Dr Ira Shah
MD, DCH (Gold Medalist), FCPS, DNB

A 5 years old female child born of non consangineous marriage was referred for incidentally detected hyperammonemia 2 years back during an episode of Tuberculous Meningitis.

2 years back, patient had TBM and hyperammonemia (S.NH3- 2000 mcg/dl) with normal liver function tests. She was treated with sodium benzoate at that time.

In the present episode, patient had projectile vomiting and fever with positive meningeal signs. Her development and milestones were normal and she had no skin or hair changes. CSF analysis was suggestive of pyogenic meningitis that responded to 14 days of antibiotics. During the initial phase of pyogenic meningitis her S.NH3 was 1319 mcg/dl that decreased to 169 mcg/dl (Normal – 30 to 90 mcg/dl) by Day14. Her liver function tests were normal and there was no evidence of acidosis. In view of the hyperammonemia with no acidosis, a urea cycle defect was suspected.

Her urinary aminoacidogram and plasma aminoacidogram were normal. There was no evidence of hypoglycemia. An MRI brain showed atrophy of the cerebellum predominantly involving the cerebellar vermis. There were gliotic areas seen in bilateral medial frontal region with atrophy of both frontal lobes predominantly more on the left side, which was suggestive of an ornithine transcarbamylase transferase (OTC) deficiency. Her urine orotic acid could not be done due to unavailability. Thus, she was suspected to have either ornithine transcarbamylase transferase (OTC) deficiency or a Carbamyl phosphate synthetase (CPS) deficiency. However, in view of normal milestones, a diagnosis of OTC deficiency was more likely.

In view repeated meningitis, serum immunoglobulins and C3 were done which were normal. MRI of brain was not suggestive of any CSF rhinorrhea or otorrhoea.

She was treated with protein restriction (1-2gm/kg/day), sodium benzoate, arginine and carnitine. She tolerated the above treatment regime well.

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.

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

1. Sodium benzoate : combines with endogenous glycine to from hippuric acid that is cleared by the kidneys.
   
2. Phenyl acetate : conjugates with glutamine to form phenylacetylglutamine, which is excreted in urine.
   
3. 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).
   
4. Citrulline : It is useful in patients with OTC deficiency.