Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.

Francesco Bruni, Ivano Di Meo, Emanuele Bellacchio, Bryn D Webb, Robert McFarland, Zofia M A Chrzanowska-Lightowlers, Langping He, Ewa Skorupa, Isabella Moroni, Anna Ardissone, Anna Walczak, Henna Tyynismaa, Pirjo Isohanni, Hanna Mandel, Holger Prokisch, Tobias Haack, Penelope E Bonnen, Bertini Enrico, Ewa Pronicka, Daniele Ghezzi, Robert W Taylor, Daria Diodato

Journal: Human mutation 2019;39(4):563-578

PMID: 29314548

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Abstract

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.

Address: Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom.; Molecular Neurogenetics Unit, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.; Genetics and Rare Diseases, Research Division, 'Bambino Gesù' Children Hospital, Rome, Italy.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.; Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland.; Child Neurology Unit, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.; Molecular Neurogenetics Unit, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.; Child Neurology Unit, Foundation IRCCS Neurological Institute "C. Besta", Milan, Italy.; Department of Molecular and Translational Medicine DIMET, University of Milan-Bicocca, Milan, Italy.; Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Warsaw, Poland.; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.; Department of Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Institute of Human Genetics and Metabolic Diseases, Galilee Medical Center, Nahariya, Israel.; Institute of Human Genetics, Technische Universität München, Munich, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.; Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, 'Bambino Ges.' Children's Research Hospital, Rome, Italy.; Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.; Molecular Neurogenetics Unit, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

DOI: 10.1002/humu.23398

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MeSH Terms: Child, Child, Preschool, Cohort Studies, Female, HLA Antigens, Humans, Infant, Infant, Newborn, Male, Mitochondrial Encephalomyopathies, Mitochondrial Proton-Translocating ATPases, Mutation, Missense, Oxidative Phosphorylation, Phylogeny, Valine-tRNA Ligase