Moderate neonatal hyperammonemia (range, 200 to 400 μmol/L) is associated with depression of the central nervous system, poor feeding, and vomiting. Seizures are not characteristic. Respiratory alkalosis may occur. This type of hyperammonemia may be caused by partial or more distal blocks in urea synthesis and commonly is caused by disorders of organic acid metabolism (producing a metabolic acidosis) that secondarily interfere with the elimination of nitrogen.
Infants who are affected by defects in the urea cycle may continue to do well while receiving the low-protein intake of breast milk, developing clinical hyperammonemia when dietary protein is increased or when catabolic stress occurs. Vomiting and lethargy may progress to coma. Seizures are not typical. During a crisis, the plasma ammonia level is usually 200 to 500 μmol/L. However, as the ammonia level decreases with decreased protein intake, the condition may go unrecognized for years, especially in the absence of central nervous system symptoms. If a crisis occurs during an epidemic of influenza, the child mistakenly may be thought to have Reye syndrome.
Disorders of the urea cycle Lethal hyperammonemia is common
Disorders of the propionate Severe hyperammonemia may pathway precede acidosis
Disorders of fatty acid catabolism Reye-like syndrome possible and of ketogenesis
Transient neonatal Idiopathic, self-limited hyperammonemia
Portal-systemic shunting Thrombosis of portal vein, cirrhosis, hepatitis
Mitochondrial DNA depletion Typically associated with elevated lactate level
Drug intoxication: salicylate, Obtain drug levels valproic acid, acetaminophen
Hyperinsulinism/ Clinical hypoglycemia, hyperammonemia syndrome subclinical hyperammonemia
Non-metabolic liver disease Ensure evaluation of hepatic including infections such as function and appropriate herpes, cytomegalovirus infectious disease workup All disorders that cause hypoglycemia: Most hepatic glycogen storage diseases Galactosemia, hereditary fructose intolerance Fructose-1,6-bisphosphatase deficiency Disorders of fatty acid beta oxidation Glucose transporter deficiency
Disorders of the propionate pathway HMG-CoA lyase deficiency Menkes disease Pyruvate carboxylase deficiency (PCD) Maple syrup urine disease
Mitochondrial disease: POLG deficiency Iron-sulfur cluster disease
Maple syrup urine disease Nonketotichyperglycinemia Diseases producing extreme hyperammonemia:
Disorders of the urea cycle Disorders of the propionate pathway
Disorders of beta oxidation Congenital lactic acidosis (PCD)
HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA.
Older children may have neuropsychiatric or behavioral abnormalities (see Fig. 51-2).
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Any organ or system can be injured by toxic accumulation of any of the metabolites involved in inborn errors. Symptoms relate to organ-specific or system-specific toxicity and injury. Examples include nervous system (seizures, coma, ataxia), liver (hepatocellular damage), eye (cataracts, dislocated lenses), renal (tubular dysfunction, cysts), and heart (cardiomyopathy, pericardial effusion) (Table 51-5).
Disorders whose pathophysiology results in energy deficiency (e.g., disorders of fatty acid oxidation, mitochondrial function/oxidative phosphorylation, or carbohydrate metabolism) may manifest myopathy; central nervous system dysfunction, including mental retardation and seizures; cardiomyopathy; vomiting; hypoglycemia; or renal tubular acidosis.