PMID 21290785


Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, is characterized by a severe neonatal onset form and a late onset form. The severe neonatal onset form, which is indistinguishable from that of other urea cycle disorders, is characterized by hyperammonemia within the first few days after birth accompanied by vomiting, lethargy, hypothermia, and poor feeding. In the absence of treatment, lethargy, seizures, and coma worsen, resulting in death. In contrast, the late onset form ranges 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 that appear to be unrelated to the severity or duration of hyperammonemic episodes include: (1) neurocognitive deficiencies (attention deficit hyperactivity disorder [ADHD], developmental disability, seizures, and learning disability); (2) liver disease (hepatitis, cirrhosis); (3) trichorrhexis nodosa (coarse brittle hair that breaks easily); and (4) systemic hypertension. Elevated plasma ammonia concentration (>150 µmol/L, sometimes up to ≥2000-3000 µmol/L), elevated plasma citrulline concentration (usually 200-300 µmol/L), and elevated argininosuccinic acid in the plasma or urine establish the diagnosis of ASL deficiency. Molecular genetic testing of 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 for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.