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.
The author “Renata Oliveira” is a former worker at the Medical Genetics Unit, Hospital Pediátrico, CHUC, Coimbra, Portugal.
The author “Joana Nunes” is a former worker at the Neuroradiology Department of CHUC, Coimbra, Portugal.
Authors “Paula Garcia” and “Robert W. Taylor” supervised this work, laboratory and clinical, respectively.
Renata Oliveira and Ewen Sommerville contributed equally to the manuscript.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Biancheri R, Lamantea E, Severino M et al (2015) Expanding the clinical and magnetic resonance spectrum of leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) in a patient harboring a novel EARS2 mutation. JIMD Rep 23:85–89
Calvo SE, Compton AG, Hershman SG et al (2012) Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med 118:118ra10
Dallabona C, Diodato D, Kevelam SH et al (2014) Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82(23):2063–2071
Danhauser K, Haack TB, Alhaddad B et al (2016) EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum. Metab Brain Dis 31(3):717–721
Diodato D, Ghezzi D, Tiranti V (2014) The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol 2014:787956
Edvardson S, Shaag A, Kolesnikova O et al (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81(4):857–862
Elo JM, Yadavalli SS, Euro L et al (2012) Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 21(20):4521–4529
Grazina MM (2012) Mitochondrial respiratory chain: biochemical analysis and criterion for deficiency in diagnosis. Methods Mol Biol 837:73–91
Güngör O, Özkaya AK, Şahin Y et al (2016) A compound heterozygous EARS2 mutation associated with mild leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). Brain Dev. pii: S0387-7604(16)30030-4
Kevelam SH, Klouwer FCC, Fock JM et al (2016) Absent thalami caused by a homozygous EARS2 mutation: expanding disease spectrum of LTBL. Neuropediatrics 47(1):64–67
Kohda M, Tokuzawa Y, Kishita Y et al (2016) A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet 12(1), e1005679
Lightowlers RN, Taylor RW, Turnbull DM (2015) Mutations causing mitochondrial disease: what is new and what challenges remain? Science 349(6255):1494–1499
Pronicka E, Piekutowska-Abramczuk D, Ciara E et al (2016) New perspective in diagnostics of mitochondrial disorders: two years’ experience with whole-exome sequencing at a national paediatric centre. J Transl Med 14(1):174
Şahin S, Cansu A, Kalay E et al (2016) Leukoencephalopathy with thalamus and brainstem involvement and high lactate caused by novel mutations in the EARS2 gene in two siblings. J Neurol Sci 365:54–58
Scheper GC, van der Klok T, van Andel RJ et al (2007) Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39(4):534–539
Steenweg ME, Ghezzi D, Haack T et al (2012) Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain 135(Pt 5):1387–1394
Talim B, Pyle A, Griffin H et al (2013) Multisystem fatal infantile disease caused by a novel homozygous EARS2 mutation. Brain 136:1–3
Taskin BD, Karalok ZS, Gurkas E et al (2016) Early-onset mild type leukoencephalopathy caused by a homozygous EARS2 mutation. J Child Neurol 31(7):1–4
Taylor RW, Pyle A, Griffin H et al (2014) Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 312(1):68–77
Acknowledgements
This study was partially financed by Fundação para a Ciência e a Tecnologia (FCT) project PEst-C/SAU/LA0001/2013–2014. RWT and PFC are funded by the Wellcome Trust Centre for Mitochondrial Research (096919/Z/11/Z) and the Medical Research Council (UK) Centre for Translational Muscle Disease (G0601943). RWT receives additional support from the Lily Foundation and the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service in Newcastle upon Tyne. PFC is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives additional support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Additional information
Communicated by: Nicole Wolf, MD PhD
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Table S1
Summary of the EARS2 patients with brain image published. COX – cytochrome c oxidase; DD – developmental delay; DN - dentate nucleus; FTT - failure to thrive; FU - follow up; GP - globus pallidus; MR - magnetic resonance; PVR - periventricular rim; RC – mitochondrial respiratory chain; RRF – ragged-red fibers; SDH – succinate dehydrogenase; WM - white matter; ‘+’ – present; ‘-’ – not present; ‘n.a.’ – not assessed; ‘n.d.’ – not determined (DOCX 36 kb)
Appendices
Take-Home Message (Synopsis)
This report reinforces the phenotypic spectrum of pathogenic EARS2 variants by reporting a severe clinical manifestation and highlights diagnostic methods to recognise biochemical and biological consequences of the genetic error.
Compliance with Ethics Guidelines
Conflict of Interest
Renata Oliveira, Ewen W. Sommerville, Kyle Thompson, Joana Nunes, Angela Pyle, Manuela Grazina, Patrick F. Chinnery, Luísa Diogo, Paula Garcia and Robert W. Taylor declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from the parents of the patient for being included in the study.
Authors’ Contributions
Renata Oliveira, Joana Nunes, Manuela Grazina, Luísa Diogo, Paula Garcia and Robert W. Taylor acquired the clinical data and performed genetic, biochemical and histochemical investigations. Ewen W. Sommerville, Angela Pyle and Patrick F. Chinnery generated and analysed WES data. Ewen W. Sommerville and Kyle Thompson undertook the western blot studies. Renata Oliveira, Ewen W. Sommerville and Robert W. Taylor drafted the manuscript; all authors contributed to critical revision of the manuscript.
Rights and permissions
Copyright information
© 2016 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Oliveira, R. et al. (2016). Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 33. JIMD Reports, vol 33. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_581
Download citation
DOI: https://doi.org/10.1007/8904_2016_581
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-55011-3
Online ISBN: 978-3-662-55012-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)