Citrullinemia, Report of a Case, with Studies on Antenatal Diagnosis

Abstract

Extract: A case is described of an infant with a deficiency of liver argininosuccinate synthetase, characterized by rapidly increasing drowsiness, respiratory insufficiency, and convulsions starting 67 hr after birth, which resulted in the death of the patient on the 4th day.

Quantitative analyses of amino acids in blood plasma showed increased concentrations of citrulline (2.64 mM) lysine (1.25 mM), histidine (0.34 mM), glutamine (4.17 mM), proline (1.67 mM), glycine (1.35 mM), alanine (3.96 mM), and methionine (0.24 mM).

The activity of argininosuccinate synthetase in a liver biopsy was found to be below the limits of detection, whereas the activities of carbamylphosphate synthetase and ornithine transcarbamylase (21.8 and 55.6 μmol/min × g wet wt, respectively) I were higher than those of the control tissue.

The activity of arginase (141.1 μmol/min × g wet wt), an enzyme localized behind the enzymic block, was found to be lower than that of the controls (230–800 μmol/min × g wet wt).

It is suggested that these differences are due to adaptation of urea cycle enzymes to protein intake as demonstrated by Nuzum and Snodgrass [14] in primates.

The activity of argininosuccinate synthetase of a postmortem brain biopsy was found to be normal. This points to a different genetic origin (isoenzyme) of the brain enzyme.

Cultured amniotic cells of a fetus from a pregnancy in the same family, taken in the 20th week of pregnancy, demonstrated incorporation of ureido-¹⁴C-citrulline into trichloroacetic acid (TCA)-soluble material to an extent half of that observed with cultured amniotic cells from a normal fetus (31 dpm/μg DNA and 68 dpm/μg DNA, respectively). This has been interpreted as being due to the heterozygotic state of the fetus.

After a normal pregnancy a healthy boy was born.

Speculation: The metabolic basis for neurologic abnormalities in citrullinemia is not known. In the present case a virtual absence of argininosuccinate synthetase of liver was found, whereas the activity of the brain enzyme was normal. As the blood ammonia concentration was never found to be abnormal, it is postulated that citrulline itself is toxic, i.e., inhibitory to a biochemical reaction.

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