Molecular Basis of the Disease

Defects in the urea cycle constitute a rare group of disorders resulting in the accumulation of urea precursors, mainly ammonium and glutamine. Ornithine transcar-bamylase (OTC) deficiency, the most common inborn error of ureagenesis, is an X-linked disorder. Affected hemizy-gous males typically present in the neonatal period or later in childhood, with symptoms that include vomiting, lethargy, hypothermia, apnea due to hyperammonemia, and leading to coma or death. Recurrent episodes of metabolic crisis can result in MR. The only available treatment after an acute metabolic episode is liver transplantation, which should be performed as early as possible to prevent brain damage. In 15% to 20% of carrier females, symptoms of disease are evident. Symptomatic carrier females typically have later onset but disease also may be fatal, presumably due to an unfavorable pattern of X-inactivation in the liver.5

OTC is a homotrimeric mitochondrial matrix enzyme that catalyzes the synthesis of citrulline from ornithine and carbamyl phosphate, and is found almost exclusively in the liver and intestinal mucosa. Loss of OTC activity results in high plasma glutamine and ammonium, low plasma citrulline and an excess of orotic acid in the urine, a combined metabolic profile that is diagnostic for OTC deficiency. However, a direct assay of OTC activity performed on tissue isolated from a liver biopsy specimen is necessary to obtain unequivocal biochemical results.

The OTC gene is located on Xp21 and spans a region of 73kb that contains ten exons and encodes a protein of 354 amino acids. The overall prevalence of the disease is estimated at 1 in 50,000 in the United States, with similar statistics reported in Japan. Mutations have been identified in all ten exons; however, disease-causing mutations are less frequent in exons 1 and 7, the least conserved exons, most likely reflecting their lesser relevance to the function of the enzyme.6

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