argininosuccinate lyase

**Reaction:** Argininosuccinate → arginine + fumarate (cytosol). Fumarate links the urea cycle to the TCA cycle through the "Krebs bicycle": fumarate → malate → oxaloacetate → aspartate, which is regenerated and used by argininosuccinate synthetase. Arginine is then cleaved by arginase to ornithine + urea.

**Urea cycle order (mnemonic: "Ordinarily, Careless Crappers Are Also Frivolous About Urination"):** Ornithine → (OTC, mitochondria) citrulline → (argininosuccinate synthetase, cytosol; uses aspartate + ATP) argininosuccinate → (ASL) arginine + fumarate → (arginase) ornithine + urea. CPS I (rate-limiting, activated by N-acetylglutamate) and OTC are mitochondrial. The remaining steps are cytosolic.

**Pathophysiology of ASL deficiency (argininosuccinic aciduria):** - Second most common proximal-to-distal urea cycle defect after OTC deficiency in many series (OTC is the most common overall); it is autosomal recessive (ASL gene, chromosome 7). OTC deficiency is X-linked recessive. - Block at ASL causes accumulation of argininosuccinate (excreted in urine) and citrulline (elevated in plasma). Arginine becomes conditionally essential and is low. - Impaired nitrogen disposal leads to hyperammonemia. Ammonia crosses the blood-brain barrier, and astrocytes convert it to glutamine (glutamine synthetase), which causes osmotic swelling, cerebral edema, and depletion of α-ketoglutarate and glutamate. - Additional effects are attributed to low nitric oxide signaling, because ASL is also part of the citrulline-NO cycle. This may explain hypertension, neurocognitive deficits, and other findings that occur despite ammonia control.

**Clinical features:** - Neonatal-onset form: poor feeding, vomiting, lethargy, tachypnea, seizures, coma, and cerebral edema within the first days of life after protein intake starts. - Late-onset form: episodic hyperammonemia triggered by infection, fasting, or high protein load, plus developmental delay, hepatomegaly, and liver fibrosis. - **Trichorrhexis nodosa** (brittle, fragile hair) is a classic association. - Respiratory alkalosis occurs early, because ammonia stimulates the respiratory center.

**Diagnosis:** - Plasma ammonia is elevated. - Plasma amino acids show elevated citrulline and argininosuccinate, with low arginine. - Urine organic acids show a normal orotic acid level. Orotic acid is elevated in OTC deficiency, because carbamoyl phosphate spills into pyrimidine synthesis. It is low or normal in CPS I deficiency. - Confirm with genetic testing or enzyme assay.

**Differential by citrulline level:** - Absent or very low citrulline: CPS I or OTC deficiency (distinguish by orotic acid). - Markedly elevated citrulline: citrullinemia type I (argininosuccinate synthetase deficiency), with no argininosuccinate. - Elevated citrulline plus argininosuccinate: ASL deficiency. - Elevated arginine: arginase deficiency, which presents with spastic diplegia rather than severe neonatal hyperammonemia.

**Management:** - Acute: stop protein intake and give IV dextrose and lipids to reduce catabolism. Give nitrogen scavengers (sodium phenylacetate/benzoate, or sodium phenylbutyrate), which conjugate glycine or glutamine for renal excretion. Give IV arginine, which is key here because it enables excretion of argininosuccinate, a nitrogen-containing compound that carries two nitrogens. Use hemodialysis for severe hyperammonemia (for example, >300–500 µmol/L or coma). - Chronic: a protein-restricted diet, oral arginine supplementation, and scavengers as needed. Consider liver transplant in refractory cases.

**High-yield pearls:** - In ASL deficiency, arginine supplementation is therapeutic, because it drives nitrogen out as argininosuccinate. In arginase deficiency, arginine is restricted. - Lactulose can help reduce gut ammonia in some cases. - Hyperammonemia plus respiratory alkalosis in a neonate suggests a urea cycle defect. Metabolic acidosis suggests an organic acidemia instead.