title: EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.
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.
authors.affiliation: 1 Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.
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authors.lastname: Byrne
authors.affiliation: 2 Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK.
authors.forename: Lara
authors.initials: L
authors.lastname: Jansen
authors.affiliation: 3 Department of Neuroradiology, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: U-King-Im
authors.affiliation: 3 Department of Neuroradiology, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.
authors.forename: Ata
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authors.affiliation: 4 Department of Pathology, Boston Children's Hospital, Boston MA 02115, USA.
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authors.affiliation: 5 Department of Clinical Neuropathology, King's College Hospital, London, UK.
authors.forename: Istvan
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authors.affiliation: 6 Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK.
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authors.affiliation: 13 Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman.
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authors.affiliation: 16 Center for Human and Molecular Genetics at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
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authors.affiliation: 16 Center for Human and Molecular Genetics at The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
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authors.affiliation: 21 Division of Pediatric Neurology, University of Utah School of Medicine and Primary Children's Medical Centre, Salt Lake City, Utah, USA.
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authors.affiliation: 22 University of Utah School of Medicine, Moran Eye Centre, Salt Lake City, Utah, USA.
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authors.affiliation: 25 Division of Child Neurology and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany.
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authors.affiliation: 25 Division of Child Neurology and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany.
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authors.affiliation: 25 Division of Child Neurology and Metabolic Medicine, University Children's Hospital, Heidelberg, Germany.
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authors.affiliation: 26 Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, USA.
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authors.affiliation: 28 Dubowitz Neuromuscular Centre, ICH, London, UK.
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authors.affiliation: 32 University of Nebraska Medical Center and Childrens Hospital and Medical Center, Omaha, Nebraska, USA.
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authors.affiliation: 34 Departments of Neurology, Royal Children's Hospital and Paediatrics, University of Melbourne, and Murdoch Childrens Research Institute, Melbourne Australia.
authors.forename: Monique M
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authors.affiliation: 35 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Parkville, Australia 36 Department of Paediatrics, University of Melbourne, Parkville, Australia 37 Department of Clinical Genetics, Austin Health, Australia.
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authors.forename: Ulrike
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authors.affiliation: 42 Department of Neonatology, University Childrens Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anja
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authors.affiliation: 44 Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
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authors.affiliation: 45 Department of Paediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
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authors.affiliation: 46 Institute of Human Genetics, University Hospital Magdeburg, Germany.
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authors.affiliation: 47 Department of Clinical Genetics, Guy's Hospital, London, UK.
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authors.affiliation: 2 Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK.
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authors.affiliation: 6 Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK.
authors.forename: Mathias
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authors.affiliation: 1 Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK 6 Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK 48 Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK Heinz.Jungbluth@gstt.nhs.uk.
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mesh_terms: D061085:Agenesis of Corpus Callosum / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D002386:Cataract / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004331:Drosophila melanogaster; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051907:Lysosomal Membrane Proteins; D008297:Male; D009154:Mutation / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012189:Retrospective Studies; D033921:Vesicular Transport Proteins
chemical_list: D000071183:Autophagy-Related Proteins; C000592185:EPG5 protein, human; D051907:Lysosomal Membrane Proteins; D011506:Proteins; D033921:Vesicular Transport Proteins
keywords: EPG5; Vici syndrome; callosal agenesis; ectopic P granules autophagy protein 5; neurodegeneration; neurodevelopment