The early prenatal diagnosis of human metabolic disorders is of importance for genetic counseling of familities with a pregnancy at risk and for the potential prenatal treatment of affected fetuses, as well as for appropriate postnatal treatment. Current procedures depend on transabdominal amniocentesis at 14-18 weeks to obtain sufficient numbers of cells for standard biochemical assays of enzymes. In general the period required before analysis can be initiated is much longer than that required for karyotype analysis and in the case of some disorders it is unacceptably long to permit intervention. This project will investigate techniques for earlier, more rapid and cost effective prenatal diagnosis. One approach will be the establishment of direct, rapid, accurate stable isotope dilution assays for elevated levels of diagnostic compounds in amniotic fluid obtained by amniocentesis, avoiding the delay and cost of culturing amniocytes. Assays will be developed for ten metabolites which may be diagnostic for ten different inherited disorders. The second approach will be the assay of enzymes either directly on chorionic villi or on cells cultured from chorionic villi. This transcervical sampling of chorionic villi is done at 8-12 weeks of pregnancy, about six weeks earlier than amniocentesis. Assays for ten enzymes will be optimized, miniaturized where possible, and used to determine the normal ranges of activities in chorionic villus biopsies. Cultures of fibroblast-like mesenchymal stroma cells and of cytotrophoblasts from chorionic villus will be established and normal ranges of enzyme activities determined. These two approaches should lead to the development of new and improved techniques for the prenatal diagnosis of severe metabolic disorders much earlier in pregnancy than is currently possible. They should promote the development of approaches to prenatal therapy and the rapid initiation of early postnatal therapy prior to the time when a potentially irreversible catabolic state ensues.
| Gibson, K M; Lohr, J L; Broock, R L et al. (1989) Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria. Enzyme 41:47-55 |
| Gibson, K M; Hoffmann, G; Nyhan, W L et al. (1988) 4-Hydroxybutyric aciduria in a patient without ataxia or convulsions. Eur J Pediatr 147:529-31 |
| Hoffmann, G; Gibson, K M; Brandt, I K et al. (1986) Mevalonic aciduria--an inborn error of cholesterol and nonsterol isoprene biosynthesis. N Engl J Med 314:1610-4 |
| Sweetman, F R; Gibson, K M; Sweetman, L et al. (1986) Activity of biotin-dependent and GABA metabolizing enzymes in chorionic villus samples: potential for 1st trimester prenatal diagnosis. Prenat Diagn 6:187-94 |
