- An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist

Hyperammonemia is an important laboratory finding associated with neurometabolic disorders presenting mainly with acute encephalopathy. Normally, plasma ammonium is less than 50 mmol/l (reference range: 15-35 mmol/l); however, it may slightly increase as a result of high protein intake, exercise, or a hemolysed sample. Plasma ammonium levels are also often elevated in patients with severe hepatocellular dysfunction irrespective of the cause, including viral infection, intoxications and infection with urease-positive bacteria, particularly with stasis in the urinary tract, Reye syndrome, valproate therapy and leukemia therapy, including treatment with asparaginase. Following are the inherited metabolic disorders presenting with hyperammonemia:

  1. Urea cycle defects

    N -Acetylglutamate synthetase (NAGS) deficiency
    Carbamoyl phosphate synthetase I (CPS I) deficiency
    Ornithine transcarbamoylase (OTC) deficiency
    Argininosuccinate synthetase (AS) deficiency
    Argininosuccinate lyase (AL) deficiency
    Arginase deficiency
  2. Organic acidemias

    Isovaleric acidemia
    Propionic acidemia
    Methylmalonic acidemia
    Glutaric aciduria type II
    Multiple carboxylase deficiency
    3-Ketothiolase deficiency
  3. Congenital lactic acidosis

    Pyruvate dehydrogenase deficiency
    Pyruvate carboxylase deficiency
    Mitochondrial respiratory chain defects
  4. Fatty acid oxidation defects

    Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
    Long-chain acyl-CoA dehydrogenase (LCAD) deficiency
    Systemic carnitine deficiency
  5. Dibasic amino acid transport defects

    Lysinuric protein intolerance
    Hyperornithinemia Hyperammonemia
    Homocitrullinuria (HHH) syndrome
  6. Hyperammonemia secondary to hepatic dysfunction

    Tyrosinemia type I
    α1 -Antitrypsin deficiency
    Bile acid synthesis defects
    Respiratory chain defects
  7. Others

    Glutamate dehydrogenase deficiency
    (hyperinsulinemia-hyperammonemia syndrome)

A widely used algorithmic approach to the differential diagnosis of hyperammonemic encephalopathy is presented in [Figure 5]. A liver function test will help identify whether hyperammonemia is the result of hepatic dysfunction. The presence of moderate to severe metabolic acidosis indicates that hyperammonemia is a disturbance of either organic acid metabolism or β-oxidation of fatty acids or due to congenital lactic acidosis. The most important diagnostic information after ammonium determination, liver function tests and blood gases, is derived from the quantitative analysis of plasma amino acids. The concentration of citrulline is central to the interpretation of the results of amino acid analysis. If the citrulline concentration is markedly elevated, the most probable diagnosis is citrullinemia, resulting from the argininosuccinate synthetase defect. Extremely low citrulline levels suggest a defect in citrulline biosynthesis, which is the result of a deficiency of CPS I, OTC or NAGS. This can be further evaluated by determining the urine orotic acid and orotidine levels. Moderately elevated citrulline levels generally indicate argininosuccinic aciduria, which occurs due to AL deficiency. This disorder is characterized by the presence of markedly elevated argininosuccinate levels in plasma and urine. A normal citrulline concentration with elevated arginine levels is generally sufficiently specific to diagnose arginase deficiency. In typical lysinuric protein intolerence, plasma arginine, ornithine and lysine levels are markedly reduced. At the same time, a marked increase is observed in the excretion of these compounds in urine, along with increased levels of urinary orotic acid and orotidine. In the HHH syndrome, a disorder characterized by a defective transport of ornithine into the mitochondria, plasma ornithine levels are markedly elevated and urinary orotic acid and orotidine levels are increased. In neonates, symptoms of hyperammonemia during the first 24 h after birth observed in a premature infant is suggestive of transient hyperammonemia of the newborn (THAN).

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