Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment

Mol Genet Metab. 2017 Mar;120(3):207-212. doi: 10.1016/j.ymgme.2016.12.011. Epub 2016 Dec 24.


Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid β-oxidation cycle between 22 citrin-deficient children (age, 3-13years) with normal liver functions and 37 healthy controls (age, 5-13years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p<0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p<0.001). The plasma level of 3-OH-butyrate derived from fatty acid β-oxidation was significantly higher in the affected group (p<0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p<0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.

Keywords: Adaptation period; Adult-onset type II citrullinemia; Citrin deficiency; Free fatty acid β oxidation; Sodium pyruvate therapy; Tricarboxylic acid cycle.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Citric Acid / blood
  • Citric Acid Cycle* / drug effects
  • Citrullinemia / drug therapy*
  • Citrullinemia / metabolism*
  • Fatty Acids / metabolism*
  • Female
  • Fumarates / blood
  • Humans
  • Ketoglutaric Acids / blood
  • Malates / blood
  • Male
  • Oxidative Stress / drug effects
  • Pyruvates / administration & dosage*
  • Pyruvates / pharmacology
  • Treatment Outcome


  • Fatty Acids
  • Fumarates
  • Ketoglutaric Acids
  • Malates
  • Pyruvates
  • Citric Acid
  • malic acid

Supplementary concepts

  • Adult-onset citrullinemia type 2