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Cell 4, 735–743 endothelial growth factor. Nat. Med. 8, 128–135 Urea-cycle disorders as a paradigm for inborn errors of hepatocyte metabolism Asad Mian and Brendan Lee Urea-cycle disorders (UCDs) are a group of inborn errors of hepatocyte including (but not limited to) organic acidemias, metabolism that are caused by the loss of enzymes involved in the process of fatty-acid-oxidation disorders and amino transferring nitrogen from ammonia to urea, via the urea cycle (UC). Recent acidopathies. UCDs are cell-autonomous disease genetic analyses of inherited disorders that present with hyperammonemia processes and, therefore, a cure requires the demonstrate the function of cellular transporters that regulate the availability correction of significant numbers of hepatocytes. of UC intermediates. The regulation of UC intermediates, such as arginine, These disorders also represent a unique genetic could have far reaching implications on nitric-oxide synthesis and vascular model for understanding how gene–environment tone. Hence, each UCD and UC-related disorder constitutes a unique interactions affect nitrogen homeostasis, which gene-nutrient interaction that is crucial for postnatal homeostasis. Recent is affected by the intake of both energy molecules advances in the diagnosis and management of UCDs include the application of and protein. The recent discoveries of several in vivo metabolic-flux measurements. Cumulative morbidity is still high cellular transporters show how the availability despite dietary and pharmacological therapies and, hence, both cell and gene of urea cycle (UC) intermediates further impacts therapies are being pursued as possible long-term corrective treatments. these processes. Although gene-replacement therapy has suffered recent clinical setbacks, new vector developments offer hope for the treatment of cell-autonomous Urea cycle: pathway to phenotype defects of hepatocyte metabolism. The UC is the only metabolic pathway capable of disposing of excess nitrogen. It converts nitrogen, Urea-cycle disorders (UCDs) are seen as models of derived from dietary protein intake (i.e. enteral classic inborn errors of hepatocyte metabolism. sources) and the breakdown of endogenous protein Hence, new developments in their diagnosis and (i.e. peripheral sources), into urea, which is treatment are relevant to a host of other disorders, water-soluble and easily excreted from the body (Fig. 1). http://tmm.trends.com 1471-4914/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(02)02437-1 584 Review TRENDS in Molecular Medicine Vol.8 No.12 December 2002 Fig. 1. The flow of nitrogen intermediates in the urea Ornithine cycle (UC). The UC converts nitrogen, derived Extracellular space from dietary protein intake and the breakdown Diet and + – NH4 HCO3 of endogenous protein catabolism (catabolism), into urea, which can be excreted from the body. The steps + – of this cycle, and the six NH4 + HCO3 enzymes involved, are indicated in red. The Glutamate NAGS Ornithine dashed red arrow depicts + NAG CPS-I Ornithine Urea the overflow of excess Acetyl CoA carbamyl phosphate (CP) OTC ARG1 into pyrimidine synthesis CP and, hence, to orotic acid, Mitochondrion which is excreted in the Arginine urine. The dashed green Citrulline Arginine arrow depicts the NOS generation of nitric oxide Aspartate (NO) when arginine is converted into citrulline by nitric oxide synthase NO ASL (NOS). The green cylinders Orotic acid Citrulline denote the ornithine and citrulline transporter (ORNT1; SLC25A15), Aspartate ASS and the blue cylinders represent the cationic- Argininosuccinate amino-acid transporter found on intestinal- and Cytoplasm kidney-epithelial cells (SLC7A7). The purple cylinder denotes citrin, a TRENDS in Molecular Medicine mitochondrial aspartate and glutamate transporter (SLC25A13). Two moles of nitrogen (one from ammonia and one catabolism, although protein intake through feeding Abbreviations: ARG1, arginase; ASL, from aspartate) are transferred into two moles also contributes. Initial signs include somnolence argininosuccinate lyase; of urea and a deficiency in any of the six classical and poor feeding, and these are usually followed by ASS, argininosuccinate enzymes of the pathway causes a UCD (Table 1). vomiting, lethargy and coma (Box 1). A common early synthetase; CPS-I, carbamyl-phosphate- With the exception for argininemia, which often symptom in newborns with hyperammonemia is synthetase-I; NAG, presents with spastic diplegia, the neonatal central hyperventilation, which is thought to result N-acetyl-glutamate; NAGS, presentation of UCDs is characterized by from cerebral edema caused by accumulation of N-acetyl-glutamate hyperammonemia, encephalopathy and respiratory ammonia and other metabolites, and leads to synthase; OTC, ornithine transcarbamylase. alkalosis. However, disorders associated with partial respiratory alkalosis [5]. Progressive cerebral activity of the urea cycle can present late, with edema ultimately leads to abnormal posture and pleiotropic manifestations ranging from normal encephalopathy, with hypoventilation and respiratory development with acute metabolic decompensation, arrest. In addition, approximately 50% of infants to psychiatric illness (Box 1). Rapid diagnosis and with severe hyperammonemia have seizures [5]. treatment are crucial in preventing neurological Hyperammonemia can be chronic or acute, the acute injury [1,2] and it is generally accepted that the form resulting from metabolic decompensation duration, frequency and degree of hyperammonemia associated with stressors, such as viral illness or contribute to cumulative neurological morbidity. childbirth [5]. In patients with partial urea-cycle- The overall frequency of UCDs is approximately enzyme deficiencies, symptoms do not present until one per 30 000 live births [3]. They all have an after the newborn period. This delay is most common Asad Mian Dept of Molecular and autosomal recessive inheritance