UREA CYCLE DISORDERS

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CHAPTER 110 UREA CYCLE DISORDERS

The urea cycle is a sequence of six enzymatic and two transport steps necessary to metabolize and excrete the nitrogen generated by the breakdown of amino acids in protein and other nitrogen-containing molecules (Fig. 110-1). The diet and the breakdown of endogenous tissues, particularly of skeletal muscle, are important sources of protein. Endogenous protein breakdown during episodes of acute catabolism presents the deficient ureagenic system with an overwhelming burden and results in the hyperammonemia that occurs in acute infections, after parturition, or during the menstrual cycle.¹ The complete urea cycle is found only in the liver, although individual enzymes are present at lesser levels in other organs and may have additional metabolic roles. Severe liver disease with biosynthetic failure may also result in a deficient urea cycle and hyperammonemia. The first three enzymes in this cycle, N-acetylglutamate synthase (NAGS), carbamoyl phosphate synthase I (CPSI), and ornithine transcarbamylase (OTC) function inside mitochondria, and the latter three, argininosuccinic acid synthase, argininosuccinic acid lyase (ASL), and arginase, act in the cytosol. The two transporters are for ornithine and aspartate. Defects in citrin, the transporter for aspartate, causes citrin deficiency, also called citrullinemia type II. Defects in ornithine translocase, the transporter for ornithine, causes ornithine translocase deficiency (ORNT1), also called hyperammonemia, hyperornithinemia, and homocitrullinuria syndrome.

Figure 110-1 The six primary enzymatic steps of the urea cycle are shown in bold capital letters. Function of ornithine transporter (ORNT) and aspartate transporter (CITR) is necessary for the movement of substrates in and out of the mitochondrion. ARG1, arginase; ASL, argininosuccinic acid lyase; ASS, argininosuccinic acid synthase; Co-A, coenzyme A; CP, carbamoyl phosphate; CPS-1, carbamoyl phosphate synthase; NAG, N-acetylglutamate; NAGS, N-acetylglutamate synthase; NO, nitric oxide; NOS, nitric oxide synthase; OTC, ornithine transcarbamylase.

Defects in all six steps of the urea cycle and in the transporters are known. Any deficiency of these proteins may result in the accumulation of excess ammonia in the body. Ammonia is toxic to the central nervous system, and any continuous or intermittent elevation of ammonia can result in encephalopathy and neurological damage. This damage can lead to seizures, psychosis, mental retardation, and death. The essential genetic characteristics of the eight disorders are summarized in Table 110-1.

TABLE 110-1 Disorders of the Urea Cycle^*

DEFINITION

The diagnosis of a urea cycle disorder is based on clinical examination and on biochemical, enzymatic, and molecular analyses. A urea cycle defect is first suspected in an infant with anorexia, alterations in respiratory function and thermoregulation, lethargy, seizures, and deteriorating neurological status or in a child with decreased appetite, vomiting, lethargy, behavioral abnormalities, and an altered finding on neurological examination. In the affected older child or adult, blood ammonia determination should be part of the evaluation of any acute encephalopathy or recurrent late-onset psychosis or somnolence.² The diagnosis is supported by an elevated plasma ammonia concentration with a normal anion gap and a normal serum glucose concentration (Fig. 110-2). An encephalopathic electroencephalographic pattern during an episode of hyperammonemia and evidence of brain atrophy on magnetic resonance imaging, although nonspecific, provide further support for the diagnosis of a urea cycle defect.

Figure 110-2 Sequence of tests used in the differential diagnosis of hyperammonemia and urea cycle disorders. ASL, argininosuccinic acid lyase; ASS, argininosuccinic acid synthase; CPSI, carbamoyl phosphate synthase I; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase.

(Modified from Summar ML, Tuchman M: Urea Cycle Disorders Overview. In GeneReviews at GeneTests. Seattle: University of Washington, Seattle, April 2003.)

Plasma quantitative amino acid analysis can be used to aid in the delineation of the specific urea cycle disorder. Plasma amino acid analysis reveals reduced levels of arginine in all urea cycle disorders except arginase deficiency, in which arginine levels are elevated. Citrulline levels can also aid in discriminating the various urea cycle defects. Citrulline is produced by the first three enzymes, NAGS, CPSI, and OTC, and decreased levels are found when the level of any of these enzymes is deficient. In contrast, citrulline levels are increased with deficiencies of argininosuccinic acid synthase and ASL, because citrulline serves as a substrate for these more distal reactions. Urinary orotic acid levels are also used to differentiate CPSI and NAGS deficiency from OTC deficiencies. In the former, orotic acid levels are normal or reduced, whereas in the latter, they are elevated. A definitive diagnosis is made through measurement of enzyme activity, often from a liver tissue sample. If liver biopsy is not possible, diagnosis can be based on family history, clinical presentation, amino acid and orotic acid testing, and molecular genetic testing. These laboratory studies are carried out in highly specialized laboratories, which can be found on the GeneTests website (www.genetests.org).

EPIDEMIOLOGY

Seven of the eight urea cycle disorders—NAGS, CPSI, argininosuccinic acid synthase, ASL, arginase, ORNT1, and citrin deficiencies—are inherited as autosomal recessive traits. OTC deficiency is an X-linked disorder. Because of the absence of nationwide neonatal screening for these disorders, the true incidence of the individual urea cycle defects is not known. The estimated combined incidence for all urea cycle defects is 1 per 8200. OTC deficiency has the highest incidence, and arginase and NAGS deficiencies, the lowest.

CLINICAL FEATURES

Severity of symptoms and age at onset are related, at least partially, to the position of the deficient enzyme in the pathway and to the degree of the enzymatic defect. Urea cycle disorders usually manifest either in the neonatal period or later in childhood. Manifestation in the neonatal period results from severe deficiency one of the first five enzymes in the cycle: NAGS, CPSI, OTC, argininosuccinic acid synthase, or ASL. Clinical manifestation after the neonatal period usually results from milder or partial defects of these enzymes, from arginase deficiency, or from disorders of one of the two transporters.

Severe deficiency of any of the urea cycle enzymes except arginase results in the accumulation of ammonia and other intermediate metabolites during the first few days of life. Unlike these disorders, arginase, ORNT1, and citrin deficiencies infrequently result in symptomatic elevation of plasma ammonia in the neonatal period and are the mildest of the eight urea cycle disorders. In patients with partial defects of these enzymes, a metabolic crisis with ammonia accumulation may be triggered by intercurrent illnesses or by stress at almost any time in life. Although these disorders share common symptoms, the severity and age at first manifestation can vary a great deal between and within the specific disorders.

Many newborns with a severe enzyme deficiency initially appear well but rapidly develop hyperammonemia and lethargy, anorexia, abnormal respiratory patterns, hypothermia, seizures, abnormal posturing, and deterioration into coma. This process is accompanied by cerebral edema. Severe deficiency of NAGS, CPSI, OTC, argininosuccinic acid synthase, or ASL, the first five enzymes in the cycle, almost invariably manifests within the first few days after birth and has a high mortality rate. Children with arginase, ORNT1 and citrin deficiencies can present in childhood, but episodes of symptomatic hyperammonemia are uncommon. In partial urea cycle enzyme deficiencies, individuals do well until an intercurrent illness or other stress results in a metabolic crisis with ammonia accumulation. In these individuals, the first recognized clinical episode may be delayed for months or years, and these patients typically have serial and milder elevations of plasma ammonia concentration throughout their lives. These individuals may have only recurrent abdominal pain, and the first indication of an inborn error may be developmental delay resulting from ammonia intoxication.

Although the clinical signs and symptoms of the specific urea cycle disorders vary to a degree, a typical hyperammonemic episode is marked by loss of appetite, vomiting, lethargy, and behavioral abnormalities. The episode can be quite subtle and nonspecific. These initial symptoms progress to coma if there is no therapeutic intervention. Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brainstem. Seizures are common with severe hyperammonemia and are present in about half of affected patients. Respiratory alkalosis secondary to the hyperventilation caused by cerebral edema is a common early finding. Hypoventilation and respiratory arrest can occur as pressure on the brainstem increases.

Deficiency of the sixth enzyme, arginase, typically manifests in childhood with growth failure, developmental delay, and/or school failure and affects primarily the central nervous system. Episodic hyperammonemia of variable degree can occur but is rarely severe enough to be life-threatening. Typically, birth and early childhood are normal. At the age of 1 to 3 years, there is growth failure, and spasticity begins to develop. Soon, development, previously normal, slows or stops, and the child begins to lose previously achieved developmental milestones. If untreated, arginase deficiency progresses to severe spasticity with joint contractures, loss of ambulation, and severe mental retardation. Seizures are common and can usually be well controlled.

Neurotoxicity

A common manifestation of all urea cycle disorders is episodic encephalopathy associated with hyperammonemia. Although ammonia is a well-recognized neurotoxin, the nature and specific effect that hyperammonemia may have on the central nervous system is not well understood. During a crisis, hyperammonemia causes increased blood-brain barrier permeability, depletion of intermediates of energy metabolism, and disaggregation of microtubules. Ammonia is toxic to the central nervous system even when levels are only mildly elevated, as during long-term therapy. Mildly elevated ammonia levels may cause alterations of axonal development and alterations in brain amino acid and neurotransmitter levels.

Glutamine, an amino acid usually in equilibrium with ammonia and present in much higher levels in the blood, is also a likely proximate toxin. The elevated levels of glutamine in blood are mirrored in the cerebrospinal fluid and have been associated with astrocyte swelling and cerebral hypercirculation. Although cerebrospinal fluid glutamine is not usually monitored, instances of patients with neurological symptoms disproportionate to plasma ammonia levels have been associated with higher elevations of cerebrospinal fluid glutamine levels. Elevated glutamine levels may also cause neurotransmitter abnormalities. Chronically elevated glutamine levels stimulate the transport of large neutral amino acids, including tryptophan. Elevated amounts of tryptophan are converted to serotonin and quinolinic acid, both levels of which are elevated in the brains of OTC-deficient patients. These changes in serotonin metabolism may contribute to the behavioral, sleep and feeding problems seen in patients with urea cycle disorders. Clinicians’ ability to measure brain glutamine by magnetic resonance spectroscopy is improving, and these studies may become an essential part of the evaluation of any patient suspected of having a urea cycle disorder. Therapy could then focus on lowering the brain glutamine levels as an endpoint.

Neuroimaging Abnormalities and Neuropathology

Head ultrasonography performed on neonates during initial presentations has revealed cerebral edema with largely obliterated ventricles. In surviving patients, the edema recedes with normalization of ammonia level, and the ventricles often become enlarged, as one manifestation of the cerebral atrophy that has occurred (Fig. 110-3). Hyperammonemic episodes at later ages are also accompanied by cerebral edema, which becomes even more dangerous once cranial sutures have fused. After hyperammonemic coma, magnetic resonance imaging and computed tomography also demonstrate increased sulcal markings, bilateral symmetrical low-density white matter lesions, and diffuse atrophy, sparing the cerebellum. In patients who have died during a hyperammonemic crisis, neuropathological changes have included intracerebral hemorrhage, prominent cerebral edema, swelling of type II astrocytes, and generalized neuronal cell loss (Fig. 110-4). Neuropathology in older children has included ulegyria, cortical atrophy with ventriculomegaly, and prominent cortical neuronal loss.

Figure 110-3 Serial ultrasonograms of the head in a newborn with hyperammonemia caused by ornithine transcarbamylase deficiency. A, Study at presentation, demonstrating narrow ventricles secondary to brain edema. B, Study performed 4 days later, with ammonia level under control and remitting edema. The ventricles are of near-normal size. C, Study performed 6 days after presentation, demonstrating enlargement of ventricles secondary to brain atrophy caused by hyperammonemia and cerebral edema.

Figure 110-4 Neuropathology of hyperammonemic syndromes. Chronic hyperammonemia resulting from urea cycle enzymopathies. A, Alzheimer type II cells (left, arrow) have enlarged nuclei and margination of chromatin in this hematoxylin and eosin–stained section. Doublets suggestive of a proliferative response are frequently seen (right, arrowhead). B, Electron micrograph revealing swelling of a perivascular astrocyte (Ast) from a patient with acute liver failure, who died of brain herniation.

(From Felipo V, Butterworth RF: Neurobiology of ammonia. Prog Neurobiol 2002; 67:259-279.)

Cognitive Deficits

Nearly all infants with a complete enzymatic deficiency who survive their initial hyperammonemic coma are left with mental retardation and other developmental disabilities. There is a documented inverse correlation between duration, and not peak level, of hyperammonemia and neurocognitive outcome. Neonates in stage III coma longer than 72 hours invariably have mental retardation. Cognitive outcome is better in children with complete defects who were treated prospectively. Patients with partial enzyme deficiencies also have a significant risk of developmental disabilities, and even asymptomatic OTC-heterozygous women have cognitive deficits and are at risk for learning disabilities and attention deficit/hyperactivity disorder.

ETIOLOGY AND PATHOPHYSIOLOGY

The eight urea cycle disorders result from the inability to metabolize nitrogen produced from the breakdown of protein and other nitrogen-containing molecules. This waste nitrogen is converted into ammonia (NH₄⁺) and transported to the liver, where it is normally processed through the urea cycle. Ammonia is toxic to the nervous system and is normally converted to urea, which is nontoxic, before being excreted in the urine.

The enzymes, in order of their role in the pathway from the entry of ammonia, are

1. NAGS

2. CPSI

3. OTC

4. Argininosuccinic acid synthase

5. ASL

6. Arginase

7 and 8. Two transporters: citrin and ornithine translocase

N-Acetylglutamate Synthase Deficiency

NAGS, the first enzyme in the urea cycle, serves to produce a cofactor necessary for the normal function of the enzyme CPSI. Because CPSI is rendered inactive in the absence of NAGS, the clinical pictures of these two disorders are very similar and are described in detail in the next section. Affected patients may present with neonatal hyperammonemia or with milder and intermittent episodes. Because there have been few cases, a clear description of the presentation and course is not available. The enzyme is confined to the liver, and cloning of the gene now allows diagnosis, which was most often made on liver biopsy by mutation analysis of the NAGS gene.

Carbamoyl Phosphate Synthase I Deficiency

CPSI deficiency, together with OTC deficiency in boys, is the most severe of the urea cycle disorders. Individuals with complete deficiency of this enzyme develop very high levels of ammonia in the neonatal period. CPSI deficiency can be lethal in newborns, and children rescued from their initial event are at high risk for chronic, recurrent, and extreme episodes of hyperammonemia. CPSI and other specific urea cycle disorders occur in milder forms when some enzymatic activity is preserved. Individuals with partial CPSI deficiency can develop the first symptoms at almost any time during life. Often an intercurrent illness or other stressful event triggers a crisis in these patients. In addition to ammonia levels that rise to 2000 μmol/L or greater, plasma amino acid levels may be greatly altered. There is a generalized increase in all amino acids with a particular increase in the transaminating amino acids: alanine, glutamate, and glutamine.

The gene for CPSI deficiency has been cloned, and the specific mutations for any patient can, in principle, be determined. If the specific mutations are known, prenatal diagnosis becomes possible. If they are not known, prenatal diagnosis may nonetheless be accomplished by haplotype analysis both of the parents and of the fetus. Heterozygous gene carriers are not thought to be at risk for acute hyperammonemia in this disorder. However, subtle effects of the carrier status for this and other urea cycle disorders may exist. Diagnosis in low-risk newborns by screening is not possible with the technology currently available.

Ornithine Transcarbamylase Deficiency

OTC deficiency is an X-linked recessive disorder resulting in severe disease in affected boys. As in CPSI deficiency, boys with complete OTC deficiency rapidly develop high levels of ammonia soon after birth. Patients who recover from their first crisis are at risk for repeated bouts of hyperammonemia. Girls with a disease-causing mutation on one of the X chromosomes can be either asymptomatic or have partial enzymatic deficiency. Female patients with partial disease may develop hyperammonemia throughout their lives and may require treatment.

Infrequently, female patients may be affected severely enough to develop fatal neonatal hyperammonemia or to suffer from a fatal or damaging episode during childhood. Some female carriers are protein intolerant and adopt a low-protein diet because it makes them feel better. Female carriers are at risk for hyperammonemia when faced with the metabolic demands of pregnancy, and particular caution is warranted in this situation. Female carriers have, on average, lower IQ scores than do their noncarrier female relatives.

The OTC gene has been cloned, and sequencing of all exons reveals mutations in 75% of affected male patients and 50% of affected female patients who present with hyperammonemia. As automated sequencing of DNA evolves, mutations in a larger proportion of patients will be ascertained. The clinical biochemical findings are similar to those found in NAGS and CPSI deficiencies, with one prominent and diagnostically important exception. The carbamyl phosphate that accumulates behind the enzyme block leaks from the mitochondrion into the cytoplasm and is channeled into pyrimidine biosynthesis. Two intermediates in this pathway, orotic acid and orotidine, accumulate; this allows OTC deficiency to be distinguished from NAGS and CPSI deficiency without the need for any enzymatic or molecular testing.

Argininosuccinic Acid Synthase Deficiency (Citrullinemia Type I Deficiency)

Citrullinemia type I deficiency is caused by a deficiency of the enzyme argininosuccinate synthase, which converts citrulline and aspartate into argininosuccinate. Complete defects in this enzyme result in extremely elevated levels of citrulline. Severe defects cause neonatal hyperammonemia, and a fatal outcome results. Partial defects of this distal enzyme in the cycle result in milder clinical phenotypes; some patients are asymptomatic, and others have repeated but attenuated episodes of hyperammonemia. Chronic mild or even subclinical hyperammonemia may impair intellectual development.

In contrast to the first three disorders in the cycle, citrulline levels are elevated in argininosuccinic acid synthase deficiency. In the mildest cases, citrulline levels may be normal or near normal except during acute episodes. Changes in other amino acids resemble those seen in OTC deficiency. The argininosuccinic acid synthase gene has been cloned, and numerous mutations are known. The condition is inherited as an autosomal recessive trait and carriers are not known to be symptomatic. Prenatal diagnosis is feasible either through genetic testing or by measuring citrulline levels and enzymatic activity in amniotic fluid cells. Neonatal screening is effective when blood levels of citrulline are measured by tandem mass spectrometry.

Argininosuccinic Aciduria Deficiency

Although most known cases of ASL deficiency are clinically mild, complete deficiency of this enzyme can result in neonatal hyperammonemia and death. Affected patients present with developmental delay and a variety of neurological symptoms. ASL deficiency is characterized by extremely high levels of argininosuccinic acid in blood and all tissues, even in asymptomatic cases, which suggests that argininosuccinic acid may not be toxic and that all symptoms may be caused by elevations in ammonia level alone. However, because successful treatment of hyperammonemia from birth has been followed by developmental and neurological problems, doubt has been cast on this belief. In addition, elevated levels of argininosuccinic acid may contribute to the liver disease seen with this disorder, which can cause liver failure and necessitate transplantation. The diagnosis can be established by measuring the enzyme in red blood cells or in skin fibroblasts. The gene has been cloned, and prenatal diagnosis can be made reliably from the argininosuccinic acid levels in amniotic fluid. Neonatal screening based on elevated citrulline levels ought to be possible.

Arginase Deficiency (Hyperargininemia)

Arginase is the sixth and final enzyme of the urea cycle and converts arginine to urea and ornithine. Urea is excreted from the body, and ornithine is recycled. A block in this enzyme activity results in high levels of arginine. However, arginase deficiency is the least likely of the urea cycle disorders to cause neonatal hyperammonemia. The clinical presentation and progression were described previously. In most patients, arginine level alone is elevated in plasma, although glutamine level may also rise when ammonia levels are elevated. Ammonia levels are often normal between acute episodes.

In contrast to other urea cycle disorders, the proximate toxin may be arginine and not ammonia or glutamine, and this may account for the different symptoms. The liver form of arginase (ARGI) is absent in red blood cells. A second arginase (ARGII) is present at lower levels in the mitochondria of many tissues and may in part be responsible for the milder clinical expression of arginase deficiency. The ARGI gene has been cloned, and a number of mutations are known. Prenatal diagnosis is possible by mutation analysis and by measuring arginase levels in red blood cells obtained by percutaneous umbilical blood sampling. Diagnosis in the newborn should be possible by tandem mass spectrometric analysis of arginine levels in blood.

Transporter Deficiencies: Citrin Deficiency and Ornithine Translocase Deficiency

Defects in the ornithine transporte ornithine translocase and in the aspartate transporter citrin result in hyperammonemia and can produce a severe and often subacute illness after the neonatal period. Defects in the ornithine transporter cause hyperammonemia, hyperornithinemia, and excess amounts of urinary homocitrulline. Citrin deficiency causes elevations in citrulline and ammonia levels and was formerly referred to as citrullinemia type II.

TREATMENT

The diagnosis, treatment, and management of a patient with a urea cycle defect should be provided by a team of specialists working in concert with the primary medical providers who will provide care locally during minor catabolic episodes and provide routine care for minor illness and health maintenance. Treatment involves acute management of hyperammonemic episodes and long-term management to optimize nutrition, growth, and development. During an acute episode of hyperammonemia, the goals of treatment are (1) to rapidly reduce the plasma ammonia level, (2) to enhance the excretion of nitrogen through alternative pathways by pharmacological intervention, (3) to reduce the amount of exogenous nitrogen, (4) to minimize catabolism of body protein by maximizing nutritional support, and (5) to reduce the risk of neurological damage. This chapter can provide only general guidelines for care and cannot be used as a step-by-step protocol. Contact with a metabolic specialist should be established as quickly as possible.³

Acute Management

Each of the inborn errors of the urea cycle can be associated with episodes of hyperammonemia. Most interventions apply to all of these, although each has its unique characteristics. Vomiting and altered mental status usually indicate a plasma ammonia concentration greater than 150 μmol/L and demand acute intervention. In this situation, the patient should be hospitalized, protein should be completely eliminated from the diet for at least 24 to 48 hours, intravenous sodium benzoate/sodium phenylacetate should be started, and dialysis should be considered. Any elevation of ammonia carries the risk of permanent brain damage and should be treated aggressively. There is a direct correlation between the extent of neurological damage and the duration and severity of the hyperammonemic episode. It is important to reduce the level of ammonia as quickly as possible, and the most effective way to accomplish this is through dialysis and pharmacological intervention.

Dialysis

Severe hyperammonemia with ammonia concentrations greater than 250 μmol/L is nearly uniformly associated with altered mental status and stupor. Ammonia concentrations higher than 500 μmol/L are associated with severe brain edema and irreversible brain damage and can be life-threatening. In this situation, dialysis is the most efficient means of lowering ammonia levels. The form of dialysis to be used depends on the patient’s age, access to a treatment center, and clinical status and on available resources. Hemodialysis or hemoperitoneal dialysis is most effective, but an expert team is required. If ammonia continues to accumulate at a slower rate, peritoneal dialysis may be effective in maintaining a normal ammonia concentration. Exchange transfusion appears to be the least effective approach and is not recommended. Dialysis can be stopped when plasma ammonia falls below 200 μmol/L. If the concentration of plasma ammonia rebounds after dialysis is discontinued, further dialysis may be required.

Alternative Pathway Therapy

To lower ammonia levels, dialysis may be complemented by medications that enhance the metabolism and excretion of nitrogen through alternative metabolic pathways. These medications include arginine, sodium phenylacetate, and sodium benzoate.⁴ The choice of medications depends on the specific enzymatic deficiency. Patients with NAGS, CPSI, or OTC deficiency have impaired biosynthesis of arginine in the liver and other tissues and should receive maintenance doses of arginine or arginine hydrochloride. The starting dosage is 250 mg/kg/day in younger patients, which should be adjusted depending on plasma levels 4 hours or more after administration. Citrulline, whose conversion to arginine “absorbs” one ammonia nitrogen, may be substituted for the arginine. Arginine supplementation is also needed in ASL deficiency, but in this instance, it cannot be substituted with citrulline. In the liver, arginine is converted into ornithine (see Fig. 110-1), which may drive ammonia into citrulline, a less toxic metabolite. Argininosuccinate is actively secreted by the kidneys, and excess arginine drives ammonia into argininosuccinate, a far less toxic compound. There is now some concern that argininosuccinate may have liver toxicity, and current emphasis with this disorder revolves around multimodal therapy.

Arginase deficiency requires that no arginine or precursor amino acid be given. An important step forward was made in the early 1980s, when Brusilow and Horwich (2001) and Batshaw and collaborators (1987) documented that benzoate and phenylacetate anions divert ammonia from a defective (or normal) urea cycle to apparently harmless byproducts, benzoylglycine and phenylacetylglutamine.⁵ The reactions are shown in Figure 110-5. Benzoate is conjugated with glycine to form benzoylglycine (hippuric acid), and one molecule of ammonia is diverted to replace the glycine. Similarly, when the glutamines are replaced, two molecules of ammonia are consumed. The reactions are stoichiometric, and large quantities of the anions are given. Because excessive amounts of these anions are toxic, they need to be administered under the supervision of specialists in metabolic disorders. When administered with arginine, these nitrogen-scavenging compounds may control moderate episodes of hyperammonemia, in which the trigger of catabolism is not great. With defects in distal enzymes of the urea cycle, arginine alone is often adequate for clearing elevated ammonia levels, whereas defects of proximal enzymes usually necessitate sodium phenylacetate and sodium benzoate in addition to arginine. A loading dose of all three medications is given first, followed by constant infusion until oral administration can be started, usually when ammonia levels fall below 100 μmol/L.