The enzymology of chorionic villi and the first trimester diagnosis of metabolic disorders

Abstract

The advantage of prenatal diagnosis of genetic metabolic disorders during the first 8–11 weeks of pregnancy using chorionic villi rather than at 18 weeks or later using cultured amniotic cells is so great that it is not surprising that many laboratories are now engaged in assessing the normal metabolic activities of chorionic villi. Indeed, in the short mme since Kazy et al. (1982) first reported the presence of lysosomal enzymes in normal villi, diagnostic studies have been carried out in pregnancies at risk for several different diseases and some affected fetuses correctly detected. These diseases are almost all recessive conditions with a 25% risk of recurrence and comprise one of the highest risk groups for which second-trimester diagnosis is currently carried out. About 60 diseases have been diagnosed in utero in the second trimester and techniques exist for almost as many more (for review, see Benson and Fensom, 1985). It seems likely that most of these conditions will prove amenable to first trimester diagnosis although the specific techniques which are required for each disease and which have been developed for use with amniocytes need to be evaluated carefully before application to villi. The effect of gestational age on enzyme activities in normal villi over the whole diagnostic period must be studied and consideration must be given to the fact that the disease-specific enzyme assays developed for amniotic cells may lack this specificity when applied to villi, particularly when artificial substrates are employed. In the development of methods for second-trimester diagnosis, enzymatic properties of cultured fibroblasts from affected patients and their parents have been compared with those of normal amniotic cells, and this has been invaluable for optimizing the discrimination between affected, heterozygous and normal genotypes. Unfortunately, no exactly analogous postnatal equivalent to cultured fibroblasts from affected patients exists for comparison with normal villi, and the applicability of the assays for first trimester diagnosis will only be proven by carrying out test diagnoses in at-risk pregnancies. It is essential, therefore, that a confirmatory amniocentesis is carried out to verify a normal result while methods are being developed. Already some errors have occurred where affected fetuses were missed after analysis of villi and diagnosed at amniocentesis (Young and Patrick, 1983; Fensom et al., 1984a; Simoni et al., 1984; Fowler and Cooper, 1984), and while maternal contamination was probably responsible for some of these errors the possibility of non-optimal enzymology should also be considered. In addition to carrying out confirmatory amniocentesis the division of villus sample for direct assay, and assay after tissue culture, would appear to be prudent. In a pregnancy at risk for argininosuccinic aciduria, analysis of cultured villi allowed diagnosis of an affected fetus which was missed by direct assay of villi (Vimal et al.,1984;see also below).