The central function of the urea cycle is the irreversible detoxification of ammonia to urea. Distinct disorders involve each of the six enzymes of the cycle (Figure 25.1) [1, 2]. These include deficiencies of the mitochondrial matrix enzymes N-acetylglutamate synthase (EC; MIM 237310; prevalence <1:2,000,000), ornithine transcarbamylase (OTCD; EC; MIM 311250; 1:56,000) (Chapter 26), and carbamoyl phosphate synthetase (CPSD; EC; MIM 237300; 1:300,000) (Chapter 27) or the cytosolic enzymes argininosuccinate synthetase 1 (citrullinemia type 1; EC; MIM 215700; 1:250,000; Chapter 28), argininosuccinate lyase (argininosuccinic aciduria; EC; MIM 207900; 1:218,000; Chapter 29), and arginase 1 (argininemia; EC; MIM 207800; 1:950,000; Chapter 30), as well as deficiencies of the aspartate glutamate carrier citrin (citrullinemia type 2, frequent in East Asians; MIM 605814, <1:2,000,000 outside China and Japan) and the mitochondrial ornithine transporter 1 (HHH [hyperammonemia, hyperornithinemia, and homocitrullinuria] syndrome; MIM 238970; <1:2,000,000; 208Chapter 31). In addition, there is a syndrome of transient hyperammonemia of the newborn [3], in which the early clinical manifestations mimic those of the severe defects of urea cycle enzymes and may be fatal, but if the patient can get through the first 5 days of life, the problem disappears and prognosis is good. Mitochondrial carbonic anhydrase VA deficiency [4] and lysinuric protein intolerance (Chapter 32) are also associated with episodic hyperammonemia, but the major expression of the latter is distinct with extreme failure to thrive.