PubMed1987
Nearly 4000 different human disorders are supposed or known to be due to a single gene mutation. In about 10%, an early diagnosis is possible by the demonstration of specific abnormalities of metabolites in blood and/or urine, an abnormal structure/function of a particular (enzyme) protein or by the (in)direct demonstration of the gene mutation using DNA analysis. These methods of molecular analysis can often also be used for carrier detection. Early identification of couples at risk of handicapped offspring followed by genetic counselling forms the basis for prevention. Follow-up studies have shown that more than half of the couples at risk of a child with a genetic disease refrain from pregnancy. An important alternative for couples at risk is prenatal monitoring and selective abortion. During the last 10-15 years, the technology of fetal diagnosis of genetic diseases has improved and the number of Mendelian disorders that can be diagnosed in utero has increased to more than 100. In the second-trimester of pregnancy, about two dozen inborn errors of metabolism have been diagnosed by metabolite analysis of amniotic fluid supernatant using gas chromatography-mass spectrometry or electrophoretic methods. About 5000 pregnancies at risk of different types of haemoglobinopathy, haemophilia, alpha-1-antitrypsin deficiency and a few other diseases not expressed in amniotic fluid cells have been investigated by biochemical analysis after fetal blood sampling. The most common approach towards fetal diagnosis of inborn errors of metabolism has been the demonstration of a specific enzyme deficiency in cultured amniotic fluid cells. In this way some 60 different diseases have been diagnosed, usually after 2-4 weeks of cultivation after amniocentesis at 16 weeks gestation. In addition, some 20 other Mendelian disorders have been diagnosed in utero by ultrasonography and non-biochemical analysis of amniotic fluid cells or fetal skin biopsies. The introduction of chorionic villus sampling has offered the possibility of first-trimester fetal diagnosis of a large number of Mendelian disorders. The overall diagnostic experience until mid-1986 amounts to about 1500 pregnancies at risk. Some 45 different inborn errors have been diagnosed by enzyme assays directly on chorionic villus homogenate or after incubation with radiolabelled precursors of intact villi followed by chromatography or other types of analysis. In a few instances, cell cultivation for a period of 2-3 weeks is required to establish a reliable biochemical diagnosis.