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Urea Cycle Disorders Treatment Guidelines

The following definitions are provided as a reference for physicians. A list of definitions for patients and family has also been provided - click here.

Contents: Diagnosis | Treatment | Treatment Issues | Long Term Management

Diagnosis

The most important step in diagnosing urea cycle disorders is clinical suspicion of hyperammonemia. A blood ammonia level is the first laboratory test in evaluating a patient with a suspected urea cycle defect. Particular care should be taken in drawing a blood ammonia since there is significant variability depending on proper technique and handling The clinician should remember that treatment should not be delayed in efforts to reach a final diagnosis, and that later stages of treatment should be tailored to the specific disorder. In addition to plasma ammonia, laboratory data useful in the diagnosis of UCDs include, pH, CO2, the anion gap, blood lactate, plasma acylcarnitine profile acylcarnitines, plasma and urine amino acids, and urine organic acid analyses including the specific determination of orotic acid.(1, 2) Patients with true urea cycle defects will typically have normal glucose and electrolyte levels. The pH and CO 2 can vary with the degree of cerebral edema and hyper- or hypo-ventilation. In neonates it should be remembered that the basal ammonia level is elevated over that of adults, which typically is less than 35 µmol/L (less than 110 µmol/L in neonates). An elevated plasma ammonia level of 150 µmol/L (>260 µg/dl) or higher in neonates and > 100 µmol/l (175 µg/dl) in older children and adults, associated with a normal anion gap and a normal blood glucose level, is a strong indication for the presence of a urea cycle defect. Quantitative amino acid analysis can be used to evaluate these patients and arrive at a tentative diagnosis. Elevations or depressions of the intermediate amino containing molecules arginine, citrulline, and argininosuccinate (Figure 1, Diagnostic Flow Chart) will give clues to the point of defect in the cycle. The amino acid profile in sick newborns can be quite different from those in children and adults which should be taken into account.(2) The levels of the nitrogen buffering amino acid glutamine will also be quite high and can serve as confirmation of the hyperammonemia. If a defect in NAGS, CPSI, or OTC is suspected, the presence of the organic acid orotic acid in the urine can help distinguish the diagnosis. Orotic acid is produced when there is an overabundance of carbamyl phosphate which spills into the pyrimidine biosynthetic system. The determination of urine organic acids and plasma acylcarnitines will also herald the presence of an organic aciduria. Other genetic defects that affect ammonia detoxification are lysinuric protein intolerance, the hyperinsulinism-hyperammonemia syndrome, hypoprolinemia (paradoxical fasting hyperammonemia) and pyruvate cxarboxylase deficiency. All of them are very rare and important hints would be obtained through the investigations outlined above.

Figure 1. Diagnostic Flow Chart for Acute Hyperammonemia

Click on diagram to view a larger version

Enzymatic and genetic diagnosis is available for all of these disorders. For CPSI, OTC, and NAGS, enzymatic diagnosis is made on a liver biopsy specimen freshly frozen in liquid nitrogen.(3) Enzymatic testing for ASS, ASL can be done on fibroblast samples and arginase can be tested on red blood cells.(4) Clinically approved DNA sequence analysis is only available for OTC at the time of this printing, but its availability for the other disorders is anticipated soon, as it is available outside the US. A frequently updated web resource for testing information can be found at the NIH sponsored site: http://www.geneclinics.org.

Treatment of Urea Cycle Disorders

This section provides an overview of UCD management.(2, 5-8) The treatment of these patients requires a highly-coordinated team of specialists trained in caring for patients with inborn errors of metabolism. Emergency management of patients in hyperammonemic coma resulting from a UCD is based on three interdependent principles: first, physical removal of the ammonia by dialysis or some form of hemofiltration; second, reversal of the catabolic state through caloric supplementation and in extreme cases, hormonal suppression (glucose/insulin drip); and third, pharmacologic scavenging of excess nitrogen. These are not consecutive but should be pursued independently in parallel as quickly as possible.(8-10) (Figure 3, Emergency Management)

Figure 2: Treatment Team and Organization

  • Metabolic Specialist
    • coordinate treatment and management
  • Intensive care team
    • assist with physiologic support
    • ventilator management
    • sedation and pain management
  • Nephrologist or dialysis team
    • manage dialysis
    • manage renal complications
  • Surgical team
    • large bore catheter placement
    • liver biopsy as necessary
    • gastrostomy tube placement (if indicated)
  • Pharmacy staff
    • formulate nitrogen scavenging drugs
    • cross check dosing orders in complex management
  • Laboratory staff
    • analyze large volume of ammonia samples in acute phase
    • analyze amino acids and other specialty labs
  • Nursing staff
    • execute complex and rapidly changing management plan
    • closely monitor patient for signs of deterioration or change
  • Nutritionist
    • maximize caloric intake with neutral nitrogen balance
    • educate family in management of complex very low-protein diet
  • Social work
    • rapidly identify resources for complex outpatient treatment regimen
    • work with families in highly stressful clinical situation
  • Genetic Counselor
    • educate family in genetics of rare metabolic disease
    • identify other family members at potential risk (OTC particularly)
    • ensure proper samples are obtained for future prenatal testing
    • contact research/diagnostic centers for genetic testing

Figure 3: Emergency Management

  • Fluids, dextrose, and interlipid to mitigate catabolism and typical dehydration (attempt 80 cal/kg/day)
  • Antibiotics and septic workup to treat potential triggering events or primary sepsis (continue through treatment course)
  • Contact and possible transport to treatment-capable institute as soon as possible
  • Remove protein from intake (P.O. or TPN)
  • Establish central venous access
  • Provide physiologic support (pressors, buffering agents, etc.). (Renal output is critical to long term success).
  • Stabilize airway as cerebral edema may result in sudden respiratory arrest

If ammonia does not fall with high-calorie infusion plus pharmaceutical measures, central venous access should be established at once and dialysis begun immediately at the highest available flow rate if plasma ammonia >500 m mol/l . Dialysis is very effective for the removal of ammonia and the clearance is dependent on the flow through the dialysis circuit.(11, 12) In severe cases of hyperammonemia, provision for hemofiltration should be made to follow the dialysis until the patient is stabilized and the catabolic state is reversed. Some patients will reaccumulate ammonia after their initial round of dialysis and may require additional periods of dialysis. Most patients will have a slight rise in ammonia after dialysis since removal by scavengers and the liver will not be as effective. This slight rise usually does not necessitate repeat dialysis.

The importance of the management of the catabolic state can not be overstressed.(6) Since the catabolism of protein stores is often the triggering event for hyperammonemia, the patient will not stabilize and ammonia will continue to rise until it is reversed. Fluids, dextrose and Intralipid® should be given to blunt the catabolic process. The patient should be assessed for dehydration and fluids replaced. Since these patients suffer from cerebral edema, care should be taken to avoid overhydration. The nitrogen scavenging drugs are usually administered in a large volume of fluid which should be taken into consideration. A regimen of 80-120 kcal/kg/day is a reasonable goal. The administration of insulin and glucose are useful. At the same time, protein must be temporarily removed from intake (PO or TPN). Supplementation of arginine serves to replace arginine not produced by the urea cycle (in addition to the partial cycle function it can stimulate) and prevents its deficiency from causing additional protein catabolism. Refeeding the patient as soon as practicable is useful since more calories can be administered this way. The use of essential amino acid formulations in feeding can reduce the amount of protein necessary to meet basic needs.(6) Table 1 is extracted from Singh et al and lists the proposed caloric needs for patients with urea cycle disorders.(6)

Table 1: Recommended Daily Nutrient Intakes (Ranges) for Infants, Children, and Adults With Urea Cycle Disorders

  Nutrient
Age Protein Patient Keal Intake Energy Fluid
Infants
0 to 3 months 2.20 - 1.25(g/kg) 150 - 101(kcal/kg) 150 - 125(kcal/kg) 160 - 130(mL/kg)
3 to 6 months 2.00 - 1.15 (g/kg) 100 - 80 (kcal/kg) 140 - 120 (kcal/kg) 160 - 130 (mL/kg)
9 to 12 months 1.60 - 0.90 (g/kg) 80 - 75 (kcal/kg) 120 - 110(kcal/kg) 130 - 120(mL/kg)
 
Girls and Boys
1 to 4 years 8 - 12 (g/day) 800 - 1040 (kcal/day) 945 - 1890 (kcal/day) 945 - 1890 (mL/day)
4 to 7 years 12 - 15 (g/day) 1196 - 1435 (kcal/day) 1365 - 2415 (kcal/day) 1365 - 2245 (mL/day)
7 to 11 years 14 - 17 (g/day) 1199 - 1693 (kcal/day) 1730 - 3465 (kcal/day) 1730 - 3465 (mL/day)
 
Women
11 to 15 years 20 - 23 (g/day)   1575 - 3150 (kcal/day) 1575 - 3150 (mL/day)
15 to 19 years 20 - 23 (g/day)   1260 - 3150 (kcal/day) 1260 - 3150 (mL/day)
less than or equal to 19 years 22 - 25 (g/day)   1785 - 2625 (kcal/day) 1875 - 2625 (mL/day)
 
Men
11 to 15 years 20 - 23 (g/day)   2100 - 3885 (kcal/day) 2100 - 3885 (mL/day)
15 to 19 years 21 - 24 (g/day)   2200 - 4095 (kcal/day) 2200 - 4095 (mL/day)
less than or equal to 19 years 23 - 32 (g/day)   2625 - 3465 (kcal/day) 2625 - 3465 (mL/day)

Emergency pharmacologic management with ammonia scavengers and arginine is initiated as soon as possible using the drug combination sodium phenylacetate and sodium benzoate (Ammonul, Ucyclyd Pharma), ideally while the dialysis is being arranged and the diagnostic workup is under way. Two agents are used in combination to trap nitrogen in excretable forms. Sodium benzoate combines with glycine to make hippurate which is excreted by the kidneys (or removed in the dialysate), and sodium phenylacetate combines with glutamine to make phenacetylglutamine which is also excreted in the urine.(13, 14) The body replaces these amino acids using excess nitrogen. It is suspected that the removal of glutamine by phenylacetate has the additional benefit of removing a compound suspected of having a major role in the neurotoxicity of these disorders.(15-20) Currently administering a second loading dose to the patient after the initial phase is not recommended. Arginine must also be administered continuously in the acute phase of treatment of urea cycle disorders. In addition to replenishing circulating amino acid levels, arginine can utilize those parts of the cycle not affected by genetic blocks and incorporate some nitrogen. Since arginine is the precursor for nitric oxide production, it is worth considering modification of the arginine dose downward if the patient develops vasodilation and hypotension. Table 2 lists doses for the acute management of these patients according to the diagnosis at the time of treatment (information extracted from FDA package insert). Due to the potential for toxicity (lethal in extreme cases) of these drugs consultation with an experienced metabolic physician is recommended before starting treatment.(21) A resource for finding these physicians and other treatment suggestions is found in the home page for this web site at: www.RareDiseasesNetwork.org/ucdc.

Table 2: Ammonul Dosage and Administration Summary Tables

Patient Population: Neonates to Young Children: NAGS, CPS and OTC Deficiency

 

Components of Infusion Solution

Dosage Provided

 

Ammonul

Arginine HCl Injection, 10%

Dextrose Injection, 10%

Sodium Phenylacetate

Sodium Benzoate

Arginine HCl

Loading Dose (90 min)

2.5 mL/kg

2.0 mL/kg

greater or equal to 25 mL/kg

250 mg/kg

250 mg/kg

200 mg/kg

Maintenance Dose

2.5 mL/kg/24 hr

2.0 mL/kg/24 hr

greater or equal to 25 mL/kg

250 mg/kg/24 hr

250 mg/kg/24 hr

200 mg/kg/24 hr

Patient Population: Neonates to Young Children: Unknown, ASD and ASL Deficiency

 

Components of Infusion Solution

Dosage Provided

 

Ammonul

Arginine HCl Injection, 10%

Dextrose Injection, 10%

Sodium Phenylacetate

Sodium Benzoate

Arginine HCl

Loading Dose (90 min)

2.5 mL/kg

6.0 mL/kg

greater or equal to 25 mL/kg

250 mg/kg

250 mg/kg

600 mg/kg

Maintenance Dose

2.5 mL/kg/24 hr

6.0 mL/kg/24 hr

greater or equal to 25 mL/kg

250 mg/kg/24 hr

250 mg/kg/24 hr

600 mg/kg/24 hr

Patient Population: Older Children and Adults: NAGS, CPS and OTC Deficiency

 

Components of Infusion Solution

Dosage Provided

 

Ammonul

Arginine HCl Injection, 10%

Dextrose Injection, 10%

Sodium Phenylacetate

Sodium Benzoate

Arginine HCl

Loading Dose (90 min)

55 mL/m 2

2.0 mL/kg

greater or equal to 25 mL/kg

5.5 g/m 2

5.5 g/m 2

200 mg/kg

Maintenance Dose

55 mL/m 2 /24 hr

2.0 mL/kg/24 hr

greater or equal to 25 mL/kg

5.5 g/m 2 /24 hr

5.5 g/m 2 /24 hr

200 mg/kg/24 hr

Patient Population: Unknown, ASD and ASL Deficiency

 

Components of Infusion Solution

Dosage Provided

 

Ammonul

Arginine HCl Injection, 10%

Dextrose Injection, 10%

Sodium Phenylacetate

Sodium Benzoate

Arginine HCl

Loading Dose (90 min)

55 mL/m 2

6.0 mL/kg

greater or equal to 25 mL/kg

5.5 g/m 2

5.5 g/m 2

600 mg/kg

Maintenance Dose

55 mL/m 2 /24 hr

6.0 mL/kg/24 hr

greater or equal to 25 mL/kg

5.5 g/m 2 /24 hr

5.5 g/m 2 /24 hr

600 mg/kg/24 hr

After the initial loading phase and dialysis, the patient's dose should be converted to the maintenance doses of the ammonia scavengers listed in the manufacturers packaging insert (Table 1). If the exact enzyme defect is known the amount of arginine administered can be adjusted downward. If chronic therapy is warranted the patient can then be switched to the oral pro-drug of phenylacetate, phenylbutyrate (Buphenyl). The usual total daily dose of Buphenyl Tablets and Powder for patients with urea cycle disorders is 450 - 600 mg/kg/day in patients weighing less than 20 kg, or 9.9 - 13.0g/m2/day in larger patients. The tablets and powder are to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day). Citrulline supplementation is recommended for patients diagnosed with deficiency of n-acetylglutamate synthase, carbamylphosphate synthetase or ornithine transcarbamylase; citrulline; daily recommended intake is 0.17g/kg/day or 3.8g/m2/day. Arginine supplementation is needed for patients diagnosed with deficiency of argininosuccinic acid synthetase; arginine (free base) daily intake is recommended at 0.4 - 0.7g/kg/day or 8.8 - 15.4g/m2/day. In patients with n-acetylglutamate synthetase, the use of carbamyl glutamate has been demonstrated to be very effective(22), and a study investigating its utility is listed in this web site at: www.RareDiseasesNetwork.org/ucdc.

Other Treatment Issues

In all instances intensive care treatment has to be meticulous. Ventilator or circulatory support may be required Anticonvulsive medication to control seizures and sedation or head cooling to reduce cerebral activity could be of benefit to these patients but has not been clinically evaluated for effect. Antibiotic therapy and evaluation for sepsis is recommended because sepsis is an important consideration in the primary presentation and if present may lead to further catabolism. Electrolytes and acid-base balance are to be checked every 6 hours during the initial phase of treatment. The use of osmotic agents such as mannitol is not felt to be effective in treating the cerebral edema from hyperammonemia but this is mainly anecdotal. In canines, opening the blood brain barrier with mannitol resulted in cerebral edema by promoting the entry of ammonia into the brain fluid compartment.(23, 24) Intravenous steroids and valproic acid should be avoided. Other measures include physiologic support (pressors, buffering agents to maintain pH and buffer arginine HCl, etc.) and maintenance of renal output, particularly if ammonia scavengers are being used. Finally, it is imperative to reassess continuation of care after the initial phase of treatment.

Rapid response to the hyperammonemia is indispensable for a good outcome.(25, 26) Acute symptomatology centers around cerebral edema, disruptions in neurochemistry and pressure on the brainstem. The resulting decrease in cerebral blood flow plus prolonged seizures, when they occur, are poor prognostic factors. In adults, because the sutures of the skull are fused, sensitivity to hyperammonemia appears considerably greater than in children.(8) Thus treatment should be aggressive and intensified at a lower ammonia concentration than in children.

Neurologic Evaluation: Cerebral studies should be conducted to determine the efficacy of treatment and whether continuation is warranted. EEG should be performed to assess both cerebral function and evidence of seizure activity. If available, MRI determined cerebral blood flow can be used to establish if venous stasis has occurred from cerebral edema. Evaluation of brain stem function and higher cortical function are useful to assess outcome. Finally, the decision for continuation is based on baseline neurologic status, duration of the patient's coma and potential for recovery, and whether the patient is a candidate for transplantation. If the basic urea cycle defect is severe enough, liver transplantation should be considered. Criteria for transplantation are of course linked back to neurologic status, duration of coma, and availability of donor organs. Diagnostic samples of DNA, liver, and skin should be obtained since they can be central in family counseling and future treatment issues.

Long Term Management

Every effort should be made to avoid triggering events. It is imperative to prevent or quickly interrupt a catabolic state at an early stage of impending decompensation during subsequent illnesses or surgeries, as well as during any event resulting in significant bleeding or tissue damage. As this usually happens at home, it is essential to educate the family about how to react adequately.(7, 8, 27, 28) All patients should carry an emergency card or bracelet containing essential information and phone numbers as well as instructions on emergency measures. Every patient should relate to physicians and a hospital with a dedicated team of metabolic specialists who can be reached at any time. For vacations it is usually prudent to enquire about metabolic services in the respective destination.

Long-term diet modification with nutritional oversight is often necessary in patients with chronic episodes of hyperammonemia. Patients should also avoid dehydration, an especially common occurrence among adults in connection with alcohol intake, hiking, and airline flights. Not all adult patients who recover from a hyperammonemic episode require chronic nitrogen scavengers, but they ought to be considered since many of these patients can become more brittle as time goes on. In particular, IV steroids for asthma and administration of valproic acid are contraindicated.

Should psychiatric problems occur over the long term, care givers should be alert to the possibility of hyperammonemia. In addition, many patients with citrullinemia type 2, in particular, have presented with mental disturbance.(29, 30)

Clinical observations of patients with argininosuccinic acid lyase deficiency demonstrate a high incidence of chronic progressive cirrhosis with eventual fibrosis of the liver. This finding is not commonly seen in the other urea cycle disorders and studies are underway to better determine the exact pathophysiology. It is important to provide genetic counseling in order to assess risk to other family members.

Reference List

1. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr 2001; 138(1 Suppl):S21-S29.

2. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138(1 Suppl):S30-S39.

3. Tuchman M, Tsai MY, Holzknecht RA, Brusilow SW. Carbamyl phosphate synthetase and ornithine transcarbamylase activities in enzyme-deficient human liver measured by radiochromatography and correlated with outcome. Pediatr Res 1989; 26(1):77-82.

4. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr 2001; 138(1 Suppl):S21-S29.

5. Summar ML. Presentation and management of urea cycle disorders outside the newborn period. Crit Care Clin 2005; 21(4 Suppl):ix.

6. Singh RH, Rhead WJ, Smith W, Lee B, King LS, Summar M. Nutritional management of urea cycle disorders. Crit Care Clin 2005; 21(4 Suppl):S27-S35.

7. Lee B, Singh RH, Rhead WJ, Sniderman KL, Smith W, Summar ML. Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin 2005; 21(4 Suppl):S19-S25.

8. Summar ML, Barr F, Dawling S et al. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 2005; 21(4 Suppl):S1-S8.

9. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138(1 Suppl):S30-S39.

10. Summar M, Pietsch J, Deshpande J, Schulman G. Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia. J Pediatr 1996; 128(3):379-382.

11. Summar M. Current strategies for the management of neonatal urea cycle disorders. J Pediatr 2001; 138(1 Suppl):S30-S39.

12. Summar M, Pietsch J, Deshpande J, Schulman G. Effective hemodialysis and hemofiltration driven by an extracorporeal membrane oxygenation pump in infants with hyperammonemia. J Pediatr 1996; 128(3):379-382.

13. Batshaw ML. Sodium benzoate and arginine: alternative pathway therapy in inborn errors of urea synthesis. Progress in Clinical & Biological Research 1983; 127:69-83.

14. Batshaw ML, Brusilow SW. Evidence of lack of toxicity of sodium phenylacetate and sodium benzoate in treating urea cycle enzymopathies. Journal of Inherited Metabolic Disease 1981; 4(4):231.

15. Batshaw ML, Brusilow SW. Treatment of hyperammonemic coma caused by inborn errors of urea synthesis. Journal of Pediatrics 1980; 97(6):893-900.

16. Brusilow SW, Valle DL, Batshaw M. New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 1979; 2(8140):452-454.

17. Brusilow SW. Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatric Research 1991; 29(2):147-150.

18. Butterworth RF. Effects of hyperammonaemia on brain function. [Review] [75 refs]. Journal of Inherited Metabolic Disease 1998; 21 Suppl 1:6-20.

19. Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatric Research 1993; 33(1):77-81.

20. Willard-Mack CL, Koehler RC, Hirata T et al. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 1996; 71(2):589-599.

21. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 2001; 138(1 Suppl):S46-S54.

22. Morizono H, Caldovic L, Shi D, Tuchman M. Mammalian N-acetylglutamate synthase. Mol Genet Metab 2004; 81 Suppl 1:S4-11.

23. Fujiwara M. Role of ammonia in the pathogenesis of brain edema. Acta Medica Okayama 1986; 40(6):313-320.

24. Fujiwara M, Watanabe A, Shiota T et al. Hyperammonemia-induced cytotoxic brain edema under osmotic opening of blood-brain barrier in dogs. Res Exp Med (Berl) 1985; 185(6):425-427.

25. Brusilow SW. Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy. Prog Liver Dis 1995; 13:293-309.

26. Brusilow SW. Disorders of the urea cycle. Hospital Practice (Office Edition) 1985; 20:65-72.

27. Smith W, Kishnani PS, Lee B et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin 2005; 21(4 Suppl):S9-17.

28. Dixon MA, Leonard JV. Intercurrent illness in inborn errors of intermediary metabolism. Arch Dis Child 1992; 67(11):1387-1391.

29. Saheki T, Kobayashi K, Iijima M et al. Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle. Mol Genet Metab 2004; 81 Suppl 1:S20-S26.

30. Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet 2002; 47(7):333-341.

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For Physicians: Disorder Definitions

 

Carbamyl Phosphate Synthetase (CPS) Deficiency N-Acetylglutamate Synthase (NAGS) Deficiency Argininosuccinate Synthetase Deficiency (Citrullinemia One) Argininosuccinate Lyase Deficiency Arginase Deficiency (Hyperargininemia) Hyperornithinemia, Hyperammonemia and Homocitrullinuria (HHH) Syndrome Ornithine Transcarbamylase (OTC) Deficiency Citrin Deficiency (Citrullinemia Two)