Citrullinemia

A clinically and biochemically heterogenous, inherited disorder caused by argininosuccinate synthetase deficiency that leads to hyperammonemia with neurologic consequences.

Argininosuccinate Synthetase Deficiency.

Unknown because no database exists and many cases may go undiagnosed. However, the overall incidence has been estimated to be approximately 1:250,000 people in the general population. The incidence of citrullinemia type II in Japan is approximately 1:100,000. No sexual predilection has been reported.

Autosomal recessive, with frequent compound heterozygotes. Citrullinemia types I and III are caused by abnormalities of the gene for argininosuccinate synthetase, which is located on 9q34. The gene causing citrullinemia type II has been mapped to 7q21.3.

Under normal conditions, the enzyme argininosuccinate synthase (ASS) catalyzes the condensation of citrulline and aspartic acid to form argininosuccinic acid. Deficiency of ASS leads to marked elevation in the plasma citrulline concentration. There is a relative deficiency of ASS enzyme activity in citrullinemia type I and absent activity in type III. Patients with type II have an abnormality of hepatic argininosuccinate synthetase only, and liver biopsy uniformly shows liver steatosis. Citrulline also can be metabolized outside the liver, although to a lesser degree, because skin fibroblasts, brain, and kidney can express ASS. The reaction of citrulline with aspartic acid is associated with the elimination of one waste nitrogen molecule, while a second waste nitrogen molecule is incorporated into the urea cycle. Because this reaction is compromised, however, the overall capacity of the urea cycle in disposing nitrogen is cut roughly in half. Consequently, affected patients are at risk for developing hyperammonemia, which results in neurologic deterioration.

Enzyme activity assays in cultured fibroblasts in types I and III or in liver cells in type II.

The most common form of the disease presents in the neonatal period with symptoms from hyperammonemia caused by protein intake at 24 to 72 hours of age. Poor feeding and lethargy progress to vomiting, irritability, impaired consciousness, tachypnea, seizures, and apnea. Intracranial pressure is usually increased because of cerebral edema. If unrecognized, the condition progresses to coma and finally death. Surviving infants usually show a lower intelligence quotient. However, some children present later with a subacute form of citrullinemia, which may manifest as mental retardation and other neurologic symptoms such as ataxia. They may show episodic vomiting and hyperammonemia triggered by minor illnesses or other catabolic episodes. The late-onset form of the disease, designated type II, occurs in late childhood or adulthood. Symptoms include enuresis, delayed menarche, insomnia, recurrent vomiting, tremors, episodes of confusion after meals, lethargy, hallucinations, behavioral changes, seizures, and brief episodes of coma. Independent of the type of citrullinemia, the majority of these patients die within a few years after symptom onset. Treatment in the neonatal period includes supportive therapy, intravenous glucose and insulin to suppress the protein catabolism, and use of sodium benzoate and phenylacetate to provide an alternative pathway for nitrogen excretion. Subsequent care depends upon restriction of protein intake to the minimal amount necessary for growth, use of α-keto analogues of essential amino acids, and arginine supplementation. Subsequent episodes of hyperammonemia, triggered by inappropriate diet, drugs (e.g., valproic acid, haloperidol), or illness causing decreased caloric intake and increased protein catabolism can be managed with intravenous glucose and arginine. Orthotopic liver transplantation has been used successfully to treat citrullinemia type II.

Perform a neurologic examination and check for signs of increased intracranial pressure. Obtain a complete blood count and serum concentrations of electrolytes, glucose, and ammonia.

Be aware of the potential for precipitation of hyperammonemia associated with fasting, trauma, surgical stress, or gastrointestinal hemorrhage. In the presence of increased intracranial pressure, a rapid-sequence induction technique (preferably with rocuronium), mild hyperventilation, and intravenous agents or low-dose volatile anesthetics for maintenance are recommended. Prolonged mechanical ventilation may be necessary in patients with preoperative signs of respiratory distress or muscular hypotonia. Regional anesthesia may be advantageous not only from a pharmacologic point of view, but also because it allows assessment of neurologic function at any given time. However, spinal anesthesia must be avoided in the presence of increased intracranial pressure.

Hyperammonemia may be triggered by interaction with various medications. A case report in the literature cites haloperidol specifically causing this reaction in citrullinemia. Sodium valproate has been shown to cause hyperammonemia in urea cycle disorders and should therefore be avoided. Presumably other drugs also can be responsible, so vigilance is essential. Perioperative nutrition should be poor in protein to prevent hyperammonemia.

Argininemia: An urea cycle disorder that leads to hyperammonemia and neurologic symptoms, which are less severe than in other forms of urea cycle abnormalities.

HHH Syndrome: A genetically transmitted inborn error of metabolism caused by a defect in the transport of ornithine into the mitochondrial matrix, clinically characterized by early growth retardation, learning disabilities, periodic confusion, and ataxia.

Methylmalonic Acidemia (MMA): A heterogeneous inborn error of metabolism leading to metabolic acidosis and accumulation of methylmalonic acid and its by-products.

N-Acetylglutamate Synthetase Deficiency: Congenital mitochondrial disorder affecting the metabolism of ammonium resulting in hyperammonemia.

Ornithine Carbamoyltransferase Deficiency (OTCD): A rare genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase. The lack of this enzyme results in excessive hyperammonemia, which is a known neurotoxin. Clinically, these patients present with vomiting, refusal to eat, progressive lethargy, or coma.

Propionic Acidemia: An inborn error of metabolism affecting the mitochondrial catabolism of valine and isoleucine. Untreated, this situation results in ketoacidosis, lethargy, coma, and finally death.