Urea cycle defects and hyperammonemia: Tissue breakdown of amino acids results in production of free ammonia, which is converted to urea through the urea cycle (Kreb’s cycle). Ammonia is highly toxic to the CNS and leads to brain dysfunction, vomiting and even coma and death. In neonates, hyperammonemia presents as refusal to feed, vomiting, tachypnea and lethargy progressing to coma.

Hyperammonemia is seen in conditions such as urea cycle defects, organic acidemias like propionic acidemia, Methyl malonic acidemia, isovaleric acidemia, ketothiolase deficiency, multiple carboxylase deficiency, glutaric acidemia Type II and hyperornithinemia - hyperammonemia – homocitrullinemia syndrome.

In children with organic acidemias, hyperammonemia is commonly associated with severe acidosis.

Recurrent episodes of hyperammonemia (manifested by vomiting, ataxia, mental confusion) with periods of well-being and normal mental development are seen in heterozygote females and in some affected males with ornithine transcarbamylase (OTC) deficiency. It is an X-linked dominant disorder. These episodes usually occur during periods of stress, following high protein diet and during infections. Death may occur during these episodes. It is the commonest of all urea cycle disorders. It is differentiated from Carbamyl phosphate synthetase (CPS) deficiency by increase in urinary orotic acid levels in the former.

CPS deficiency and N - acetylglutamate synthetase (NAG) deficiency are autosomal recessive conditions characterized by hyperammonemia in infants. Late forms of CPS deficiency are characterized by mental retardation with episodes of vomiting and lethargy.

Treatment of Hyperammonemia

Because ammonia is poorly cleared by the kidneys, its removal from the body must be expedited by formation of compounds with high renal clearance.

	Sodium benzoate : combines with endogenous glycine to from hippuric acid that is cleared by the kidneys.
	Phenyl acetate : conjugates with glutamine to form phenylacetylglutamine, which is excreted in urine.
	Arginine : supplies urea cycle with ornithine and N-acetylglutamate and is effective in treatment of hyperammonemia due to defects of urea cycle (except in patients with arginase deficiency).
	Citrulline : It is useful in patients with OTC deficiency.

Management of acute hyperammonemia:

	Protein restriction
	Provide adequate calories, fluids and electrolytes intravenously
	Loading doses of :-
	Sodium benzoate (250mg/kg)
	Sodium phenylacetate (250 mg /kg)
	Arginine hydrochloride (200-800mg/kg)
	Continuous infusion of :
	Sodium benzoate (250- 500 mg/kg/day)
	Sodium phenylacetate (250-500 mg/kg/day)
	Arginine (200-800 mg/kg/day)
	If above treatment fails, peritoneal dialysis or hemodialysis may be required.

Note :-
- Benzoate and phenylacetate should be used with caution in newborn infants with    hyperbilirubinemia as it displaces bilirubin from albumin.
- Arginine should not be used in patients with arginase deficiency and    hyperammonemia due to organic acidemias.

Long term therapy
- Protein restriction (1-2 gm/kg/day)
- Sodium benzoate (250-500mg/kg/day)
- Phenylacetate (250-500 mg/kg/day)
- Arginine (200-400 mg/kg/day)

OR
- Citrulline (200-400 mg/kg/day) in patients with OTC deficiency.
- Carnitine Supplementation is recommended because benzoate and phenylacetate    may cause carnitine deficiency.