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

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Argininosuccinate Synthetase Deficiency.

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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.

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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.

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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.

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

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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 ...

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