Table 5. [Long-Term Treatment of Manifestations in...]. - GeneReviews®

Manifestation/ Concern	Treatment	Considerations/Other
Risk for hyperammo- nemia	Protein restriction Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See Table 6.) Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency. Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements.	When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does. Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth. Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies. High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia.
Nitrogen scavengers provide alternative routes for nitrogen disposal & allow more protein intake [Batshaw et al 2001, Berry & Steiner 2001]. Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m²/day sodium phenylbutyrate & 3.8 g/m²/day L-citrulline in persons weighing ≥25 kg. Treatment should be accompanied by an appropriate low-protein diet. Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [Häberle et al 2012]. Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m²/day.	Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects. Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [Scaglia et al 2004, Häberle et al 2012].
Risk for life- threatening hyper- ammonemic crisis	Liver transplantation. See Prevention of Primary Manifestations.
DD/ID ¹	See Developmental Delay / Intellectual Disability Management Issues.
Seizure disorder	Treatment w/ASM as directed by experienced neurologist. Note: Valproic acid is contraindicated for treatment of seizures in urea cycle disorders, as it can cause a hyperammonemic crisis.	Education of parents/caregivers ²

Manifestation/
Concern

Treatment

Considerations/Other

Risk for
hyperammo-
nemia

Protein restriction

Protein intake restricted to RDA for protein or amt necessary to allow growth & prevent catabolism depending on severity of disease (See Table 6.)
Use of an essential amino acid medical food may be needed to maintain normal essential amino acid levels in those on significant protein restriction, even those w/partial OTC deficiency.
Diet should also provide vitamins, minerals, & trace elements to meet recommended needs, either in a calorie-rich protein-free formula or in the form of supplements.

When protein intake is too low, protein catabolism can cause chronic hyperammonemia just as high protein intake does.
Gastrostomy tube feedings help avoid malnutrition in persons who: self-restrict protein intake, object to taste of essential amino acid formulas used to treat urea cycle disorders, &/or cannot consume adequate calories for growth.
Careful monitoring of plasma amino acid concentrations is needed to detect essential amino acid deficiencies.
High glutamine concentrations are interpreted as evidence of poor metabolic control & harbinger of hyperammonemia.

Nitrogen scavengers provide alternative routes for nitrogen disposal & allow more protein intake [Batshaw et al 2001, Berry & Steiner 2001].

Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day sodium phenylbutyrate & 170 mg/kg/day L-citrulline in children <25 kg; & 9.9-13.0 g/m²/day sodium phenylbutyrate & 3.8 g/m²/day L-citrulline in persons weighing ≥25 kg. Treatment should be accompanied by an appropriate low-protein diet.
Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling an addl nitrogen molecule into the urea cycle. (2) If sodium benzoate is being used instead of sodium phenylbutyrate recommended dose is ≤250 mg/kg/day in children <25 kg (max: 12 g/day) [Häberle et al 2012].
Glycerol phenylbutyrate (same mechanism as sodium phenylbutyrate & significantly more palatable) is another treatment option. Dose: 5-12.3g/m²/day.

Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate (vs phenylbutyrate) is the ammonia scavenger of choice in many European countries & Australia because it is felt to have fewer side effects.
Phenylbutyrate causes menstrual dysfunction & body odor, & appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to ↑ renal losses of potassium [Scaglia et al 2004, Häberle et al 2012].

Risk for life-
threatening
hyper-
ammonemic
crisis

Liver transplantation. See Prevention of Primary Manifestations.

DD/ID ¹

See Developmental Delay / Intellectual Disability Management Issues.

Seizure
disorder

Treatment w/ASM as directed by experienced neurologist. Note: Valproic acid is contraindicated for treatment of seizures in urea cycle disorders, as it can cause a hyperammonemic crisis.

Education of parents/caregivers ²

From: Ornithine Transcarbamylase Deficiency

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