Allopurinol-induced orotidinuria: a test for mutations at the ornithine carbamoyltransferase locus in women

Article Abstract:

Abnormalities of an enzyme called ornithine carbamoyltransferase can lead to death or coma in male newborn infants, or to mental retardation and bizarre behavior in less severe cases. The disorder is X-linked and can, therefore, be transmitted by the mother to her offspring. Determination of whether a woman is a carrier of an abnormal gene for ornithine carbamoyltransferase could aid in family planning, but conventional tests that use large doses of nitrogen have several disadvantages, including lack of specificity and the discomfort they produce in patients. A screening method is described and tested that uses a dose of allopurinol, which produces orotidine and orotic acid in the urine of women with a defective gene. Five groups were tested: normal, non-carriers (25 women); obligate heterozygotes (women with one or more affected children and additional familial evidence of the disorder, 24); probable heterozygotes (two or more affected children but no other familial evidence, 13); mothers of one affected male (15); and mothers of one affected female (12). Levels of orotic acid and orotidine were measured in urine collected at different times after administration of oral allopurinol. The test was considered positive if one or more values after the first collection period was elevated. Results showed that elevations in orotidine excretion were similar for the obligate (96 percent) and probable heterozygotes (85 percent), but considerably higher than for the normal women, none of whom showed an elevation. Similar results were obtained for orotic acid values, although more overlap among the groups occurred for this variable. Possible explanations for the false negative results (normal values in women with defective children) are evaluated. The test is simple, noninvasive, and reliable, and should be administered to women who might carry an abnormal ornithine carbamoyltransferase gene. (Consumer Summary produced by Reliance Medical Information, Inc.)

Measurement, Testing, Carboxylic acids, Allopurinol

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Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus

Article Abstract:

Deficiency in the enzyme ornithine carbamoyltransferase is a hereditary, X-linked disorder that can manifest itself to varying degrees. Males with the deficiency may experience hyperammonemic (associated with high blood levels of ammonia) coma, and often die, as newborns; or they can have behavior problems or mental retardation throughout life. Girls with an abnormal gene for this enzyme appear clinically normal, although they may exhibit symptoms. The case studies of five female carriers of defective genes for ornithine carbamoyltransferase are reported. All these otherwise healthy patients developed signs of severe central nervous system disorders and coma, most during the postpartum period, and two died. Coma in two women who had not recently given birth was not associated with any obvious event. Blood and urine samples were collected from an additional 18 normal women and 16 asymptomatic carriers of a mutant gene for ornithine carbamoyltransferase. Results of these analyses indicated that carriers had a higher level of blood glutamine and blood ammonium, and lower levels of arginine and citrulline. These findings are typical of disorders of nitrogen metabolism. Overall, it appears that women who are carriers of this mutation are at risk for hyperammonemic coma. Symptoms of this type of coma, including lethargy, stupor, and cortical dysfunction, should precipitate evaluation for ornithine carbamoyltransferase deficiency, especially when they occur around the time of childbirth. (Consumer Summary produced by Reliance Medical Information, Inc.)

Diagnosis, Causes of, Coma, Coma (Medicine), Puerperium

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Long-term treatment of girls with ornithine transcarbamylase deficiency

Article Abstract:

Treating girls with ornithine transcarbamylase deficiency with sodium phenylbutyrate appears to prevent the long-term neurologic damage characteristic of this disease. Ornithine transcarbamylase converts dietary nitrogen to urea, which is excreted in the urine. People with the enzyme deficiency cannot produce urea, so ammonia builds up in their blood, which can damage the brain. Thirty-two girls with the deficiency were treated with sodium phenylbutyrate, which safely excretes dietary nitrogen. The treatment reduced the risk of neurologic complications and stabilized many of the girls' intellectual function.

Drug therapy, Protein metabolism disorders

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