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 184.108.40.206; MIM 237310; prevalence <1:2,000,000), ornithine transcarbamylase (OTCD; EC 220.127.116.11; MIM 311250; 1:56,000) (Chapter 26), and carbamoyl phosphate synthetase (CPSD; EC 18.104.22.168; MIM 237300; 1:300,000) (Chapter 27) or the cytosolic enzymes argininosuccinate synthetase 1 (citrullinemia type 1; EC 22.214.171.124; MIM 215700; 1:250,000; Chapter 28), argininosuccinate lyase (argininosuccinic aciduria; EC 126.96.36.199; MIM 207900; 1:218,000; Chapter 29), and arginase 1 (argininemia; EC 188.8.131.52; 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 , 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  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.