title: EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum.
abstract: Mitochondrial aminoacyl tRNA synthetases are essential for organelle protein synthesis. Genetic defects affecting the function of these enzymes may cause pediatric mitochondrial disease. Here, we report on a child with fatal neonatal lactic acidosis and recurrent hypoglycemia caused by mutations in EARS2, encoding mitochondrial glutamyl-tRNA synthetase 2. Brain ultrasound revealed agenesis of corpus callosum. Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species (ROS) production, and altered mitochondrial morphology. Our report further illustrates the clinical spectrum of the severe neonatal-onset form of EARS2 mutations. Moreover, in this case the live-cell parameters appeared to be more sensitive to mitochondrial dysfunction compared to standard diagnostics, which indicates the potential relevance of fibroblast studies in children with mitochondrial diseases.
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Danhauser
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr 1, 85764, Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr 1, 85764, Neuherberg, Germany.
authors.forename: Bader
authors.initials: B
authors.lastname: Alhaddad
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Melcher
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Seibt
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr 1, 85764, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr 32, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr 1, 85764, Neuherberg, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Medical Faculty, Department of Diagnostic and Interventional Radiology, University Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Klee
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: Institute of Human Genetics, Technische Universität München, Trogerstr 32, 81675, Munich, Germany. Prokisch@helmholtz-muenchen.de.|Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstr 1, 85764, Neuherberg, Germany. Prokisch@helmholtz-muenchen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, Moorenstr 5, 40225, Düsseldorf, Germany. Felix.Distelmaier@med.uni-duesseldorf.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
mesh_terms: D000140:Acidosis, Lactic / Q000000981:diagnostic imaging / Q000235:genetics*; D061085:Agenesis of Corpus Callosum / Q000000981:diagnostic imaging / Q000235:genetics*; D001921:Brain / Q000000981:diagnostic imaging; D017809:Fatal Outcome; D005975:Glutamate-tRNA Ligase / Q000235:genetics*; D006801:Humans; D007003:Hypoglycemia / Q000000981:diagnostic imaging / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D028361:Mitochondrial Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D012008:Recurrence; D014463:Ultrasonography
chemical_list: C000614184:EARS2 protein, human; D005975:Glutamate-tRNA Ligase
keywords: LTBL; Mitochondrial morphology; Mitochondrial translation; OXPHOS; ROS