Antenatal diagnosis of inborn errors of metabolism.

The introduction of experimental treatment for lysosomal storage disorders and the increasing understanding of the molecular defects behind many inborn errors have overshadowed the fact that for many affected families the best that can be offered is a rapid, accurate prenatal diagnostic service. Many conditions remain at best only partially treatable and as a consequence the majority of parents seek antenatal diagnosis in subsequent pregnancies, particularly for those disorders resulting in a poor prognosis in terms of either life expectancy or normal neurological development. The majority of inborn errors result from a specific enzyme deficiency, but in some the primary defect is in a transport system or enzyme cofactor. In some conditions the biochemical defect is limited to specific tissues only and this serves to restrict the material available for antenatal diagnosis for these disorders. Fortunately for many inborn errors the metabolic defect is generalised and both amniotic and chorion villus cells can be used as a diagnostic tissue. Before contemplating prenatal diagnosis it is essential that a firm biochemical diagnosis has been established in the index case. It is unsafe to rely only on a clinical or histological diagnosis as many of the inherited disorders share a similar phenotype. To ease interpretation of results obtained on the fetus it is necessary to know the heterozygote levels of enzyme activity in the parents; occasionally these are remarkably low and can lead to difficulties in ascribing fetal genotype. The properties of some enzymes are appreciably different when studied at different times of gestation. In addition, the activity obtained from chorion villus material may be very different from that obtained on amniotic fluid cells. It is essential that the correct tissue is collected at the most appropriate time. Liaison with the laboratory staff performing the test is mandatory if mistakes are to be avoided. Prenatal testing by analysis of fetal DNA by either a gene specific DNA probe or gene tracking using restriction fragment length polymorphisms (RFLPs) requires proband DNA for comparison. This underlies the importance of establishing fibroblast cultures from all patients diagnosed as having a metabolic disorder as well as ensuring that blood is taken from all relevant family members for DNA extraction and storage. Most prenatal testing for metabolic disease is performed in a few specialised laboratories. Sample requirement and techniques used in prenatal diagnosis By far the majority of antenatal diagnoses are performed on samples obtained by either amniocentesis or chorion villus biopsy. For some disorders, however, the defect is not detectable in this material and more invasive methods have been applied to obtain a diagnostic sample.