The urea cycle, which consists of a series of five biochemical reactions, has two roles. In order to prevent the accumulation of toxic nitrogenous compounds, the urea cycle incorporates nitrogen not used for net biosynthetic purposes into urea, which serves as the waste nitrogen product in mammals. The urea cycle also contains several of the biochemical reactions required for the de novo synthesis of arginine.
Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis (the earliest objective evidence of encephalopathy). Five well-documented diseases (each with considerable genetic and phenotypic variability) have been described, each representing a defect in the biosynthesis of one of the normally expressed enzymes of the urea cycle. Four of these five diseases—deficiencies of carbamyl phosphate synthetase (CPS) (OMIM 237300), ornithine transcarbamylase (OTC) (OMIM 311250), argininosuccinic acid synthetase (AS) (OMIM 215700), and argininosuccinate lyase (AL) (OMIM 207900)—are characterized by signs and symptoms induced by the accumulation of precursors of urea, principally ammonium and glutamine. The most dramatic clinical presentation of these four diseases occurs in full-term infants with no obstetric risk factors who appear normal for 24 to 48 hours and then exhibit progressive lethargy, hypothermia, and apnea all related to very high plasma ammonium levels.
Milder forms of these diseases occur; they may present with signs of encephalopathy at any age from infancy to adulthood. The most common of these late-onset diseases occurs in female carriers of a mutation at the OTC locus of one of their X chromosomes. The late-onset cases present with respiratory alkalosis and episodic mental status changes progressing, if not emergently treated, to cerebral edema, brainstem compression, and death. The acute encephalopathy is characterized by brain edema and swollen astrocytes, the cause of which is attributed to intraglial accumulation of glutamine resulting in osmotic shifts of water into the cell. Axons, dendrites, synapses, and oligodendroglia are normal. A fifth disease, arginase deficiency (OMIM 107830), is characterized by a clinical picture consisting of progressive spastic quadriplegia and mental retardation; symptomatic hyperammonemia, which can be life-threatening, occurs neither as severely or as commonly as in the other four diseases. Apart from OTC deficiency, which is inherited as an X-linked disorder, the other four diseases are inherited as autosomal-recessive traits. Carrier status of OTC mutations in women is determined by pedigree analysis and molecular methods. For fetuses at risk, antenatal diagnosis is available by a number of methods, particular to each disease, including enzyme analysis of fibroblasts cultured from aminocytes, as well as molecular (DNA) methods.
Molecular genetic analysis of the urea cycle enzymes has addressed their structure and expression and has permitted DNA-based diagnosis of deficiency, in many cases by direct analysis of mutations. Using the cloned complementary DNA as probes, expression in liver of RNA for all the enzymes has been observed to be increased severalfold by starvation. RNA coding for the 160-kDa subunit of the CPS I homodimer is detected almost exclusively in the liver and translates a precursor ...