Elevated concentrations of endogenous NO-synthase-antagonist ADMA in patients with citrullinemia

Introduction: Argininosuccinate-synthase-deficiency in citrullinemia results in an elevation of ammonia and citrulline in plasma. Ammonia-values alone do not correlate with the neurologic outcome of those patients (Lücke et al., Akt. Neuropäd. 2002); citrulline concentrations may be important as well. The precise mechanism of neurological damage is unclear. ADMA (asymmetric-D-methyl-arginine) is an endogenous antagonist of NOS (nitric oxide-synthase). The endothelial synthetised ADMA is predominantly degraded by a hydrolase. This hydrolase and the NOS are inhibited by citrulline. An elevation of citrulline during metabolic crisis may reduce the NO-induced vascular dilatation resulting in ischemia and cerebral dysfunction; increased lactate concentrations during metabolic crises seem to support this hypothesis.

Methods: We determined the ADMA-concentrations in plasma of non-catabolic patients with citrullinemia and healthy children of the same age using a GC/MS-method.

Results: Compared to healthy controls (n=5, mean=865nM, SD=113) ADMA concentrations were significantly (p<0.025) increased in patients with citrullinemia (n=4, mean=1178nM, SD 209).

Conclusion: We suspect, that an increase of citrulline concentration during a metabolic crisis will result in an even more pronounced down-regulation of NO-metabolism – a mechanism that in part might explain the crisis-induced neurologic damage in citrullinemia.

Keywords: citrullinemia, NO, ADMA