Antenatal Diagnosis of Defects of Ureagenesis

Abstract

The approach usually taken to the intrauterine diagnosis of inborn errors of metabolism is to assay a particular enzyme in cultured amniotic cells, the rationale being that if the enzyme is normally present, its absence can be used to indicate fetal disease. Of the five inborn errors of ureagenesis, however, only two, ie citrullinemia and argininosuccinic aciduria, can be diagnosed in this manner because argininosuccinic acid synthetase and argininosuccinic acid lyase are the only urea cycle enzymes normally found in these cells. Both of these disorders have now been detected in utero,87,88 (S. D. Cederbaum and C. R. Scott, unpublished observations, 1980), and several other fetuses at risk have been correctly diagnosed as unaffected88-90 (S. I. Goodman, unpublished observations, 1980). Enzyme deficiency in cultured amniotic cells can be demonstrated directly21,22,91 or by examining the incorporation of 14C into arginine or cell protein.21,73,88,89,92 Further, fetuses with argininosuccinic aciduria have shown increased concentrations of argininosuccinic acid in amniotic fluid at amniocentesis87,88 (S. D. Cederbaum, unpublished observations, 1980) and delivery,93 with its amount remaining undetected when the fetus was not affected88 (S. I. Goodman, unpublished observations, 1980). Argininosuccinic acid is accumulated by the affected fetus, eg it is the most prominent free amino acid in its liver87,94 and, as it is poorly reabsorbed from the glomerular filtrate by cells of the proximal tubule,71 it probably enters the amniotic fluid in fetal urine.95 Thus, provided that a fetus has an intact urinary tract, whether or not it has argininosuccinic aciduria can probably be established within hours of amniocentesis merely by examining the fluid for the acid and/or its anhydrides by ion-exchange chromatography.