Nitric-Oxide Supplementation for Treatment of Long-Term Complications in Argininosuccinic Aciduria

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.

Argininosuccinic aciduria: from a monogenic to a complex disorder

“…ASL and ASS1 are key players in the citrulline-NO cycle, in which citrulline is regenerated from arginine for the synthesis of NO. Using stable-isotope labeling of the guanidino group of arginine, we were able to show that subjects with ASA had decreased fractional transfer of the guanidino nitrogen from 15 N 2 -arginine to 15 N-citrulline, reflecting decreased NO production. This was despite the fact that subjects with ASA had higher arginine flux and higher plasma concentrations of arginine as compared with the controls.…”

“…14 Corroborating these human studies, liver-targeted gene therapy with Asl in mice with ASA resulted in correction of the hyperammonemia and survival, but these mice still demonstrated reduced fractional transfer of guanidino nitrogen from 15 N 2 -arginine to 15 N-citrulline, indicating decreased systemic NO production. Furthermore, NO production in the aortic vessels of these mice was impaired, elucidating the occurrence of hypertension.…”

“…[31][32][33] Mice with ASA indeed show elevation of free radicals in the vessels as well as in plasma and urine. 14,15 Increased free radical production could add to the tissue damage, contributing to the vessels and liver injury. 34 In addition, in the context of ASA, it may be particularly damaging because argininosuccinate could be converted to guanidinosuccinic acid, a known cellular and neuronal toxin.…”

“…[17][18][19] Supporting this notion, hepatic disease and hypertension have been reported in patients with ASA who have good metabolic control. 13,15,[20][21][22] These data suggest that the complex phenotype observed in ASA involves mechanisms beyond the blockade in ureagenesis and that ASA could serve as an example of a complex IEM in which disease phenotype extends beyond the loss of the enzymatic function of ASL. The current therapeutic modalities used in the chronic treatment of ASA are dietary restriction and arginine supplementation, which are primarily geared toward the prevention of hyperammonemia.…”

“…However, despite fewer hyperammonemic episodes, studies have demonstrated that subjects with ASA have a greater risk for poor neurocognitive outcome, 10 hypertension, and liver disease. [11][12][13][14][15][16] Even subjects with milder forms of ASA who are diagnosed early in life by newborn screens can develop neurocognitive deficiencies, attention deficit/hyperactivity disorder, developmental disability, and seizures despite early treatment intervention. [17][18][19] Supporting this notion, hepatic disease and hypertension have been reported in patients with ASA who have good metabolic control.…”