Sandra Pereira1, Mariana Adrião2, Mafalda Sampaio2,3, Margarida Ayres Basto4, Esmeralda Rodrigues2,5, Laura Vilarinho6, Elisa Leão Teles2,5, Isabel Alonso7,8, Miguel Leão9,10. 1. Department of Pediatrics, Centro Hospitalar São João (CHSJ), Porto, Portugal. sandravdpereira@gmail.com. 2. Department of Pediatrics, Centro Hospitalar São João (CHSJ), Porto, Portugal. 3. Neuropediatric Unit, Department of Pediatrics, CHSJ, Porto, Portugal. 4. Department of Neuroradiology, CHSJ, Porto, Portugal. 5. Metabolic Diseases Unit, Department of Pediatrics, CHSJ, Porto, Portugal. 6. Newborn Screening, Metabolism and Genetics Unit, Human Genetics Department, National Institute of Health Dr. Ricardo Jorge, Porto, Portugal. 7. UnIGENe and Centre for Predictive and Preventive Genetics (CGPP), Institute of Molecular and Cellular Biology (IBMC), University of Porto, Porto, Portugal. 8. Institute of Research and Innovation in Health, University of Porto, Porto, Portugal. 9. Neurogenetics Unit, Department of Medical Genetics, SJHC, Porto, Portugal. 10. Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.
Abstract
INTRODUCTION: Combined oxidative phosphorylation deficiency 20 (COXPD20) is a mitochondrial respiratory chain complex (RC) disorder, caused by disease-causing variants in the VARS2 gene, which encodes a mitochondrial aminoacyl-tRNA synthetase. Here we describe a patient with fatal mitochondrial encephalopathy caused by a homozygous VARS2 gene missense variant. CASE REPORT: We report the case of a girl, the first child of non-consanguineous and healthy parents, born from an uneventful term pregnancy, who presented, in the neonatal period, major hypotonia and microcephaly. At 4 months of age she showed poor eye contact, nystagmus, global psychomotor development delay and failure to thrive, without dysmorphic features. Focal seizures started at 24 months which evolved to a severe epileptic encephalopathy and finally to super refractory status epilepticus, leading to her death at 28 months of age. Etiologic investigation encompassing metabolic and genetic causes failed to disclose a diagnosis. Post-mortem exome sequencing allowed the identification of a pathogenic variant in VARS2 gene in the homozygous state (c.1100C > T, p.Thr367Ile) in the patient, inherited from her heterozygous parents, leading to the diagnosis of COXPD2. CONCLUSION: To the best of our knowledge, this is the fifth case described in the literature of a child with disease-causing variant in VARS2. With this report we expand the knowledge about the phenotype associated with this very rare mitochondrial defect, further emphasizing the use of exome sequencing as a very powerful diagnostic tool.
INTRODUCTION: Combined oxidative phosphorylation deficiency 20 (COXPD20) is a mitochondrial respiratory chain complex (RC) disorder, caused by disease-causing variants in the VARS2 gene, which encodes a mitochondrial aminoacyl-tRNA synthetase. Here we describe a patient with fatal mitochondrial encephalopathy caused by a homozygous VARS2 gene missense variant. CASE REPORT: We report the case of a girl, the first child of non-consanguineous and healthy parents, born from an uneventful term pregnancy, who presented, in the neonatal period, major hypotonia and microcephaly. At 4 months of age she showed poor eye contact, nystagmus, global psychomotor development delay and failure to thrive, without dysmorphic features. Focal seizures started at 24 months which evolved to a severe epilepticencephalopathy and finally to super refractory status epilepticus, leading to her death at 28 months of age. Etiologic investigation encompassing metabolic and genetic causes failed to disclose a diagnosis. Post-mortem exome sequencing allowed the identification of a pathogenic variant in VARS2 gene in the homozygous state (c.1100C > T, p.Thr367Ile) in the patient, inherited from her heterozygous parents, leading to the diagnosis of COXPD2. CONCLUSION: To the best of our knowledge, this is the fifth case described in the literature of a child with disease-causing variant in VARS2. With this report we expand the knowledge about the phenotype associated with this very rare mitochondrial defect, further emphasizing the use of exome sequencing as a very powerful diagnostic tool.
Authors: Saskia B Wortmann; David A Koolen; Jan A Smeitink; Lambert van den Heuvel; Richard J Rodenburg Journal: J Inherit Metab Dis Date: 2015-03-04 Impact factor: 4.982
Authors: Robert W Taylor; Angela Pyle; Helen Griffin; Emma L Blakely; Jennifer Duff; Langping He; Tania Smertenko; Charlotte L Alston; Vivienne C Neeve; Andrew Best; John W Yarham; Janbernd Kirschner; Ulrike Schara; Beril Talim; Haluk Topaloglu; Ivo Baric; Elke Holinski-Feder; Angela Abicht; Birgit Czermin; Stephanie Kleinle; Andrew A M Morris; Grace Vassallo; Grainne S Gorman; Venkateswaran Ramesh; Douglass M Turnbull; Mauro Santibanez-Koref; Robert McFarland; Rita Horvath; Patrick F Chinnery Journal: JAMA Date: 2014-07-02 Impact factor: 56.272
Authors: Daria Diodato; Laura Melchionda; Tobias B Haack; Cristina Dallabona; Enrico Baruffini; Claudia Donnini; Tiziana Granata; Francesca Ragona; Paolo Balestri; Maria Margollicci; Eleonora Lamantea; Alessia Nasca; Christopher A Powell; Michal Minczuk; Tim M Strom; Thomas Meitinger; Holger Prokisch; Costanza Lamperti; Massimo Zeviani; Daniele Ghezzi Journal: Hum Mutat Date: 2014-06-24 Impact factor: 4.878
Authors: Elham Kayvanpour; Michael Wisdom; Maximilian K Lackner; Farbod Sedaghat-Hamedani; Jes-Niels Boeckel; Marion Müller; Rose Eghbalian; Jan Dudek; Shirin Doroudgar; Christoph Maack; Norbert Frey; Benjamin Meder Journal: Int J Mol Sci Date: 2022-06-30 Impact factor: 6.208