Metabolomics analysis reveals dysregulation in one carbon metabolism in Friedreich Ataxia

Mol Genet Metab. 2022 Aug;136(4):306-314. doi: 10.1016/j.ymgme.2022.06.002. Epub 2022 Jun 13.


Friedreich Ataxia (FA) is a rare and often fatal autosomal recessive disease in which a mitochondrial protein, frataxin (FXN), is severely reduced in all tissues. With loss of FXN, mitochondrial metabolism is severely disrupted. Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion. We predicted this dysregulated metabolism would present a unique metabolite profile in blood of FA patients versus Controls (Con). Plasma from 10 FA and 11 age and sex matched Con subjects was analyzed by targeted mass spectrometry and untargeted NMR. This combined approach yielded quantitative measurements for 540 metabolites and found 59 unique metabolites (55 from MS and 4 from NMR) that were significantly different between cohorts. Correlation-based network analysis revealed several clusters of pathway related metabolites including a cluster associated with one‑carbon (1C) metabolism composed of formate, sarcosine, hypoxanthine, and homocysteine. Receiver operator characteristics analyses demonstrated an excellent ability to discriminate between Con and FA with AUC values >0.95. These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.

Keywords: Biomarkers; Friedreich Ataxia; Metabolomics; One‑carbon metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / metabolism
  • Carbon / metabolism
  • Carbon / therapeutic use
  • Friedreich Ataxia* / drug therapy
  • Friedreich Ataxia* / metabolism
  • Humans
  • Metabolomics
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism


  • Biomarkers
  • Mitochondrial Proteins
  • Carbon