Carrier detection in ornithine transcarbamylase deficiency

Abstract

We have studied six known heterozygotes for ornithine transcarbamylase (McKusick 31125; OTC) deficiency. All had abnormal results when tested by measurement of urine orotic acid after protein loading. Duodenal mucosa OTC assay detected fewer of the known heterozygotes but was a useful supplementary test. Urine orotic acid excretion after protein loading is influenced by age and results from women being tested must be compared with those from controls of appropriate age.

Failure of protein loading tests to identify heterozygosity for ornithine carbamoyltransferase deficiency

“…The amounts of known interfering substances (Kesner et al, 1975) present in urine are most unlikely to have caused an inhibition of colour development to the major degree necessary to cause "false negative" results in Mrs G.'s loading tests. Further, the levels of orotic acid measured in her fasting urine specimens were slightly higher than the fasting levels reported by Haan et al (1982) who used a more specific chromatographic method. We consider that the mother's heterozygosity is established historically and that, further, more invasive tests for confirmation cannot be justified at present.…”

“…Others have confirmed the observation that this relatively simple and non-invasive test identifies heterozygotes more reliably than the measurement of blood ammonia after a similar protein or ammonia load (Hokanson et al, 1978;Haan et al, 1982) and also more reliably than measurement of OCT in intestinal biopsies (Haan et at., 1982). The wide variation in the clinical expression of the defect observed in carrier females has been attributed to variations in inactivation of the mutant X chromosomes in liver parenchymal cells which are frequently tetraploid.…”

“…On similar grounds there is the expectation that the protein loading test will not detect all asymptomatic heterozygotes. Nevertheless, in four reported series, all 14 obligate heterozygotes to whom the test was applied demonstrated a marked increase in orotic acid excretion which could be easily distinguished from the small increase in controls (Goldstein et al, 1974;Hokanson et al, 1978;Batshaw et aI., 1980;Haan et al, 1982).…”

Ornithine Transcarbamylase Deficiency in Male Adolescence and Adulthood

“…Another possiblity is that a mutant OTC might have altered kinetic properties in which there is higher activity or greater af in family members of the other 2 pa tients, the data were less striking, but 1 of the sisters (Ni-II-11) of patient 1 excreted an ele vated level of orotic acid in the urine after protein loading, and the daughter (Ok-III-4) of patient 2 had elevated levels on the same diet. The data may not conclusively identify these individuals as heterozygous, particu larly the daughter of patient 2, since age de pendency has been reported for orotic acid uria after a protein load [34], Nevertheless, it may be presumed that both patients had heritable OTC deficiency. In addition to these laoding-test results, a brother (Ni-II-4) of patient 1 died of a dis ease which was probably identical with that of the proband, and a grandson (Ni-IV-3) of this patient developed a hyperammonemic crisis suggestive of OTC deficiency.…”

Immunocytochemical localization of ornithine carbamoyl‐transferase in the liver and intestinal mucosa

“…OCT activity in the duodenal mucosa is 5-10% that in the liver (Haan et al, 1982). Our results suggest that the amount of OTC in the mitochondria of the duodenal mucosa is half that in the mitochondria of liver cells.…”