Abstract
A rapid (3 day) procedure has been evaluated for the prenatal diagnosis (Dx) of Fabry's disease, an X-linked lipidosis resulting from defective α-galactosidase A activity (α-gal A) and the accumulation of trihexosyl ceramide (GL-3). In 7 at-risk pregnancies Dx was based on 1) specific assay of thermolabile α-gal A, 2) α-gal A inhibition by myoinositol (Myo) and melibiose (Mel), and 3) GLC quantitation of GL-3 in amniotic fluid (AF). These data were supported by careful X and Y chromatin studies of uncultured amniotic cells (UAC) and subsequently by α-gal A and karyotype analyses in cultured (C) AC. Normal mean (range;n) α-gal A in AF, UAC and CAC were 0.93 nmoles/h/ml (0.50-1.3;10),1.76 nmoles/h/mg Pr (0.65-4.0;14), and 116.7 nmoles/h/mg Pr (58.1-210.0;10), respectively. Myo and Mel inhibited normal AF α-gal A activity by 50 and 85%, respectively. Normal mean AF GL-3 concentration was 0.35 nmoles/ml (0.18-0.46;5). Of the 7 pregnancies monitored, 1 affected hemizygote, 1 normal male and 2 heterozygous (het) and 2 normal female fetuses were diagnosed 3 days after amniocentesis. The affected fetus had no detectable α-gal A and 10X higher levels of GL-3 in AF, and was Y-chromatin positive. Each Dx was confirmed by enzyme and karyotype analyses in CAC. The affected pregnancy was terminated and the Dx documented by biochemical and ultrastructural studies. Postnatal studies confirmed the other Dx with the exception of the 2 het females who were not carriers by postnatal assay. These results indicate that the prenatal Dx of Fabry's disease can be made rapidly and reliably by these procedures.
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