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Clinical Characteristics: Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form and a late-onset form: The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency (ASLD) that appear to be unrelated to the severity or duration of hyperammonemic episodes: Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability). Liver disease (hepatitis, cirrhosis). Trichorrhexis nodosa (coarse brittle hair that breaks easily). Systemic hypertension., Diagnosis/testing: Elevated plasma ammonia concentration (>100 µmol/L), elevated plasma citrulline concentration (usually 100-300 µmol/L), and elevated argininosuccinic acid in the plasma or urine establish the diagnosis of ASLD. Identification of biallelic pathogenic variants in ASL by molecular genetic testing or – in limited instances – by significantly reduced ASL enzyme activity from skin fibroblasts, red blood cells, or in a flash-frozen sample from a liver biopsy help in confirmation of the diagnosis. Note: All 50 states in the US include ASL deficiency in their newborn screening programs., Management: Treatment of manifestations: Treatment involves rapid control of hyperammonemia during metabolic decompensations and long-term management to help prevent episodes of hyperammonemia and long-term complications. During acute hyperammonemic episodes, oral protein intake is discontinued, oral intake is supplemented with intravenous lipids and/or glucose, and intravenous nitrogen-scavenging therapy is used. If ammonia levels do not normalize, hemodialysis is the next step. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management; for those not responsive to these measures, oral nitrogen-scavenging therapy can be considered. Orthotopic liver transplantation (OLT) is considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy. Surveillance: Monitoring the concentration of plasma amino acids to identify deficiency of essential amino acids and impending hyperammonemia at intervals depending on age and metabolic status. Agents/circumstances to avoid: Excess protein intake; less than recommended intake of protein; prolonged fasting or starvation; obvious exposure to communicable diseases; valproic acid; intravenous steroids; hepatotoxic drugs (in those with hepatic involvement). Evaluation of relatives at risk: Testing of at-risk sibs (either by molecular genetic testing if the family-specific pathogenic variants are known or by biochemical testing) shortly after birth can reduce morbidity by permitting early diagnosis and treatment of those who are affected., Genetic Counseling: ASL deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing and preimplantation diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified., (Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.)