Argininosuccinic aciduria

Argininosuccinic aciduria (ASA), also known as argininosuccinate lyase deficiency (ASLD), is a rare inherited metabolic disorder belonging to the urea cycle defects. It is caused by deficiency of the enzyme argininosuccinate lyase (ASL), which is essential for the conversion of argininosuccinic acid to arginine and fumarate in the urea cycle — the metabolic pathway responsible for removing nitrogen (ammonia) from the body. When this enzyme is deficient, toxic levels of ammonia and argininosuccinic acid accumulate in the blood, leading to damage primarily affecting the brain and liver. Argininosuccinic aciduria presents in two main clinical forms. The severe neonatal form manifests within the first few days of life with hyperammonemia, poor feeding, lethargy, vomiting, hypothermia, respiratory distress, and seizures, which can rapidly progress to coma and death if untreated. The late-onset (subacute or chronic) form may present in infancy, childhood, or even adulthood with episodic hyperammonemia triggered by illness or protein intake, intellectual disability, developmental delay, behavioral abnormalities, and hepatic involvement including hepatomegaly and liver fibrosis. A distinctive feature of ASA compared to other urea cycle disorders is the high frequency of trichorrhexis nodosa (brittle, fragile hair) and chronic liver disease, which can occur even in metabolically stable patients. Systemic hypertension has also been reported. Treatment of argininosuccinic aciduria involves a combination of dietary protein restriction, arginine supplementation (to facilitate alternative nitrogen excretion as argininosuccinic acid through the kidneys), and nitrogen-scavenging medications such as sodium benzoate and sodium phenylbutyrate. Acute hyperammonemic crises require emergency management including intravenous glucose, nitrogen scavengers, and potentially hemodialysis. Liver transplantation may be considered in severe or recurrent cases, though it does not fully correct the systemic manifestations of the disease. Newborn screening programs in many countries now detect ASA through elevated citrulline levels on tandem mass spectrometry, enabling early diagnosis and treatment. Long-term neurodevelopmental outcomes remain variable even with treatment, and lifelong metabolic monitoring is essential.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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