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Neonatal lactic acidosis explained by LARS2 defect

Pediatric Research (2022)Cite this article

Back in the year 2009, we presented in this journal a neonate with an unusual combination of congenital lactic acidosis and bilateral calcifications in the adrenal medulla1. After prenatal ultrasound examination at 21 weeks had revealed intrauterine growth retardation and pericardial effusions, labor was induced at 38 weeks of pregnancy. The patient was hypotonic at birth, had respiratory insufficiency necessitating intubation and artificial ventilation, hepatomegaly and severe cardiomegaly. Intensive care was withdrawn in accordance with parents’ wishes on day 38. At the time, the patient’s causal genetic defect had remained unknown, yet clinical and biochemical evidence ticked all the boxes of an underlying mitochondrial defect. Postmortem spectrophotometric evaluation then revealed decreased oxidative phosphorylation activities in heart muscle (complex IV) and liver (complexes I, III, IV and V), and normal activities in skeletal muscle and cultured skin fibroblasts. Blue-native polyacrylamide gel electrophoresis of liver extracts confirmed decreased activities of complexes III and IV and showed the presence of subcomplexes of complex V. Thanks to the great genetic leap forward taken by medical research ever since, we were now able to thoroughly investigate the patient’s whole exome extracted from preserved cultured skin fibroblasts. These investigations picked up compound heterozygous missense variants in the gene encoding the mitochondrial leucyl-tRNA synthetase (LARS2): c.302 A > G (p.His101Arg) and c.516 G > T (p.Arg172Ser). Nuclear-encoded mitochondrion-specific aminoacyl-tRNA synthetases exist for 17 of the 20 proteogenic amino acids, and pathogenic mutations have now been reported for each one of these2. At the time we published our casus, LARS2 defects had not been reported, yet between the year 2013 and now, a total of 23 patients have been described that carry disease-causing LARS2 variants (Table 1)1,3,4,5,6,7,8,9,10,11,12,13. Their diverse associated disease phenotypes, which include Perrault syndrome, multisystem disease, leukodystrophy and intellectual disability, do not appear to have an obvious link with genotype. With the casus we presented in this journal and now have characterized at the molecular level, more than twenty patients with 18 unique combinations of disease-causing LARS2 variants have been reported so far, only one was homozygous the others concerned compound heterozygous variants.

Table 1 Published patients carrying disease-causing LARS2 variants.
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Authors and Affiliations

  1. Department of Child Neurology & Metabolism, Ghent University, Ghent, Belgium

    Boel De Paepe, Joél Smet, Rudy Van Coster & Arnaud Vanlander

  2. Institute of Human Genetics, School of Medicine, Technische Universität München, 81675, Munich, Germany

    Robert Kopajtich

  3. Institute of Neurogenomics, Helmholtz Zentrum München, 85764, Neuherberg, Germany

    Holger Prokisch

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  1. Boel De Paepe
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  2. Joél Smet
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  4. Holger Prokisch
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  5. Rudy Van Coster
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  6. Arnaud Vanlander
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Contributions

Conceptualization and data curation: B.D.P., J.S., R.K. and A.V.; formal analysis and methodology: A.V., R.V.C. and H.P.; project administration, resources and supervision: R.V.C. and A.V.; manuscript draft preparation: B.D.P.; review, editing and approval of the final version: all authors.

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Correspondence to Boel De Paepe.

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R.V.C. and A.V. are members of the European Reference Network for Hereditary Metabolic Disorders, MetabERN. The remaining authors declare no competing interests.

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De Paepe, B., Smet, J., Kopajtich, R. et al. Neonatal lactic acidosis explained by LARS2 defect. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02169-7

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