Argininosuccinic Aciduria · What It Is, Causes, Signs and Symptoms, Treatment, and More

Argininosuccinic aciduria is a rare, inherited metabolic disorder characterized by a deficiency in the enzyme argininosuccinate lyase, which breaks down argininosuccinic acid into arginine and fumarate. A deficiency in this enzyme results in elevated levels of argininosuccinic acid and, as a result, excess ammonia buildup in the blood. Because it is a neurotoxin, excessively high ammonia levels in the body can lead to severe, life-threatening metabolic complications, neurocognitive deficits, and developmental delays.

Broadly, infants with argininosuccinic aciduria may present with similar symptoms to those of sepsis (i.e., a life-threatening systemic infection), including the inability to autoregulate body temperature, poor feeding, altered mental status, nausea, vomiting, and rarely, coma. Moreover, typical long-term complications include liver disease, cognitive deficits, seizures, brittle hair, and hypertension. Symptom severity and onset vary depending on whether individuals have partial or complete loss of argininosuccinate lyase enzyme activity.  

Specifically, those with complete loss of enzyme activity (referred to as severe form) often show signs and symptoms of the disease as early as the first 30 days of life. Infants with argininosuccinic aciduria may appear well in the first 24 to 48 hours of life, but symptoms often appear after feeding, since breast milk and formula contain proteins. Individuals may also experience more severe manifestations, including breathing abnormalities, neurologic complications (e.g., seizures, coma), accumulation of fluid in the brain, developmental delay, and liver disease. Although the underlying mechanisms for liver disease are poorly understood, it is thought to be related to chronic liver inflammation, dysregulation of arginine-derived intermediates, and glycogen metabolism. 

Individuals who are carriers with partial enzyme deficiencies may experience symptom onset later on in life, during childhood or early adulthood, in what is known as the late-onset form. Additionally, the clinical presentation in carriers with partial enzyme activity is typically mild and non-specific. Symptoms include chronic nausea, vomiting, lethargy, failure to thrive, ataxia (lack of coordination), brittle hair, and headaches. Symptomatic episodes are associated with triggers including protein-rich diets, infections, stress, and medications, such as valproic acid.

Treatment of argininosuccinic aciduria focuses on supportive care measures to manage symptoms and prompt ammonia removal. Supportive care measures include hydration with intravenous fluids to maintain an adequate urine output and supplemental oxygen if respiratory distress is present. Ammonia removal can be accomplished through nitrogen scavenging therapy using a preparation of sodium phenylacetate-sodium benzoate. Both these compounds help “trap” excess nitrogen, forming complexes that are easily excreted into the urine. Arginine deficiency can lead to a catabolic state which further stimulates muscle and protein breakdown, increasing the nitrogenous load, and exacerbating the disease. Intravenous arginine supplementation may also be used in the initial management of metabolic decompensation secondary to arginine deficiency. In severe cases that are refractory to nitrogen scavenging therapy and medications, hemodialysis may be required to remove excess ammonia. In some individuals presenting with progressive liver disease, or if medical therapy is not enough to prevent disease episodes, liver transplantation might be necessary. 

After resolution of the acute episode, individuals may transition to oral sodium phenylbutyrate, which promotes urinary excretion of nitrogenous waste. Individuals should avoid drugs that can increase nitrogen or ammonia levels in the blood (e.g., glucocorticoids, valproic acid, mannitol) and restrict protein intake, to minimize the nitrogen load from protein breakdown. Individuals should establish regular follow-up visits with a metabolic specialist and develop an emergency protocol to recognize signs and symptoms of acute hyperammonemia (e.g., nausea, vomiting, altered mental status, weakness, lethargy).