title: Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy.
abstract: MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Ait-El-Mkadem
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Manal
authors.initials: M
authors.lastname: Dayem-Quere
authors.affiliation: Institute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Gusic
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Chaussenot
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bannwarth
authors.affiliation: Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: François
authors.affiliation: Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Emmanuelle C
authors.initials: EC
authors.lastname: Genin
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Fragaki
authors.affiliation: Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Catharina L M
authors.initials: CLM
authors.lastname: Volker-Touw
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Vasnier
authors.affiliation: CNRS UMR 7592, Jacques Monod Institute, Paris Diderot University, 75205 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Serre
authors.affiliation: Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Koen L I
authors.initials: KLI
authors.lastname: van Gassen
authors.affiliation: Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lespinasse
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Richter
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rouzier
authors.affiliation: INSERM U1127, CNRS UMR 7225, Sorbonne Universités, l'Université Pierre et Marie Curie (Paris 06) UMR S1127, Institut du Cerveau et de la Moelle Épinière Department of Genetics, Pitié-Salpêtrière University Hospital, 75013 Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.affiliation: Service de Neurologie Pédiatrique, Centre de Référence pour les Épilepsies Rares, Centre Hospitalier Universitaire de Strasbourg, 67098 Strasbourg, France.
authors.forename: Anne
authors.initials: A
authors.lastname: De Saint-Martin
authors.affiliation: Service de Neurologie Pédiatrique, Centre de Référence pour les Épilepsies Rares, Centre Hospitalier Universitaire de Strasbourg, 67098 Strasbourg, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Abi Warde
authors.affiliation: Laboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Monique G M
authors.initials: MGM
authors.lastname: de Sain-van der Velde
authors.affiliation: Laboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Judith J M
authors.initials: JJM
authors.lastname: Jans
authors.affiliation: Department of Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Department of Informatics, Technical University of Munich, 85748 Garching, Germany.
authors.forename: Ziga
authors.initials: Z
authors.lastname: Avsec
authors.affiliation: Department of Informatics, Technical University of Munich, 85748 Garching, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Mertes
authors.affiliation: Institute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Bonnen
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Informatics, Technical University of Munich, 85748 Garching, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagneur
authors.affiliation: Department of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Hasselt
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Delahodde
authors.affiliation: Institute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Laboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
authors.forename: Sabine A
authors.initials: SA
authors.lastname: Fuchs
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France. Electronic address: paquis@hermes.unice.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000595:Amino Acid Sequence; D001927:Brain Diseases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002952:Citric Acid Cycle / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008291:Malate Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D008958:Models, Molecular; D009154:Mutation
chemical_list: D005650:Fumarates; D008293:Malates; C030298:malic acid; C032005:fumaric acid; C000619306:MDH2 protein, human; D008291:Malate Dehydrogenase