title: Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features.
abstract: 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.
authors: Human Genetics Department, Centro Hospitalar de São João, Alameda Prof. Hernâni Monteiro, 4200, Porto, Portugal. renata.oliveira@chsj.min-saude.pt.
authors: Renata
authors: R
authors: Oliveira
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Ewen W
authors: EW
authors: Sommerville
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Kyle
authors: K
authors: Thompson
authors: Imaging Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.
authors: Joana
authors: J
authors: Nunes
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors: Angela
authors: A
authors: Pyle
authors: CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors: Manuela
authors: M
authors: Grazina
authors: Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.|MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK.
authors: Patrick F
authors: PF
authors: Chinnery
authors: Metabolic Unit - Child Development Center, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
authors: Luísa
authors: L
authors: Diogo
authors: Metabolic Unit - Child Development Center, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.
authors: Paula
authors: P
authors: Garcia
authors: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Robert.taylor@ncl.ac.uk.
authors: Robert W
authors: RW
authors: Taylor
keywords: EARS2; Early onset mitochondrial disease; LTBL; Mitochondrial translation defects