US EPA

2979801 

Book/Book Chapter 

Urea Cycle Disorders Overview 

1993 

University of Washington, Seattle 

Seattle (WA) 

GeneReviews(®) 

English 

20301396 

CLINICAL CHARACTERISTICS: The urea cycle disorders (UCD) result from defects in the metabolism of waste nitrogen from the breakdown of protein and other nitrogen-containing molecules. Severe deficiency or total absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Infants with a severe urea cycle disorder are normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma. In milder (or partial) deficiencies of these enzymes and in arginase (ARG) deficiency, ammonia accumulation may be triggered by illness or stress at almost any time of life. In these disorders the elevations of plasma ammonia concentration and symptoms are often subtle and the first recognized clinical episode may not occur for months or decades.

DIAGNOSIS/TESTING: The diagnosis of a urea cycle disorder is based on clinical suspicion and biochemical and molecular genetic testing. A plasma ammonia concentration of 150 μmol/L or higher associated with a normal anion gap and a normal plasma glucose concentration is an indication for the presence of a UCD. Plasma quantitative amino acid analysis and measurement of urinary orotic acid can distinguish between the specific UCDs. A definitive diagnosis of a urea cycle defect depends on either molecular genetic testing or measurement of enzyme activity. Molecular genetic testing is possible for all urea cycle defects.

GENETIC COUNSELING: Deficiencies of CPS1, ASS1, ASL, NAGS, and ARG are inherited in an autosomal recessive manner. OTC deficiency is inherited in an X-linked manner. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk using molecular genetic testing is possible for any of the urea cycle disorders if the pathogenic variant(s) in the family are known.

MANAGEMENT: Treatment of manifestations: Acute severe hyperammonemia: Dialysis and hemofiltration to reduce plasma ammonia concentration; intravenous administration of arginine hydrochloride and nitrogen scavenger drugs to allow alternative pathway excretion of excess nitrogen; restriction of protein for 12 to 24 hours to reduce the amount of nitrogen in the diet; calories given as carbohydrates and fat; and physiologic stabilization with intravenous fluids and cardiac pressors while avoiding overhydration. Prevention of primary manifestations: Long-term management: prevention of catabolism to avoid hyperammonemic episodes by dietary restriction of protein, use of specialized formulas, and use of oral nitrogen-scavenging drugs. Prevention of secondary complications: Minimize risk of respiratory and gastrointestinal illnesses; routine immunizations; multivitamin and fluoride supplementation; appropriate use of antipyretics. Surveillance: Routine monitoring by a physician experienced in the treatment of metabolic disorders. Agents/circumstances to avoid: Valproic acid (Depakote(®)); prolonged fasting or starvation; intravenous steroids; large boluses of protein or amino acids. Evaluation of relatives at risk: Identification of affected at-risk relatives before symptoms occur allows dietary therapy and other measures to prevent hyperammonemia. 

Pagon, RA; Adam, MP; Ardinger, HH; Wallace, SE; Amemiya, A; Bean, LJH; Bird, TD; Dolan, CR; Fong, CT; Smith, RJH; Stephens, K