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Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival

European Journal of Human Genetics volume 29, pages 533–538 (2021)Cite this article

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Abstract

Mitochondrial translation is essential for the biogenesis of the mitochondrial oxidative phosphorylation system (OXPHOS) that synthesizes the bulk of ATP for the cell. Hypomorphic and loss-of-function variants in either mitochondrial DNA or in nuclear genes that encode mitochondrial translation factors can result in impaired OXPHOS biogenesis and mitochondrial diseases with variable clinical presentations. Compound heterozygous or homozygous missense and frameshift variants in the FARS2 gene, that encodes the mitochondrial phenylalanyl-tRNA synthetase, are commonly linked to either early-onset epileptic mitochondrial encephalopathy or spastic paraplegia. Here, we expand the genetic spectrum of FARS2-linked disease with three patients carrying novel compound heterozygous variants in the FARS2 gene and presenting with spastic tetraparesis, axial hypotonia and myoclonic epilepsy in two cases.

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Fig. 1: Family pedigrees, neuroimaging findings in patients carrying FARS2 variants and evolutionary conservation of the amino acids affected by these variants.
Fig. 2: Decreased abundance of mtPheRS protein and an impaired mitochondrial translation in patient fibroblasts expressing different FARS2 variants.

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Acknowledgements

We thank the patients and their families for participating in this study.

Funding

Grant Numbers: AFM-TELETHON, nr. 19876, nr. 22529, nr. 22251; ANR, GENOMIT ANR-15-RAR3-0012-07.

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Authors and Affiliations

  1. Department of Genetics, Necker Enfants Malades Hospital, Paris Descartes-Sorbonne Paris Cité University, Paris, France

    Giulia Barcia, Marlène Rio, Zahra Assouline, Julie Steffann, Arnold Munnich & Jean-Paul Bonnefont

  2. French Reference Center for Mitochondrial Diseases (CARAMMEL), Paris, France

    Giulia Barcia, Zahra Assouline, Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont & Agnès Rötig

  3. Laboratory for Genetics of Mitochondrial Disorders, UMR U1163, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France

    Coralie Zangarelli, Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont, Agnès Rötig, Metodi D. Metodiev & Benedetta Ruzzenente

  4. Department of Pediatric Radiology, INSERM UMR 1163, INSERM U1000, Necker Enfants Malades Hospital, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France

    Charles-Joris Roux & Nathalie Boddaert

  5. Reference Center for Inherited Metabolic Diseases, Necker Enfants Malades Hospital, Imagine Institute, Paris Descartes University, INEM-1151, G2M, MetabERN, Paris, France

    Pascale de Lonlay

  6. Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France

    Isabelle Desguerre

Authors
  1. Giulia Barcia
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  2. Marlène Rio
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  3. Zahra Assouline
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  4. Coralie Zangarelli
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  5. Charles-Joris Roux
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  6. Pascale de Lonlay
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  8. Isabelle Desguerre
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  9. Arnold Munnich
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  10. Jean-Paul Bonnefont
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  11. Nathalie Boddaert
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  13. Metodi D. Metodiev
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  14. Benedetta Ruzzenente
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Correspondence to Benedetta Ruzzenente.

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Barcia, G., Rio, M., Assouline, Z. et al. Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival. Eur J Hum Genet 29, 533–538 (2021). https://doi.org/10.1038/s41431-020-00757-x

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