Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism.

Abstract

Urea cycle disorders (UCD) are human conditions caused by the dysregulation of nitrogen transfer from ammonia nitrogen into urea. The biochemistry and the genetics of these disorders were well elucidated. Earlier diagnosis and improved treatments led to an emerging, longer-lived cohort of patients. The natural history of some of these disorders began to point to pathophysiological processes that may be unrelated to the primary cause of acute morbidity and mortality, i.e., hyperammonemia. Carbamyl phosphate synthetase I single nucleotide polymorphisms may be associated with altered vascular resistance that becomes clinically relevant when specific environmental stressors are present. Patients with argininosuccinic aciduria due to a deficiency of argininosuccinic acid lyase are uniquely prone to chronic hepatitis, potentially leading to cirrhosis. Moreover, our recent observations suggest that there may be an increased prevalence of essential hypertension. In contrast, hyperargininemia found in patients with arginase 1 deficiency is associated with pyramidal tract findings and spasticity, without significant hyperammonemia. An intriguing potential pathophysiological link is the dysregulation of intracellular arginine availability and its potential effect on nitric oxide (NO) metabolism. By combining detailed natural history studies with the development of tissue-specific null mouse models for urea cycle enzymes and measurement of nitrogen flux through the cycle to urea and NO in UCD patients, we may begin to dissect the contribution of different sources of arginine to NO production and the consequences on both rare genetic and common multifactorial diseases.

• Authors: Fernando Scaglia, Nicola Brunetti-Pierri, Soledad Kleppe, Juan Marini, Susan Carter, Peter Garlick, Farook Jahoor, William O'Brien, Brendan Lee
• Journal: The Journal of nutrition (J Nutr) Vol. 134 Issue 10 Suppl Pg. 2775S-2782S; discussion 2796S-2797S (10 2004) ISSN: 0022-3166 [Print] United States
• PMID: 15465784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Enzymes
• Isoenzymes
• Nitric Oxide
• Urea
• Arginine

Topics

• Animals
• Arginine (metabolism)
• Argininosuccinic Aciduria
• Carbamoyl-Phosphate Synthase I Deficiency Disease (metabolism)
• Enzymes (deficiency, metabolism)
• Humans
• Hyperargininemia
• Isoenzymes (deficiency)
• Metabolism, Inborn Errors (metabolism)
• Nitric Oxide (metabolism)
• Urea (metabolism)