The
urea cycle consists of six consecutive enzymatic reactions that convert waste
nitrogen into
urea. Deficiencies of any of these
enzymes of the cycle result in
urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening
hyperammonemia.
Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of
argininosuccinic acid to
arginine and
fumarate.
ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with
hyperammonemia within the first few days after birth or as a late-onset form with episodic
hyperammonemia and/or long-term complications that include
liver dysfunction, neurocognitive deficits, and
hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma
citrulline together with elevated
argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL
enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or
enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with
hyperammonemia involves discontinuing oral
protein intake, supplementing oral intake with intravenous
lipids and/or
glucose, and use of intravenous
arginine and
nitrogen-scavenging
therapy.
Dietary restriction of
protein and dietary supplementation with
arginine are the mainstays in long-term management. Orthotopic
liver transplantation (OLT) is best considered only in patients with recurrent
hyperammonemia or metabolic decompensations resistant to conventional medical
therapy.