Newborn screening · Amino acid disorder
Argininosuccinic Aciduria · ASA
Urea cycle disorder. Hyperammonemia is the danger. Ammonia scavengers and protein restriction are the levers.
Description
Argininosuccinic aciduria, ASA, is an inherited urea cycle disorder. The enzyme argininosuccinate lyase, encoded by the ASL gene on chromosome 7, splits argininosuccinic acid into arginine and fumarate. Two damaging copies of ASL leave the urea cycle unable to clear nitrogen, ammonia accumulates in blood, and untreated newborns develop hyperammonemic encephalopathy in the first days of life. Inheritance is autosomal recessive.
Classic neonatal presentation begins within the first week with poor feeding, lethargy, vomiting, tachypnea from respiratory alkalosis, and progression to coma. Late-onset forms present in childhood or adulthood with episodic hyperammonemia, developmental delay, learning differences, or unexplained liver disease. ASA carries a distinctive long-term profile among urea cycle disorders. Affected children develop chronic liver fibrosis, hypertension, and cognitive and neurological disability even when ammonia is controlled. Trichorrhexis nodosa, a brittle hair finding, is characteristic. The mechanism for the non-ammonia features involves loss of nitric oxide signaling, because argininosuccinate lyase also functions in the citrulline-nitric-oxide cycle (Erez et al., Nature Medicine, 2011).
Detection is by newborn screening on the dried blood spot using tandem mass spectrometry, with citrulline and argininosuccinate as the screening markers. Confirmation uses plasma amino acids, urine orotic acid, and ASL gene sequencing. Pooled US newborn screening data from Therrell et al. (Genetics in Medicine, 2014) place ASA incidence at roughly 1 in 70,000 to 1 in 220,000 live births, with reported rates rising under expanded universal screening.
Treatments to date
Standard of care is lifelong protein-restricted diet supplemented with arginine, plus nitrogen scavenger drugs and emergency management of hyperammonemic crises with intravenous nitrogen scavengers, dialysis when ammonia is severely elevated, and reversal of catabolism with dextrose and lipid.
Sodium phenylbutyrate (Buphenyl) was approved by the FDA in April 1996 for chronic management of urea cycle disorders, including ASA in patients who cannot be managed by protein restriction and arginine alone. Glycerol phenylbutyrate (Ravicti) was approved by the FDA in February 2013 for chronic management of urea cycle disorders in adults and children, with the indication later extended to infants. Sodium phenylacetate combined with sodium benzoate (Ammonul) is approved as an intravenous adjunct for acute hyperammonemic encephalopathy. Arginine supplementation is part of the chronic regimen because ASA blocks the production of arginine within the urea cycle.
Liver transplantation is curative for the metabolic block and is considered for children with frequent hyperammonemic crises or progressive liver disease. Transplantation does not reverse established neurocognitive injury or correct the systemic nitric-oxide deficit in tissues outside the liver. Gene therapy and mRNA therapy programs targeting urea cycle disorders are in early clinical development. Investigational AAV-delivered ASL replacement and lipid-nanoparticle mRNA approaches have entered preclinical and Phase 1 studies through sponsors including Arcturus and Ultragenyx.