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      Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features


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          Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months. Brain MRI revealed hypogenesis of the corpus callosum, T2 signal abnormalities in the medulla oblongata, pons, midbrain, thalami, cerebellar white matter, and a lactate peak on MRS. Muscle histochemistry showed cytochrome c oxidase (COX)-deficient and ragged-red fibres, while muscle biochemical studies showed decreased activities of mitochondrial respiratory chain complexes I and IV. Whole exome sequencing (WES) identified biallelic EARS2 (NM_001083614) variants, a previously reported start-loss (c.1>G, p.Met1?) variant and a novel missense (c.184A>T, p.Ile62Phe) variant. Patient fibroblasts and muscle homogenate displayed markedly decreased EARS2 protein levels, although decreased steady-state levels of complex I (NDUFB8) and complex IV (MT-CO1 and MT-CO2) subunits were only observed in muscle. Pathogenic variants in EARS2, encoding mitochondrial glutamyl-tRNA synthetase (mtGluR), are associated with Leukoencephalopathy involving the Thalamus and Brainstem with high Lactate (LTBL), a mitochondrial disorder characterised by a distinctive brain MRI pattern and a biphasic clinical course. We further outline the unique phenotypic spectrum of LTBL and review the neuroradiological features reported in all patients documented in the literature.

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          JIMD Rep
          JIMD Rep
          JIMD Reports
          Springer Berlin Heidelberg (Berlin, Heidelberg )
          30 August 2016
          : 33
          : 61-68
          [13 ]Human Genetics Department, Centro Hospitalar de São João, Alameda Prof. Hernâni Monteiro, 4200 Porto, Portugal
          [14 ]Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH UK
          [15 ]Imaging Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
          [16 ]CNC – Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal
          [17 ]Faculty of Medicine, University of Coimbra, Coimbra, Portugal
          [18 ]Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK
          [19 ]MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK
          [20 ]Metabolic Unit – Child Development Center, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal
          [1 ]Division of Metabolism, University Children’s Hospital, Zurich, Switzerland
          [2 ]Div of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota USA
          [3 ]Health, Genetics & Genomic Med Clinical and Molecular Genetics Unit, Univ Coll London Inst of Child, London, United Kingdom
          [4 ]Managing Editor JIMD Univ Children´s Hospital Heidelberg, Univ Children´s Hospital Heidelberg, Heidelberg, Germany
          [5 ]Hayward Genetics Ctr,SL#31, Tulane Univ Medical Health Ctr, New Orleans, Louisiana USA
          [6 ]Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
          Author notes

          Communicated by: Nicole Wolf, MD PhD

          PMC5413444 PMC5413444 5413444 581
          © SSIEM and Springer-Verlag Berlin Heidelberg 2016
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          © SSIEM and Springer-Verlag Berlin Heidelberg 2017


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