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.
Communicated by: Daniela Karall
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Combined oxidative phosphorylation deficiency 20 (COXPD20) is a very rare mitochondrial respiratory chain complex disorder, caused by disease-causing variants in the VARS2 gene. Our report extends the phenotypical spectrum of VARS2-related disorders and emphasizes Exome Sequencing ability to identify variants in nuclear gene in patients with suspected mitochondrial disease.
Contributions of Individual Authors
Sandra Pereira: analysis of clinical data and drafting the article.
Mariana Adrião: analysis of clinical data and drafting the article.
Margarida Ayres Basto: acquisition and interpretation of radiological data.
Mafalda Sampaio: analysis of clinical data and critical revision of the article.
Esmeralda Rodrigues: analysis of metabolic data and critical revision of the article.
Laura Vilarinho: acquisition, analysis, and interpretation of metabolic data and critical revision of the article.
Elisa Leão Teles: analysis of metabolic data and critical revision of the article.
Isabel Alonso: acquisition, analysis, and interpretation of genetic data and critical revision of the article.
Miguel Leão: final review and approval of the version to be published.
Conflict of Interest
Sandra Pereira, Mariana Adrião, Margarida Ayres, Mafalda Sampaio, Esmeralda Rodrigues, Laura Vilarinho, Elisa Leão Teles, Isabel Alonso, and Miguel Leão declare that they have no conflict of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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© 2018 Society for the Study of Inborn Errors of Metabolism (SSIEM)
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Pereira, S. et al. (2018). Mitochondrial Encephalopathy: First Portuguese Report of a VARS2 Causative Variant. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 42. JIMD Reports, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_89
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DOI: https://doi.org/10.1007/8904_2018_89
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