Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency

PLoS One. 2017 May 2;12(5):e0176363. doi: 10.1371/journal.pone.0176363. eCollection 2017.


Mitochondrial respiratory chain dysfunction has been identified in a number of neurodegenerative disorders. Infantile cerebellar-retinal degeneration associated with mutations in the mitochondrial aconitase 2 gene (ACO2) has been recently described as a neurodegenerative disease of autosomal recessive inheritance. To date there is no biomarker for ACO2 deficiency and diagnosis relies on genetic analysis. Here we report global metabolic profiling in eight patients with ACO2 deficiency. Using an LC-MS-based metabolomics platform we have identified several metabolites with affected plasma concentrations including the tricarboxylic acid cycle metabolites cis-aconitate, isocitrate and alpha-ketoglutarate, as well as phosphoenolpyruvate and hydroxybutyrate. Taken together we report a diagnostic metabolic fingerprint for mitochondrial aconitase 2 deficiency.

MeSH terms

  • Aconitate Hydratase / deficiency*
  • Aconitate Hydratase / genetics
  • Aconitic Acid / blood
  • Adolescent
  • Biomarkers / blood
  • Child
  • Child, Preschool
  • Female
  • Heredodegenerative Disorders, Nervous System / blood
  • Heredodegenerative Disorders, Nervous System / diagnosis
  • Humans
  • Hydroxybutyrates / blood
  • Isocitrates / blood
  • Ketoglutaric Acids / blood
  • Male
  • Metabolomics / methods
  • Phosphoenolpyruvate / blood


  • Biomarkers
  • Hydroxybutyrates
  • Isocitrates
  • Ketoglutaric Acids
  • Phosphoenolpyruvate
  • Aconitic Acid
  • isocitric acid
  • ACO2 protein, human
  • Aconitate Hydratase

Grant support

TLS received financial support from Novartis Stiftung für Medizinisch-Biologische Forschung Nr. 15A039 to support this research. The awarded funds went into a general account for consumables and were not used for salaries or personnel costs. The salaries of LMC and SMP are funded through the Clinical Research Priority Program (CRPP) radiz - Rare Disease Initiative Zurich