TY - JOUR T1 - EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. JF - Brain Y1 - 2016 A1 - Byrne, Susan A1 - Jansen, Lara A1 - U-King-Im, Jean-Marie A1 - Siddiqui, Ata A1 - Lidov, Hart G W A1 - Bodi, Istvan A1 - Smith, Luke A1 - Mein, Rachael A1 - Cullup, Thomas A1 - Dionisi-Vici, Carlo A1 - Al-Gazali, Lihadh A1 - Al-Owain, Mohammed A1 - Bruwer, Zandre A1 - Al Thihli, Khalid A1 - El-Garhy, Rana A1 - Flanigan, Kevin M A1 - Manickam, Kandamurugu A1 - Zmuda, Erik A1 - Banks, Wesley A1 - Gershoni-Baruch, Ruth A1 - Mandel, Hanna A1 - Dagan, Efrat A1 - Raas-Rothschild, Annick A1 - Barash, Hila A1 - Filloux, Francis A1 - Creel, Donnell A1 - Harris, Michael A1 - Hamosh, Ada A1 - Kölker, Stefan A1 - Ebrahimi-Fakhari, Darius A1 - Hoffmann, Georg F A1 - Manchester, David A1 - Boyer, Philip J A1 - Manzur, Adnan Y A1 - Lourenco, Charles Marques A1 - Pilz, Daniela T A1 - Kamath, Arveen A1 - Prabhakar, Prab A1 - Rao, Vamshi K A1 - Rogers, R Curtis A1 - Ryan, Monique M A1 - Brown, Natasha J A1 - McLean, Catriona A A1 - Said, Edith A1 - Schara, Ulrike A1 - Stein, Anja A1 - Sewry, Caroline A1 - Travan, Laura A1 - Wijburg, Frits A A1 - Zenker, Martin A1 - Mohammed, Shehla A1 - Fanto, Manolis A1 - Gautel, Mathias A1 - Jungbluth, Heinz KW - Agenesis of Corpus Callosum KW - Animals KW - Autophagy KW - Cataract KW - Child, Preschool KW - Cross-Sectional Studies KW - Drosophila melanogaster KW - Female KW - Hippocampus KW - Humans KW - Male KW - Mutation KW - Neurodevelopmental Disorders KW - Proteins KW - Retrospective Studies AB -

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.

VL - 139 IS - Pt 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26917586?dopt=Abstract ER -