GENERAL INFORMATION
• 90% of the nitrogenous compounds that are formed as a result of protein metabolism and that are not used are converted into ammonia in the liver and ammonia is excreted from the body with the urea cycle.
• Enzyme defects in these cycle steps result in hyperammonemia.
Enzyme deficiencies in this cycle
1. Carbamoyl phosphate synthetase (CPS): It is autosomal recessive.
2. Ornithine transcarbamylase (OTC): It is X-linked partial dominant (the most common form) inherited.
3. Argininosuccinate synthetase (AS): Citrullinemia type I occurs in its deficiency. It is autosomal recessive.
4. Argininosuccinate lyase (AL): In its deficiency, argininosuccinic acidemia occurs. It is autosomal recessive.
5. Arginase: Deficiency causes arginineemia. It is autosomal recessive.
6. N-acetylglutamate (NAG) synthetase
Clinic
• Clinical findings due to hyperammonemia are refusal of feeding, vomiting, tachypnea, alkalosis, lethargy, convulsions and hypotonic encephalopathy, and coma, with the onset of feeding a few days after a normal delivery.
• On physical examination, hepatomegaly and fontanel camber due to increased intracranial pressure and dilated pupil may be seen.
• Symptoms are mostly seen after infections and protein foods and there is a feeling of disgust for protein foods.
• While citrullinemia type 1 develops in arginosuccinate synthase deficiency; Citrullinemia type 2 occurs in mitochondrial aspartate-glutamate carrier protein "citrine" deficiency. While the neonatal form progresses with tyrosinemia I-like cholestatic liver failure; The adult form with symptoms between the ages of 20-40 progresses with neuropsychiatric symptoms such as psychosis, delirium, tremor, and disorientation.
• In arginino succinic acidemia, arginine deficiency leads to dry and brittle hair (tricorhexis nodosa).
• Hyperammonemia is mild in arginase deficiency. Therefore, it is the urea cycle defect whose clinical findings are different from the others. It presents with progressive spastic diplegia, choreoathetosis and developmental delay, and later on, degenerative disease-like clinical findings.
Diagnosis:
• Ammonia level in plasma is high (>200 µmol/Lt) (The upper limit of normal ammonia level is 100 µmol/Lt in newborns and 150 µmol/Lt in prematures).
• Blood urea nitrogen (BUN) and urea values are low.
• Blood pH may be normal or high. The most important difference from organic acidemias is the absence of metabolic acidosis and ketonuria.
• Since ammonia causes swelling in the mitochondria of the liver, elevated transaminases may occur. In some cases of OTC deficiency, signs of acute liver failure may develop.
• Alanine and glutamine were increased in all defects. Citrulline is low in mitochondrial defects.
• Except for arginase deficiency, all of them are low in arginine.
• OTC deficiency is distinguished from CPS deficiency by a marked increase in orotic acid in the urine.
• Low citrulline in plasma, high urinary orotate excretion, and a family history of death in boys without ketoacidosis in a male infant with hyperammonemia confirm the diagnosis of OTC deficiency, which is the most common form.
Treatment:
Treatment of acute hyperammonemia
1. In order to reduce catabolism, IV 10% glucose, NaCl, lipid infusion and a small amount of protein (0.25 g/kg/24 hours) containing essential amino acids are given especially in the first 24 hours. When switching to oral nutrition, it is given at a dose of 0.5-1.0 g/kg/day, again with limited protein.
2. Intravenous sodium benzoate, sodium phenylacetate, phenyl butyrate and arginine hydrochloride are started to reduce ammonia.
3. Each mole of sodium benzoate combines with glycine to turn into hippuric acid and removes 1 mole of ammonia. One mole of sodium phenylacetate binds glutamine and removes 2 moles of ammonia.
4. IV arginine hydrochloride is given in all urea cycle defects except arginase deficiency. Arginine and citrulline are contraindicated in arginase deficiency.
5. Citrulline is added to the treatment in patients with OTC deficiency.
6. If ammonia cannot be reduced despite these treatments, dialysis should be performed (preferably hemodialysis; peritoneal dialysis also removes organic acids in organic acidemias; exchange transfusion should not be preferred except in newborns with hyperbilirubinemia).
long-term treatment
1. Protein in the diet is given as 1-1.5 g/kg/day.
2. They take sodium benzoate, sodium phenylacetate (or sodium phenylbutyrate) and arginine orally at home.
3. Patients with OTC deficiency are given citrulline. Arginine and citrulline are not used in arginase deficiency.
4. Carbamylglutamate therapy alone is very effective in patients with NAG synthase deficiency.
5. The use of valproate as an antiepileptic should be avoided in children with urea cycle defect as it may cause hyperammonemia attack.
6. Liver transplantation is successful in cases with OTC deficiency.
