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816 ArchivesofDiseaseinChildhood 1991;66: 816-822 CURRENT PRACTICE Arch Dis Child: first published as 10.1136/adc.66.7_Spec_No.816 on 1 July 1991. Downloaded from Antenatal diagnosis of inborn errors of metabolism M A Cleary, J E Wraith The introduction of experimental treatment for Sample requirement and techniques used in lysosomal storage disorders and the increasing prenatal diagnosis understanding of the molecular defects behind By far the majority of antenatal diagnoses are many inborn errors have overshadowed the fact performed on samples obtained by either that for many affected families the best that can amniocentesis or chorion villus biopsy. For be offered is a rapid, accurate prenatal diag- some disorders, however, the defect is not nostic service. Many conditions remain at best detectable in this material and more invasive only partially treatable and as a consequence the methods have been applied to obtain a diagnos- majority of parents seek antenatal diagnosis in tic sample. subsequent pregnancies, particularly for those disorders resulting in a poor prognosis in terms of either life expectancy or normal neurological FETAL LIVER BIOPSY development. Fetal liver biopsy has been performed to The majority of inborn errors result from a diagnose ornithine carbamoyl transferase defi- specific enzyme deficiency, but in some the ciency and primary hyperoxaluria type 1. primary defect is in a transport system or Glucose-6-phosphatase deficiency (glycogen enzyme cofactor. In some conditions the storage disease type I) could also be detected by biochemical defect is limited to specific tissues this method. The technique, however, is inva- only and this serves to restrict the material avail- sive and can be performed by only a few highly able for antenatal diagnosis for these disorders. specialised fetal diagnostic units. Fortunately for many inborn errors the metabo- lic defect is generalised and both amniotic and chorion villus cells can be used as a diagnostic FETAL BLOOD SAMPLING tissue. Fetal blood sampling could be used for the ante- Before contemplating prenatal diagnosis it is natal diagnosis of many inborn errors. The essential that a firm biochemical diagnosis has sample, however, tends to be collected late in http://adc.bmj.com/ been established in the index case. It is unsafe to pregnancy and the technique is probably best rely only on a clinical or histological diagnosis as reserved as a back up in case of failed amniotic many of the inherited disorders share a similar fluid cell culture. phenotype. To ease interpretation of results obtained on the fetus it is necessary to know the heterozygote levels of enzyme activity in the AMNIOCENTESIS parents; occasionally these are remarkably low Amniocentesis has been the most common pro- on September 30, 2021 by guest. Protected copyright. and can lead to difficulties in ascribing fetal cedure for antenatal diagnosis of metabolic dis- genotype. ease. Both the cell free amniotic fluid and cul- The properties of some enzymes are appreci- tured and uncultured amniotic fluid cells are ably different when studied at different times of useful in diagnosis. gestation. In addition, the activity obtained The procedure is usually performed at 15-16 from chorion villus material may be very diffe- weeks' gestation and most analyses can be per- rent from that obtained on amniotic fluid cells. formed within two to three weeks of culture. It is essential that the correct tissue is collected First trimester amniocentesis has been attemp- at the most appropriate time. Liaison with the ted to allow earlier diagnosis, but the smaller laboratory staff performing the test is manda- sample size and possible variation in enzyme tory if mistakes are to be avoided. activity at the earlier stage of pregnancy have Prenatal testing by analysis of fetal DNA introduced variables that need to be studied by either a gene specific DNA probe or gene before the technique can be widely applied. tracking using restriction fragment length poly- (1) Cell free amniotic fluid can be used to morphisms (RFLPs) requires proband DNA detect a number of intermediary metabolites in Willink Biochemical for comparison. This underlies the importance many inborn errors. Where possible this techni- Genetics Unit, Royal Manchester of establishing fibroblast cultures from all que should be backed by specific enzyme analy- Children's Hospital, patients diagnosed as having a metabolic dis- sis, but for many conditions does allow a quick Pendlebury order as well as ensuring that blood is taken diagnosis. It is particularily relevant for organic Manchester M27 IHA from M A Cleary all relevant family members for DNA acid disorders using stable isotope dilution gas J E Wraith extraction and storage. chromatography with mass spectrometry and Correspondence to: Most prenatal testing for metabolic disease is selected ion monitoring. -Dr Wraith. performed in a few specialised laboratories. In mucopolysaccharide disorders the pattern Antenataldiagnosisofinborn errorsofmetabolism 817 of excess glycosaminoglycan excretion can be with the technique include the possibility of Arch Dis Child: first published as 10.1136/adc.66.7_Spec_No.816 on 1 July 1991. Downloaded from detected by two dimensional electrophoresis maternal contamination and differences in and this can form the basis of a reliable antena- enzyme activity in this tissue as compared with tal test for this group of conditions. skin fibroblasts or cultured amniotic fluid cells. (2) Amniotic fluid cells in culture are a com- Despite these possible limitations most prenatal mon material used in antenatal diagnosis. In diagnoses for inborn errors are performed on most cases the enzyme activity obtained in this chorion villus samples. tissue mirrors that obtained in cultured skin fibroblasts. As well as direct enzyme assay, radiolabelled incorporation studies can be Specific inborn errors of metabolism performed on the cultured cells and a wide The appendix lists the specific inborn error, the range of disorders detected. Contamination by biochemical defect, chromosome location of the mycoplasma or other organisms is the biggest gene mutation where known, and the test used threat to antenatal diagnosis by this method. for antenatal diagnosis. Where antenatal diagnosis has been successfully achieved the method used is clearly shown. For some dis- CHORION VILLUS BIOPSY orders prenatal diagnosis is theoretically poss- Chorion villus biopsy offers the advantage of ible, although to the authors' knowledge not as first trimester diagnosis. Direct analysis of yet successfully performed. In this case the enzyme activity on fresh uncultured villus tissue most likely tissue and method are indicated with usually allows a result to be available within 24- the rider, 'possible'. The key to the abbrevia- 48 hours of the procedure. Problems associated tions used is shown at the end of the appendix. Appendix Specific inborn errors ofmetabolism Condition Enzyme deficiency Chromosome Prenatal location diagnosis (A) CARBOHYDRATE METABOLISM (i) Galactose Galactokinase deficiency Galactokinase 17q21-q22 AF, CVB 'Classical' galactosaemia Galactose-1-phosphate- 9p13 AF, CVB uridyltransferase Epimerase deficiency UDP-Galactose-4-epimerase lpter-p32 Poss CC (ii) Fructose Hereditary fructose intolerance Aldolase B 9q22 Poss DNA Fructose 1-6 bisphosphatase Frutose 1-6 bisphosphatase No http://adc.bmj.com/ deficiency (iii) Glycogen storage disease Ia Von Gierke Glucose-6-phosphatase Poss FT b Glucose-6-phosphatase Poss FT translocase (TI) c Glucose-6-phosphatase Poss FT on September 30, 2021 by guest. Protected copyright. translocase (T2) II Pompe Lysosomal acid glucosidase 17q23 AF, CVB III Debrancher enzyme Amylo-1-6-glucosidase AF, CVB deficiency IV Brancher enzyme deficiency 1-4-Glucan 6-glycosyl- AF, CVB transferase V McCardle Muscle phosphorylase 1 lql3-qter No VI Liver phosphorylase Liver phosphorylase 14 Poss FT deficiency VII Phosphofructokinase Phosphofructokinase lcen-q32 No deficiency IXa Phosphorylase kinase Phosphorylase kinase 16ql2-ql3-1 Poss FT (recessive) IXb Phosphorylase kinase Phosphorylase kinase Xql2-ql3 Poss FT (X linked) (B) AMINO ACID METABOLISM (i) Phenylalanine 'Classical' phenylketonuria Phenylalanine hydroxylase 12q22-q24- 1 DNA Tetrabiopterin homoeostasis Dihydropteridine reductase 4pl53 AF, CVB Tetrabiopterin synthesis Guanosine triphosphate MET cyclohydrolase 6-Pyruvoyltetrahydropterin MET synthase 818 Cleary, Wraith Condition Enzyme deficiency Chromosome Prenatal Arch Dis Child: first published as 10.1136/adc.66.7_Spec_No.816 on 1 July 1991. Downloaded from location diagnosis (ii) Methionine Homocystinuria Cystathionine synthase 21q22-q22-1 AF, CVB (iii) Tyrosine Tyrosinaemia I Fumarylacetoacetate hydrolase 15q23-q25 AF, CVB Tyrosinaemia II Tyrosine aminotransferase 16q22-q22 1 No (iv) Valine, leucine, isoleucine Maple syrup urine disease Branched chain ketoacid 19ql3-1-ql3-2 AF, CVB dehydrogenase (v) Glycine Non-ketotic hyperglycinaemia Glycine cleavage system 9p22 CVB (vi) Lysine Hyperlysinaemia Aminoadipic semialdehyde UNK synthase (vii) Proline Hyperprolinaemia I Proline oxidase UNK Hyperprolinaemia II Pyrroline-5-carboxylate UNK dehydrogenase Hyperimidodipeptiduria Prolidase 19ql2-ql3-2 Poss CC (viii) Ornithine Gyrate atrophy of the choroid Ornithine aminotransferase 10q26 Poss CC and retina Hyperornithinaemia- Basic defect unknown No hyperammonaemia- homocitrullinaemia (HHH syndrome) (C) UREA CYCLE DISORDERS N-acetylglutamate synthetase N-acetylglutamate synthetase
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