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: Manifestations of ASL deficiency (ASLD) that appear to be unrelated to the severity or duration of hyperammonemic episodes:
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.
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