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.
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.
phosphate synthetase deficiency
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.
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
acid synthetase deficiency
acid synthetase deficiency or citrullinemia has been mapped to chromosome
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.
acid lyase deficiency
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.
acid synthetase deficiency
acid synthetase catalyzes the formation of N-acetylglutamate.
is an allosteric activator of carbamoyl phosphate synthetase. Carbamoyl
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.
syndrome is due to impaired transport of ornithine across the inner mitochondrial
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.
hyperammonemia of the preterm infant
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.
is necessary for carbamyl phosphate synthetase activity. Treated or not
treated neonates with asymptomatic hyperammonemia do well.
RESPIRATORY CHAIN DISORDERS
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.