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Essentially all animal cells form ammonia in the course of the metabolism of amino acids and the adenine nucleotides. Mammals prevent the accumulation of ammonia, which is neurotoxic in high concentration, by converting this compound to urea via the urea cycle (Figure 13-1), which was “discovered” in 1932 by Krebs and Henseleit.1 Ureagenesis is an extremely efficient mechanism for the disposal of waste nitrogen. A healthy adult who daily consumes 50 to 100 grams of protein will excrete 10 to 20 grams of nitrogen (N) as urea, or 80% to 90% of total urinary N.

FIGURE 13-1.

Urea cycle. CPSI, carbamyl phosphate synthetase I; OTC, ornithine transcarbamylase; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; ARG, Arginase; NAGS, N-Acetyl glutamate synthase.

The urea cycle is a tightly ordered biochemical mechanism composed of five catalytic enzymes, an obligatory effector (N-acetylglutamate [NAG]) and two transport proteins. Each of these proteins now has been sequenced.2,3,4,5,6,7,8 Like most metabolic pathways, the urea cycle interacts with several other pathways, notably the citric acid cycle and the nitric oxide synthase (NOS) pathway (Figure 13-1). Such integration ensures meticulous regulation of energy balance, nitrogen metabolism, and a host of critical physiologic processes.

A congenital absence of a urea cycle enzyme or transporter characteristically results in hyperammonemia, neurotoxicity, and in severe cases, permanent brain damage or death. Prompt diagnosis and treatment favor a better clinical outcome, but diagnosis often is delayed, particularly if a patient harbors an incomplete enzyme deficiency which presents with very subtle signs and symptoms that differ from the “classical,” more severe disorder. The estimated aggregate incidence of these disorders is ~1 in 35,000 births,9 but the actual incidence likely is higher when partial defects are included.

Babies characteristically present in the first days of life if they have a near-total deficiency of the first four urea cycle enzymes (carbamyl phosphate synthetase I [CPSI], ornithine transcarbamylase [OTC], argininosuccinic acid synthetase [ASS], and argininosuccinic acid lyase [ASL]). Rare patients may be born with a mutation in N-acetylglutamate synthase (NAGS), which mediates production of NAG, an obligatory effector of the urea cycle. These infants manifest severe hyperammonemia with encephalopathy, brain swelling, and often, seizures during the first days of life. Patients with partial enzyme deficiencies become hyperammonemic in later life, even in adulthood, when an infection or other stress triggers metabolic decompensation. These patients display an array of clinical findings, including learning disabilities, headache, vomiting, recurrent lapses of consciousness, seizures, and psychiatric manifestations. Hyperammonemia is less severe than in neonatal-onset cases. Argininemia, or a defect in arginase (ARGI), results in a progressive neurologic disorder that is similar to a leukodystrophy. Defects in the transporter proteins for ornithine (hyperornithinemia-hyperammonemia-homocitrullinuria [HHH] syndrome) and aspartate (citrullinemia II) also have presentations different ...

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