The urea cycle disorders (UCD) result from genetic mutations causing defects in the metabolism of the extra nitrogen produced by the breakdown of protein and other nitrogen-containing molecules. Severe deficiency or total absence of activity of any of the first four enzymes (CPSI, 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 urea cycle disorder often initially appear normal but rapidly develop cerebral edema and the related signs of lethargy; anorexia; hyperventilation or hypoventilation; hypothermia; seizures; neurologic posturing; and coma. In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild to moderately severe elevations of plasma ammonia concentration. The hyperammonemia is usually less severe and the symptoms more subtle. Patients with Arginase deficiency may present with hyperammonemia with severe stress, but are more likely to present with progressive neurologic symptoms unrelated to hyperammonemic episodes.
The urea cycle was first described in 1932 by Krebs and Henseleit. Classic urea cycle deficiency with no enzyme activity invariably presents with overwhelming hyperammonemia in the newborn period with little effect from the environment. Patients with residual activity may go decades before encountering an environmental stress strong enough to overwhelm their marginal ureagenesis capacity and resulting in a hyperammonemic episode. Commonly distributed, functional polymorphisms in the urea cycle may not result in hyperammonemia, but instead affect the production of downstream metabolic intermediates (such as arginine) during key periods of need. These variations in intermediate molecule supply can affect other metabolic pathways such as the production of nitric oxide (NO) from citrulline/arginine and potentially the tricarboxylic acid cycle through aspartate and fumarate.
As shown in figure 1, the urea cycle is composed of five primary enzymes, one cofactor producer and two transport molecules across the mitochondrial membrane. Inborn errors of metabolism are associated with each step in the pathway and have been well described over the years. The cycle has the interesting property of having a subset of the enzymes participate in another metabolic pathway which produces nitric oxide. The urea cycle as a nitrogen clearance system is limited primarily to the human liver and intestine with carbamyl phosphate synthetase and ornithine transcarbamylase limited exclusively to those tissues. The enzymes downstream which process citrulline into arginine are ubiquitous in their distribution. As the rate-limiting enzyme in the urea cycle, CPSI functional changes would have the greatest impact on cycle function from environmental and pharmacologic stress (like valproic acid and cyclophophamide). Hepatotoxins, both chronic and acute, have long been known to affect the clearance of ammonia from the bloodstream. Through loss of liver tissue and direct effects on the enzymes of the urea cycle, the ability to clear excess nitrogen is compromised. This often results in hepatic encephalopathy which compromises the neurologic integrity of the patient. Alcohol is one of the leading causes of hepatic encephalopathy, and chronic hyperammonemia one of the more debilitating results of chronic cirrhosis. The point at which these toxins result in elevated ammonia levels is a factor of the extent of the liver damage but also the genetically determined baseline capacity of the cycle. Other agents such as the seizure medication, valproic acid, are already established as urea cycle toxins.