:Journal articles

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