Case study- Hyperammonemia

Question of the day -Hyperammonemia

A new-born becomes progressively lethargic after feeding. His respiratory rate increases and he becomes virtually comatose, responding only to painful stimuli, and exhibits mild respiratory alkalosis. Suspicion of a urea cycle disorder is aroused and evaluation of serum amino acid levels is initiated. In the presence of hyperammonemia, production of which of the following amino acids is always increased?

A. Glycine

B. Arginine

C. Proline

D. Histidine

E. Glutamine

Answer- The correct answer is Glutamine. Urea cycle disorder results in reduced ammonia disposal and hence the patients present with symptoms of hyperammonemia.

Ammonia is detoxified by coupling with Glutamate to form Glutamine. This is the first line of defense. The reaction is catalyzed by Glutamine synthetase (figure-1).

Glutamine synthetase

Figure-1- Conversion of glutamate to glutamine

In conditions of hyperammonemia, Glutamate becomes limiting and its concentration is compensated by Amination of alpha-ketoglutarate (a TCA cycle intermediate) to form Glutamate. The reaction is catalyzed by glutamate dehydrogenase (Figure-2).Glutamate can be subsequently aminated with another ammonia molecule to form Glutamine. Thus glutamine concentration increases in blood during conditions of hyperammonemia.

Glutamate dehydrogenase

Figure-2- Showing conversion of glutamate to Alpha ketoglutarate. The reversible reaction is catalyzed by glutamate dehydrogenase. The direction of the reaction depends upon the levels of NADH/NADPH. In normal health the forward reaction is favored, while in hyperammonemia the reaction proceeds towards formation of glutamate.

Ammonia intoxication

Excess of ammonia depletes glutamate and hence GABA level in brain, since Glutamate upon decarboxylation produces GABA (Figure-3).To compensate for glutamate, alpha keto glutarate is used , the decreased concentration of which subsequently depresses TCA and thus deprives brain cells of energy.  Excess Glutamine is exchanged with Tryptophan, a precursor of Serotonin, resulting in hyper excitation. The symptoms of ammonia intoxication are all due to energy depletion and a state of hyper excitation.

Glutamate decarboxylase

Figure-3- Formation of GABA from glutamate.

As regards other options-Glycine, histidine and proline have no roles in detoxification of ammonia and hence the concentrations of these amino acids remains unaffected.

Arginine level can increase depending upon the level of blockage in the urea cycle.

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