The urea cycle is a series of steps required to generate urea from nitrogen produced by protein catabolism. The cycle was first described in 1932 by Krebs and Henseleit (Krebs and Henseleit 1932). Six enzymes and two transporters are necessary for urea cycle activity. Specific deficiencies have been described with each of these. The process converts nitrogen from ammonia and aspartate into urea, which is freely excreted by the kidney (Brusilow 1995). Embedded within the urea cycle is the nitric oxide cycle. Nitric oxide is generated from arginine by nitric oxide synthase (NOS), producing citrulline (Scaglia et al. 2004). The entire urea cycle is present only in the liver. The proximal cycle (N-acetylglutamate synthase [NAGS], carbamyl phosphate synthetase [CPS], ornithine transcarbamylase [OTC]) is also present in the intestinal tract, whereas the distal cycle (argininosuccinic acid synthase [ASS], argininosuccinic acid lyase [ASL], arginase [ARG]) is active in the kidney. The most common of the urea cycle disorders (UCDs) is ornithine transcarbamylase deficiency, which is inherited in an X-linked manner. All of the others are autosomal recessive. The overall incidence of all urea cycle disorders is estimated at between 1/10,000 to 1/25,000, although patients with incomplete deficiency are likely significantly more common (Nagata, Matsuda et al. 1991). When the urea cycle function is absent or diminished, either by direct enzymatic deficiency or by secondary inhibition of the proximal four steps, nitrogen accumulates in the form of toxic ammonium. In null activity patients, this typically presents in the first days of life with hyperammonemia, resulting in central nervous system (CNS) dysfunction with overwhelming encephalopathy and coma, brain edema, seizures, and potentially death, with severe long-term neurodevelopmental sequelae if not rapidly reversed. The differential diagnosis of severe hyperammonemia includes organic acidemias, herpes-related hepatitis, and other disorders of liver function. Respiratory alkalosis and hyperventilation is classically seen in UCDs, although if encephalopathy progresses, apneas and acidosis may be seen (Burton 1998). If not recognized and reversed immediately, this may progress to fatal cerebral edema and herniation. There are multiple postulated mechanisms for ammonia-related neurotoxicity.
Irritability, Poor Feeding and Respiratory Alkalosis in Newborns: Think about Metabolic Emergencies. A Brief Summary of Hyperammonemia Management
