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At a glance

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

Synonyms

Classic Citrullinemia (for Type I); Argininosuccinate Synthetase Deficiency; Citrin Deficiency (for Type II); NICCD Syndrome.

Incidence

The estimated prevalence for Citrullinemia (CTR) Type I, the most common (classic) form of the disorder, is about 2-3:100,000 the general population. The estimated prevalence for CTR2 is highest in Japan, Korea, and China with approximately 1:20,000-50,000. No sexual predilection has been reported.

Genetic inheritance

Autosomal recessive, with frequent compound heterozygotes. CTR I is caused by abnormalities in the ASS1 (Argininosuccinate Synthetase) gene, which is located on chromosome 9q34.11. CTR2 (neonatal and adult onset) is caused by mutations in the SLC25A13 (Solute Carrier Family 25 Member 13 or Citrin) gene and has been mapped to chromosome 7q21.3. Citrin is a hepatic mitochondrial aspartate-glutamate carrier and citrin deficiency causes “neonatal intrahepatic cholestasis caused by citrin deficiency” (NICCD) and/or “failure to thrive and dyslipidemia caused by citrin deficiency” (FTTDCD), and adult-onset CTR2 (see below).

Pathophysiology

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 levels. ASS enzyme activity in CTR1 is low or absent (then occasionally referred to as CTR3 and caused by splicing mutations of ASS). Patients with CTR2, also known as Citrin Deficiency, have an abnormality of the hepatic argininosuccinate synthetase only, and liver biopsy uniformly shows liver steatosis. Citrulline can also be metabolized outside the liver, although to a lesser degree, because skin fibroblasts, brain, and kidneys can express ASS. Citrin is involved in the transport of molecules used for the metabolism of carbohydrates (glycolysis, gluconeogenesis, galactose metabolism), the assembly of proteins, and in the urea cycle. 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. Due to this reaction being compromised, however, the overall capacity of the urea cycle in disposing nitrogen is roughly cut in half. Consequently, affected patients are at risk for developing hyperammonemia, which may result in neurologic deterioration.

Diagnosis

Depends on enzyme activity assays in cultured fibroblasts for CTR1 or in liver cells for CTR2.

Clinical aspects

CTR1, 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 due to cerebral edema. If unrecognized, the condition progresses to coma and eventually death. Surviving infants often show a lower ...

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