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United States Department of Agriculture

Agricultural Research Service


Location: Children's Nutrition Research Center

Title: Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria

item Nagamani, Sandesh C.s.
item Campeau, Phillippe
item Shchelochkov, Oleg
item Premkumar, Muralidhar
item Guse, Killian
item Brunetti-pierri, Nicola
item Chen, Yuqing
item Sun, Qin
item Tang, Yaoping
item Palmer, Donna
item Reddy, Anilkumar
item Li, Li
item Slesnick, Timothy
item Feig, Daniel
item Caudle, Susan
item Harrison, David
item Salviati, Leonardo
item Marini, Juan
item Bryan, Nathan
item Erez, Ayelet
item Lee, Brendan

Submitted to: The American Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/19/2012
Publication Date: 5/4/2012
Citation: Nagamani, S., Campeau, P.M., Shchelochkov, O.A., Premkumar, M.H., Guse, K., Brunetti-Pierri, N., Chen, Y., Sun, Q., Tang, Y., Palmer, D., Reddy, A.K., Li, L., Slesnick, T.C., Feig, D.I., Caudle, S., Harrison, D., Salviati, L., Marini, J.C., Bryan, N.S., Erez, A., Lee, B. 2012. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. The American Journal of Human Genetics. 90(5):836-846.

Interpretive Summary: The urea cycle is the main pathway for the detoxification of ammonia generated from the catabolism of protein. In this report we have shown that in urea cycle disorder subjects not only urea production is compromised, but also the production of nitric oxide, a messenger molecule involved in many physiological processes. The nitric oxide deficiency results in hypertension and neurocognitive deficit. This can be overcome by the administration of a nitric oxide donor. The significance of this research is that urea cycle patients can benefit from nitric oxide donor administration to reduce blood pressure and improve neurocognitive ability.

Technical Abstract: Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.

Last Modified: 06/27/2017
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