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The immediate treatment of a urea cycle defect is to stop all protein intake and to provide enough glucose to maintain normal glucose levels. Arginine 2 mmol/kg, and sodium benzoate (3% solution) 250 mg/kg should be given over 2 hours. After the 2-hour period, arginine 2 mmol/kg per day, carnitine 150 mg/kg per day, and sodium benzoate infusion (3 % solution) 350 to 500 mg/kg per day should be provided while monitoring plasma benzoate level and sodium. Later, protein 1.2 g/kg per day with 50% as essential amino acids is added. Hemodialysis is superior to peritoneal dialysis to remove excessive ammonia.
The most frequent inherited metabolic causes of hyperammonemia in the neonatal period that primarily involve the urea cycle are: (1) carbamyl phosphate synthetase deficiency, (2) ornithine transcarbamylase deficiency, (3) argininosuccinic acid synthetase deficiency, and (4) argininosuccinic acid lyase deficiency. N-acetylglutamic acid synthetase deficiency and hyperornithinemia-hyperammonemia-homocitrullinuria syndrome will also be considered in this section, since they produce hyperammonemia and do not produce ketosis. Hyperammonemia with ketosis suggests a branched-chain amino acid or an organic acid defect. Transient hyperammonemia of the preterm infant will also be considered in this section.

Carbamyl phosphate synthetase deficiency
The gene for carbamyl phosphate synthetase deficiency has been cloned and mapped to chromosome 2p. Serum glycine and glutamate are high because they are produced in the alternate pathways for ammonia disposal. Serum arginine and citruline are low because they are not being produced. Urinary orotic acid is low. Low urinary orotic acid helps differentiate carbamyl phosphate synthetase deficiency from ornithine-transcarbamylase (OTC) deficiency. The diagnosis is established by liver biopsy. Prenatal diagnosis is possible.

Ornithine-transcarbamylase deficiency
Ornithine transcarbamylase deficiency is the only X-linked urea cycle defect. Ornithine transcarbamylase deficiency in the neonatal period only affects boys. Urinary orotic acid is elevated. The diagnosis is confirmed by liver or intestinal mucosa biopsy. The prognosis of ornithine transcarbamylase deficiency is poor.

Argininosuccinic acid synthetase deficiency
Argininosuccinic acid synthetase deficiency or citrullinemia has been mapped to chromosome 9q34. Serum citruline is high. The diagnosis may be confirmed by cultured skin fibroblasts and leukocytes studies. Prenatal diagnosis can be made by assay of citrulline in the amniotic fluid or enzymatic activity assay in cultured amniotic cells or chorionic villus material.

Argininosuccinic acid lyase deficiency
Argininosuccinic acid lyase deficiency or argininosuccinic aciduria has been mapped to chromosome 7. Serum argininosuccinic acid is high but usually not as high as urine or CSF argininosuccinic acid. Coarse and friable hair (trichorrhexis nodosa) and hepatomegaly may not be present in the neonatal period. The diagnosis may be confirmed by cultured skin fibroblasts and erthrocytes studies. Prenatal diagnosis can be made by assay of argininosuccinic acid in the amniotic fluid or enzymatic activity assay in cultured amniotic cells or chorionic villus material.

N-acetylglutamic acid synthetase deficiency
N-acetylglutamic acid synthetase catalyzes the formation of N-acetylglutamate. N-acetylglutamate is an allosteric activator of carbamoyl phosphate synthetase. Carbamoyl phosphate synthetase is the first enzyme in the urea cycle. The metabolic profile is similar to carbamyl phosphate synthetase deficiency. The diagnosis is confirmed by liver biopsy. Treatment consists of carbamylglutamate supplementation and low protein diet.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is due to impaired transport of ornithine across the inner mitochondrial enzyme. The urea cycle takes place in the cytosol and in the mitochondrion. There are two amino acids that must cross the cytosol-mitochondrion border: citrulline and ornithine. Citrulline normally crosses from the mitochondrion to the cytosol. Ornithine normally crosses from the cytosol to the mitochondrion.

Transient hyperammonemia of the preterm infant
Transient hyperammonemia of the preterm infant occurs in symptomatic and asymptomatic forms. The symptomatic form presents with seizures, coma, and evidence of significant brain stem dysfunction. Hyaline membrane disease is often present. The cause is not known. Treatment with exchange transfusion may require controlling hyperammonemia. The asymptomatic form is arginine-responsive. Arginine is needed to activate the synthesis of N-acylglutamate. N-acylglutamate is necessary for carbamyl phosphate synthetase activity. Treated or not treated neonates with asymptomatic hyperammonemia do well.


Coma in neonates with mitochondrial electron chain disorder occurs in NADH-coenzyme Q reductase (Complex I), cytochrome C oxidase (Complex IV), and in multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia type II). Complex I and IV deficiencies present with overwhelming lactic acidosis. Cardiomyopathy may be present. Lactate-to-pyruvate ratio is above 35. The diagnosis is established by finding NADH-Co Q reductase deficiency or cytochrome C oxidase deficiency in muscle. Treatment consists of riboflavin and succinate sodium administration in Complex I deficiency. There is no effective treatment for Complex IV deficiency.


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Lyon, 1996 Bachmann, 1990 Burlina, 1999 Maestri, 1999 Volpe, 1995 De Vivo, 1990 Ogier, 1990 Stanley, 1990 Would you like to see a figure about it?