title: Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy.
abstract: Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial β-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multi-organ involvement.
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kremer
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Bader
authors.initials: B
authors.lastname: Alhaddad
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Hempel
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Iuso
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, 80336 Munich, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Küpper
authors.affiliation: University Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Reka
authors.initials: R
authors.lastname: Kovacs-Nagy
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Satanovskij
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Berutti
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Gertrud
authors.initials: G
authors.lastname: Eckstein
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Max-Planck-Institute for Molecular Genetics, Otto-Warburg Laboratory, 14195 Berlin, Germany; CU Systems Medicine, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: University Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. Electronic address: meitinger@helmholtz-muenchen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, 80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
mesh_terms: D000483:Alleles; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics*; D009202:Cardiomyopathies / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D010375:Pedigree