An infant at 7 months of age presented with history of vomiting and failure to thrive. Patient improved with administration of intravenous glucose and came out of coma within 24 hours. After one month he returned with similar complaints. On evaluation he is found to have raised blood ammonia and No ketones. Also, he has high urinary glutamine, alanine and uracil. Which is the likely enzyme defect is this patient?
Ans. a. Ornithine transcarbamoylase (Ref: Nelson, 20/e p670, Harper 28/242-246) The recurrent symptoms with raised ammonia levels point towards the diagnosis of a Urea cycle defect. The most common urea cycle defect is due to deficiency of the enzyme Ornithine transcar bamoylase. Ornithine Transcarbamoylase (OTC) DeficiencyX-linked partially dominant disorderHemiazygous males are more severely affected than heterozygous females.MC form of all the urea cycle disordersQOTC Gene is mapped to the X chromosome (Xp21.I)QClinical Features:Mild forms characteristically have episodic manifestations. which may occur at any age (usually after infancy).Episodes of hyperammonemia (manifested by vomiting and neurologic abnormalities such as ataxia, mental confusion, agitation, combativeness and frank psychosis) are separated by periods of wellnessQ.These episodes usually occur after ingestion of a high-protein diet or as a result of a catabolic state such as infection.Hyperammonemic coma, cerebral edema, and death may occur during one of these attacks.Gallstones have been seen in the survivors; the mechanism remains unclearDiagnosis:Major laboratory finding during the acute attack is hyperammonemia accompanied by marked elevations of plasma concentrations of glutamine and alanine with low levels of citrulline and arginineQ.Blood level of urea is usually lowQ.Ornithine Transcarbamoylase (OTC) DeficiencyA marked increase in the urinary excretion of Orotic acid differentiates it from Carbamoyl Phosphate Synthase deficiencyQ.Orotate may precipitate in urine as a pink colored gravel or stonesQ.Treatment of Acute hyperammonemiaProvide adequate calories, fluid, and electrolytes intravenously (10% glucose, NaCl and intravenous lipids 1 g/kg/24 hour).Give priming doses of the following compounds: Sodium benzoate. Sodium phenyl acetate and Arginine hydrochlorideContinue infusion of sodium benzoate, sodium phenyl acetate, and arginine following the above priming doses. These compounds should be added to the daily intravenous fluid.Initiate peritoneal dialysis or hemodialysis if above treatment fails to produce an appreciable decrease in plasma ammonia.Citrulline is used in place of arginine in patients with OTC deficiency.Liver transplantation is a successful treatment for patients with OTC deficiency.Fig. 21: Urea cycle: pathways for ammonia disposal and ornithine metabolism. Reactions shown with interrupted arrows are the alternate pathways for the disposal of ammonia. Enzymes: (1) carbamyl phosphate synthetase (CPS). (2) ornithine transcarbamylase (OTC). (3) arginiosuccinic acid synthetase (AS). (4) argininosuccinic acid lyase (AL). (5) arginase (6) ornithine 5-aminotransferase (7) N-acetylutamate (NAG) synthetase. (8) citrin. HHH syndrome, hyperammanemia- hyperonithinemia- homocitrullinemia.
Ornithine transcarbamovlase
CPS1
Arginase
Argininosuccinate lyase
Inborn Errors of Metabolism