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Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis

Journal of Human Genetics volume 65, pages 91–98 (2020)Cite this article

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Abstract

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.

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Acknowledgements

Institutional grants of INSERM UMR_S 1256 were received from INSERM (French National Institute of Health and Medical Research) and the Region of Lorraine (France). MRB is supported by the Swiss National Science Foundation (SNSF 31003A_138521) and the Rare Disease Initiative Zurich (radiz), a clinical research priority program for rare diseases of the University of Zurich, Switzerland.

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Authors and Affiliations

  1. INSERM UMR_S 1256, NGERE—Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France

    Arnaud Wiedemann, Céline Chery, David Coelho, Justine Flayac, François Feillet, Jean-Louis Guéant & Abderrahim Oussalah

  2. Department of Biochemistry and Genetics, UMR CNRS 6214—INSERM 1083, University Hospital Centre, Angers, France

    Naïg Gueguen, Valérie Desquiret-Dumas & Pascal Reynier

  3. Department of Internal Medicine and Vascular Medicine, University Hospital Centre, Angers, France

    Christian Lavigne

  4. Department of Neurology, University Hospital Centre, Poitiers, France

    Jean-Philippe Neau

  5. Division of Metabolism and Children’s Research Centre, University Children’s Hospital, Zürich, Switzerland

    Brian Fowler & Matthias R. Baumgartner

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  1. Arnaud Wiedemann
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Correspondence to Jean-Louis Guéant or Abderrahim Oussalah.

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Wiedemann, A., Chery, C., Coelho, D. et al. Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis. J Hum Genet 65, 91–98 (2020). https://doi.org/10.1038/s10038-019-0689-y

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