Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Status:  Open

Nitric Oxide Supplementation as a Therapeutic Intervention in Argininosuccinic Aciduria (ASA/ASL)

Status: Closed/Completed

Drs. Sandesh Nagamani and Brendan Lee will study whether a dietary supplement of nitric oxide (NO) will lessen or correct the effects of NO deficiency on the arteries of individuals with argininosuccinic aciduria (ASA/ASL). The goal of the study is to better understand the role of nitric oxide deficiency in ASA and determine whether NO supplementation is an effective treatment for patients with ASA.

Eligibiity requirements:

1) At least 8 years old with known diagnosis of ASA/ASL.

2) Travel to Baylor College of Medicine in Houston, Texas.

3) Maintain the diet and treatment plan prescribed while you are in the study.

All procedures (lab testing) and the NO supplement are provided at no cost to the participant. Travel and lodging are covered.


This project focuses on studying the efficacy of nitric oxide (NO) supplementation as a treatment for the long-term complications in argininosuccinic lyase deficiency (ASLD), the second most common urea cycle disorder and a human model of NO deficiency. We hope to translate our discovery of a structural requirement for argininosuccinate lyase (ASL) for metabolite channeling of arginine to an NO synthetic complex, into a novel therapy for this disorder which is effectively diagnosed by comprehensive newborn screening. The study of ASL’s function beyond ureagenesis was prompted by the complex natural history of some ASLD patients and observations by a number of Urea Cycle Disorders Consortium (UCDC) investigators. This included neurocognitive delay, hepatic disease, and systemic hypertension that were independent of recurrent hyperammonemia. ASL is the only mammalian enzyme that can synthesize L-arginine, the sole substrate for NO synthesis by nitric oxide synthase (NOS). By studying a novel hypomorphic and conditional mouse model of ASLD and human ASLD patients, we showed that a deficiency of ASL not only leads to decreased synthesis of intracellular L-arginine but also decreased utilization of extracellular L-arginine for NO synthesis. ASL serves distinct catalytic vs. structural functions that provide a structural model for understanding why ASLD patients defy the arginine paradox, i.e., they are unable to generate NO efficiently in spite of supplemental arginine therapy. NO is a ubiquitous signaling molecule with diverse roles in vascular biology, neurogenesis, and neuronal functioning and its dysregulation is implicated in pathogenesis of hypertension and memory deficits. ASLD mice treated with liver-directed gene therapy to correct the hepatic ureagenesis defect and mice with endothelium-specific loss of ASL demonstrate endothelial dysfunction and systemic hypertension that can only be corrected by NO supplementation.

In a proof-of-principle case study, we successfully treated an ASLD patient with long-standing hypertension refractory to multiple antihypertensive medications with NO supplementation. Interestingly, NO supplementation in this patient was also associated with improvement in neuropsychological parameters. These data imply that NO deficiency at the tissue level contributes to the complications of ASLD, and preventing hyperammonemia alone may not prevent long-term morbidity in ASLD. If successful, these studies have the potential to provide the first non-nitrogen-scavenging medication to reduce the morbidity inpatients with ASLD and potentially, other urea cycle disorders (UCD).


The Effect of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine Compared to High-Dose Arginine Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA)

Status:  UCD Consortium Study 5102, Closed, Study completed


In addition to its role in the urea cycle, argininosuccinate ASL is also essential for endogenous (produced within the body) synthesis of arginine. Patients affected by ASA deficiency can have liver involvement ranging from liver enlargement (hepatomegaly) with elevations of liver enzymes to severe liver fibrosis. The cause for the increased incidence of liver dysfunction in ASA is not known, but has been thought to be due to increased argininosuccinate upstream of the enzymatic block in the urea cycle, or decreased arginine downstream of that block. The standard of care for patients with ASA has historically included arginine supplementation that compensates for the decreased endogenous synthesis in addition to promoting the excretion of nitrogen as argininosuccinic acid.

The investigators hypothesized that if increased levels of argininosuccinic acid were the predominant cause for liver dysfunction, a high dose of therapeutic arginine (500mg/kg/day) would be associated with worsening of liver functions as compared to a low dose of arginine (100mg/kg/day) combined with sodium phenylbutyrate, which would result in lower levels of argininosuccinic acid levels. To evaluate the effects of these two treatments on liver function in patients with ASA, a randomized double-blind placebo controlled cross-over trial was carried out by Dr. Brendan Lee and his team at Baylor as part of the Urea Cycle Disease Consortium research. Eleven patients completed both arms of the trial and were included in the analysis.

As expected, patients had significantly increased levels of phenylacetylglutamine and phenylacetic acid while on low-dose arginine with sodium phenylbutyrate, and higher plasma arginine and citrulline levels while on high-dose arginine.  Ammonia control was comparable between the two arms of the trial. Patients had statistically significant increases in plasma ASA levels while on high-dose arginine. AST levels were increased in the high-dose arginine arm.  Patients with abnormal liver transaminases seemed to have the most increase in liver enzymes while on high-dose arginine. The function of the liver as assessed by PT, INR, Factors VII, IX and fibrinogen were comparable between the two arms of the study.

These results reveal that high dose arginine may lead to higher liver inflammation in patients with ASA, especially in patients with existing liver dysfunction. The results have therapeutic implications, as they suggest it may be optimal to treat ASA patients who have liver dysfunction with lower doses of arginine combined with nitrogen scavenging therapy with sodium phenylbutyrate.

From left: Brendan Lee, MD, PhD, Oleg Shchelochkov, MD, Sandesh Sreenath Nagamani, MD


Brendan Lee, M.D., Ph.D., at Baylor College of Medicine in Houston, Texas, conducted a research study to determine the effectiveness of Sodium Phenylbutyrate (Buphenyl™) and low–dose arginine vs. high-dose arginine in patients diagnosed with argininosuccinic aciduria (ASA).


A Randomized Controlled Trial to Evaluate the Effects of High-Dose Versus Low-Dose of Arginine Therapy on Hepatic Function Tests in Argininosuccinic Aciduria
Nagamani SC, Shchelochkov OA, Mullins MA, Carter S, Lanpher BC, Sun Q, Kleppe S, Erez A, O'Brian Smith E, Marini JC; Members of the Urea Cycle Disorders Consortium, Lee B. Mol Genet Metab. 2012 Nov;107(3):315-21. Epub 2012 Sep 17. PMID: 23040521

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