Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy

Am J Hum Genet. 2017 Jan 5;100(1):151-159. doi: 10.1016/j.ajhg.2016.11.014.

Samira Ait-El-Mkadem ¹, Manal Dayem-Quere ¹, Mirjana Gusic ², Annabelle Chaussenot ¹, Sylvie Bannwarth ¹, Bérengère François ³, Emmanuelle C Genin ³, Konstantina Fragaki ¹, Catharina L M Volker-Touw ⁴, Christelle Vasnier ⁵, Valérie Serre ⁶, Koen L I van Gassen ⁴, Françoise Lespinasse ³, Susan Richter ⁷, Graeme Eisenhofer ⁷, Cécile Rouzier ¹, Fanny Mochel ⁸, Anne De Saint-Martin ⁹, Marie-Thérèse Abi Warde ⁹, Monique G M de Sain-van der Velde ¹⁰, Judith J M Jans ¹⁰, Jeanne Amiel ¹¹, Ziga Avsec ¹², Christian Mertes ¹², Tobias B Haack ², Tim Strom ², Thomas Meitinger ², Penelope E Bonnen ¹³, Robert W Taylor ¹⁴, Julien Gagneur ¹², Peter M van Hasselt ¹⁵, Agnès Rötig ¹⁶, Agnès Delahodde ⁵, Holger Prokisch ², Sabine A Fuchs ¹⁰, Véronique Paquis-Flucklinger ¹⁷

Affiliations

1 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.
2 Institute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
3 Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
4 Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
5 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.
6 CNRS UMR 7592, Jacques Monod Institute, Paris Diderot University, 75205 Paris, France.
7 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.
8 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.
9 Service de Neurologie Pédiatrique, Centre de Référence pour les Épilepsies Rares, Centre Hospitalier Universitaire de Strasbourg, 67098 Strasbourg, France.
10 Laboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
11 Department of Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
12 Department of Informatics, Technical University of Munich, 85748 Garching, Germany.
13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
14 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
15 Department of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
16 INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
17 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.

PMID: 27989324 DOI: 10.1016/j.ajhg.2016.11.014

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.

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