Medical Care
Immediate temporary withdrawal of protein is indicated in all patients with newly discovered hyperammonemia. Increase nonprotein caloric sources to avoid catabolism of muscle protein for energy.
Intravenous benzoate, arginine, and phenylacetate administration may be indicated as initial therapy for hyperammonemia, but such combined therapy is appropriate only prior to specific diagnosis. Hemodialysis, if available, reduces the blood ammonia levels more efficiently and quickly.
Long-term therapy should involve a low-protein diet and arginine supplementation. This diet helps produce equivalent quantities of ornithine for enhancement of urea cycle activity up to the point of argininosuccinate (ASA) lyase and, thus, enhances waste nitrogen incorporation. Inclusion of arginine in the regimen helps to offset the inability of deficient tissues to generate free arginine from ASA.
Glycerol phenylbutyrate is a pre-prodrug that undergoes metabolism to form phenylacetate. Results of a phase 3 study comparing ammonia control in adults showed glycerol phenylbutyrate was noninferior to sodium phenylbutyrate. [11] In a separate study involving young children ages 2 months through 5 years, glycerol phenylbutyrate resulted in a more evenly distributed urinary output of PAGN over 24 hours and accounted for fewer symptoms from accumulation of phenylacetate. [12]
Surgical Care
For several years, liver transplantation has been the accepted form of surgical treatment for urea cycle disorders. However, many patients have delayed development, physical debilitation, or both, disqualifying them from the procedure or greatly increasing the associated risks.
Donor cell engraftment has been reported to be an effective technique of reducing the acuity of the disease in patients with neonatal-onset ASA lyase deficiency. This modality may offer a safer approach to surgical treatment of urea cycle disorders in general and may reduce the need for patients to qualify for a place on a transplantation roster.
Consultations
See the list below:
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Medical geneticist
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Metabolic disease specialist
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Pediatric critical care specialist
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Dietitian
Diet
See Medical Care.
Prevention
Using chorionic villus sampling, prenatal diagnosis is possible as early as 11-12 weeks’ gestation. It is essential to establish the nature of the mutation in the parents first, given the large number of private mutations known to occur. This should be discussed with any family with one or more affected first-degree relatives.
Further Outpatient Care
Under no circumstances should a patient with a urea cycle defect be cared for exclusively by a primary care provider.
Consult with a biochemical geneticist/metabolic disease specialist who is skilled in treating urea cycle diseases when treating patients with argininosuccinate (ASA) lyase deficiency.
Frequent dietary and medication adjustments are essential, especially in growing infants, and should be made only with quantitative monitoring of plasma amino acid levels.
Close attention to dietary intake and adjustments is a critical part of management and should involve the help of a highly trained nutritionist.
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Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
