European Journal of Pediatrics

, Volume 173, Issue 2, pp 243–245 | Cite as

Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency

  • Ruby Haviv
  • Avraham Zeharia
  • Corinne Belaiche
  • Yishai Haimi Cohen
  • Ann Saada
Short Communication


The E3 subunit of the pyruvate dehydrogenase complex (dihydrolipoamide dehydrogenase/dihydrolipoyl dehydrogenase/DLD/lipoamide dehydrogenase/LAD), is a mitochondrial matrix enzyme and also a part of the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes. DLD deficiency (MIM #246900), is relatively frequent in the Ashkenazi Jewish population but occurs in other populations as well. Early diagnosis is important to prevent episodes of metabolic decompensation, liver failure, and encephalopathy. The clinical presentations are varied and may include Reye-like syndrome, hepatic failure, myopathy, and myoglobinuria. Laboratory markers, such as elevated urinary alpha-ketoglutarate, blood pyruvate, lactate, and ammonia, are mostly nonspecific and not always present, making the diagnosis difficult. Since we observed elevated plasma citrulline levels in a number of confirmed cases, we retrospectively examined the value of citrulline as a biochemical marker for DLD deficiency. Data was gathered from the files of 17 pediatric patients with DLD deficiency, confirmed by enzymatic and genetic analysis. The control group included 19 patients in whom urea cycle defects were ruled out but DLD deficiency was suspected. Seven of the DLD-deficient patients presented with elevated plasma citrulline levels (median value 205 μM, range 59–282 μM) (normal range 1–45 μM) while none in the control patient group. In five patients, elevated citrulline was associated with elevated plasma glutamine and metabolic acidosis. Interestingly, elevated plasma citrulline was associated with the common G229C mutation. In conclusion, we suggest that elevated plasma citrulline in the absence of urea cycle defects warrants an investigation for DLD deficiency.


Citrulline Dihydrolipoamide dehydrogenase deficiency Lipoamide dehydrogenase Pyruvate dehydrogenase 



Dihydrolipoamide dehydrogenase


Pyruvate dehydrogenase complex


Ketoglutatate dehydrogenase complex


Branched-chain keto acid dehydrogenase complex


Citrate synthase


Oxidative phosphorylation


Conflict of interest

The authors received no financial support for this study


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ruby Haviv
    • 1
    • 2
  • Avraham Zeharia
    • 2
  • Corinne Belaiche
    • 1
  • Yishai Haimi Cohen
    • 2
  • Ann Saada
    • 1
    • 3
  1. 1.Monique and Jacques Roboh Department of Genetic ResearchHadassah, Hebrew University Medical CenterJerusalemIsrael
  2. 2.Day Hospitalization Unit, Schneider Children’s Medical Center of Israel, Sackler School of MedicineTel-Aviv UniversityPetach TikvaIsrael
  3. 3.Department of Genetics and Metabolic Diseases, HadassahHebrew University Medical CenterJerusalemIsrael

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