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United States Department of Agriculture

Agricultural Research Service


item Scaglia, Fernando
item Brunetti-pierri, Nicola
item Kleppe, Soledad
item Marini, Juan
item Carter, Susan
item Garlick, Peter
item Jahoor, Farook
item O'brien, William
item Lee, Brendan

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2004
Publication Date: 10/1/2004
Citation: Scaglia, F., Brunetti-Pierri, N., Kleppe, S., Marini, J., Carter, S., Garlick, P., Jahoor, F., O'Brien, W., Lee, B. 2004. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. Journal of Nutrition. 134:2775S-2782S.

Interpretive Summary: The primary function of the urea cycle is to convert toxic ammonia released from amino acid metabolism into harmless urea for excretion in the urine. In inherited disorders of the urea cycle, this conversion is impaired, leading to high levels of blood ammonia which can cause severe illness and even death. As patients have started living longer now because of improved treatments, it has become clear that not all of the illnesses are due to high levels of ammonia. Some patients are prone to develop hepatitis, potentially leading to cirrhosis of the liver, while others develop hypertension. It is possible that the hypertension is caused by decreased synthesis of nitric oxide (NO), a potent vasodilator that is synthesized from arginine. Arginine is synthesized in the urea cycle, hence impairment of the urea cycle can affect its availability for NO synthesis. We plan to conduct studies in patients with disorders of the urea cycle and in mouse models of urea cycle disorders to investigate the contribution of different sources of arginine to NO production.

Technical 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.

Last Modified: 06/23/2017
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