Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities. Genetic counseling is recommended for affected individuals and their families.
The treatment of argininosuccinic aciduria is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).
Dietary restrictions in individuals with argininosuccinic aciduria are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants with argininosuccinic aciduria are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula (e.g., UCD-1 Ross, or Cyclinex, Mead Johnson), and a calorie supplement without protein is often used (e.g., MJ80056, Mead Johnson).
Individuals with argininosuccinic aciduria benefit from treatment with arginine, which helps to promote the excretion of nitrogen. Arginine supplementation has shown benefits in improving or reversing changes to the hair, but its impact on the long-term, chronic complications of the disorder are not fully understood. The dose of arginine is often higher than is used in other forms of urea cycle disorder and it is effective in decreasing ammonia in emergent situations of elevated ammonia. However, chronic treatment with high doses of arginine may contribute to liver disease as it produces higher levels of argininosuccinic acid. Therefore, in individuals with liver disease, lower doses should be considered for long term treatment. In this situation, other medications like alternative pathway therapies may be needed. Multiple vitamins and calcium supplements may also be used in the treatment of argininosuccinic aciduria. Finally, because of decreased production of nitric oxide in patients with argininosuccinic aciduria, the addition of low protein foods rich in nitrite may be helpful.
Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.
In some instances, despite early treatment and good metabolic control, affected individuals may develop certain symptoms such as neurocognitive deficiencies, behavior issues such as ADHD, developmental disability and seizures.
In addition to dietary restrictions and supplements, individuals with argininosuccinic aciduria are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. This is known as alternative pathway therapy or nitrogen scavenging therapy. This includes sodium benzoate, sodium phenylbutyrate, and glycerol triphenylbutyrate.
In 2013, the U.S. Food and Drug Administration (FDA) approved Ravicti (glycerol phenylbutyrate) for the chronic management of urea cycle disorders including argininosuccinic aciduria in affected individuals age 2 years and older. Ravicti is a liquid therapy that helps to remove ammonia from the body. Ravicti is used in individuals who cannot management the disorder through a low-protein diet and dietary supplements alone.
In 1996, the FDA approved Buphenyl (sodium phenylbutyrate) for chronic management of urea cycle disorders including argininosuccinic aciduria. Buphenyl is a powder therapy that helps to remove ammonia from the body. A generic form of Buphenyl is also now available.
Sodium benzoate is a powder that is not FDA approved for treatment urea cycle disorders, but it has been used in chronic treatment of urea cycle disorders. It is not believed to be as effective as Buphenyl or Ravicti based on theoretical considerations, though this has never been tested in patients.
In 2005, the FDA approved the use Ammonul (sodium benzoate and sodium phenylacetate) as an intravenous, rescue therapy for the prevention and treatment of hyperammonemia and associated disease of the brain (encephalopathy) in individuals with urea cycle disorders.
Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose.
In individuals where there is no improvement or where hyperammonemic coma develops, the removal of wastes by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with argininosuccinic aciduria during hyperammonemic coma. In some individuals, a liver transplant may be recommended. This is an option of last resort for specific individuals who have progressive liver disease, experience recurrent medical crises and hospitalizations despite therapy, or who have a poor quality of life.
Preventive Care After diagnosis of argininosuccinic aciduria, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear. Monitoring for complications such as high blood pressure, liver inflammation and fibrosis, and developmental delay should be closely monitored from the time of diagnosis.