Screening for carriers of cystic fibrosis among pregnant women: a pilot study.

Cystic fibrosis (CF) is one of the most common hereditary disorders among Caucasians. In such populations a highly prevalent mutation causing CF, delta F508, has been identified. It comprises 88% of Danish CF mutations. This mutation and five others account for 90% of all CF mutations, making carrier screening on a population basis worthy of consideration. We have therefore performed a pilot screening programme for CF carriers among pregnant women. From June 1, 1990, for the following 2 years, 6,599 women were tested: 172 were heterozygous for delta F508. Three of 162 partners tested were also heterozygous for delta F508. After genetic counselling all three couples at risk for having a child with CF requested prenatal diagnosis. One fetus was homozygous for delta F508, and the pregnancy was terminated. With currently available techniques, the screening programme presented here causes no practical problems, and screening for CF carriers can easily be run on a larger scale.

Psychological impact of carrier screening for cystic fibrosis among pregnant women.

The aim of the present study was to assess the impact of being identified carrier of cystic fibrosis. The impact was assessed in terms of retention of the result, sharing of the information about the result with relatives, non-relatives and GPs, changes in reproductive plans, and regrets about having been tested Three unsupervised questionnaires were sent to 160 women identified as carriers between 1990 and 1992 in June 1992, October 1993, and November 1994. Carriers freely shared the information about their result with relatives, friends, and GPs. The inconclusiveness of the test gave rise to some confusion. This may reflect inadequacies in the information and counselling given to carriers, but psychological factors are also believed to be responsible. Thus, false reassurance may be a problem in a carrier screening with a test that detect only a proportion of carriers. Few carriers considered changing their reproductive plans due to the result of the test. A few women identified as carrier regretted having had the test.

Studies on glutaryl-CoA dehydrogenase in leucocytes, fibroblasts and amniotic fluid cells. The normal enzyme and the mutant form in patients with glutaric aciduria.

Three patients with glutaric aciduria have been shown to possess a partial but severe defect of the enzyme glutaryl-CoA dehydrogenase in isolated leucocytes and cultured skin fibroblasts. They could readily be distinguished from heterozygotes by measuring the activity of this enzyme, as shown in a study of the two families involved. The activity of glutaryl-CoA dehydrogenase in normal cultured amniotic fluid cells was comparable to the activity in normal cultured skin fibroblasts indicating the possibility of prenatal diagnosis. Without flavin adenine dinucleotide added to the assay mixture, the activity of glutaryl-CoA dehydrogenase in fibroblasts from normal individuals was very much reduced and similar to the activity in the patients, but after addition of flavin adenine dinucleotide to saturation the activity increased 20-fold in normal subjects while only a very slight increase could be demonstrated in the patients. The Michaelis constant for the substrate glutaryl-CoA was similar for both normal and patient cell lines. The optimum assay conditions for the enzyme in cultured fibroblasts from normal individuals have been established. In contrast to our patients, we found no activity in a fibroblast cell line from a patient with glutaric aciduria diagnosed elsewhere.

Excretion of short-chain N-acylglycines in the urine of a patient with D-glyceric acidemia.

Five urine samples were collected in clinically quiet periods over a period of one year from a patient suffering from D-glyceric acidemia, and investigated for presence or absence of glycine-conjugates. The findings of isovalerylglycine, 2-methylbutyrylglycine, isobutyrylglycine, and tiglylglycine are interpreted as indications of intracelluar accumulations of isovaleryl-CoA, 2-methylbutyryl-CoA and isobutyryl-CoA. Similarly, the findings of elevated amounts of butyric acid and hexanoic acid together with butyrylglycine, hexanoylglycine, and suberic acid suggest intracellular accumulations of straight-chain acyl-CoA's. It is therefore suggested that this child has a common derangement in his acyl-CoA dehydrogenase (in addition to his primary defect). As possible secondary consequences of this, two points can be mentioned: firstly hyperglycinemia, from which the patient suffered, and secondly, diminished tendency to ketosis, a condition from which the child never suffered, not even in connection with severe intercurrent disease.

Urinary excretion of succinylacetone and delta-aminolevulinic acid in patients with hereditary tyrosinemia.

Succinylacetone was excreted in the urine from four patients, with hereditary tyrosinemia i.e., two patients with the severe infantile type with fatal outcome and two patients with less severe juvenile form. In the urine from two patients with neonatal transient tyrosinemia and from normal individuals succinylacetone was not detectable. The urinary excretion of delta-aminolevulinic acid was also increased in all patients with hereditary tyrosinemia compared to patients with neonatal transient tyrosinemia and to normal individuals. The results presented support the hypothesis of a deficiency of fumarylacetoacetase in hereditary tyrosinemia. Furthermore an analytical method for the quantitative determination of succinylacetone in urine using GC-MS is described.

Design of a pilot study to evaluate tandem mass spectrometry for neonatal screening.

In recent years, tandem mass spectrometry has generated great interest as a method for neonatal screening. The basic principle is electronically controlled separation of analytes by their mass-to-charge ratio. The advantage of this detection system is speed, the capability to analyze for many different compounds in a single analysis, and a minimal need for auxilliary assay reagents. The prevailing screening technique uses stable isotope dilution, butylesterification, and MS/MS analysis to quantify amino acids and acylcamitines in neonatal dried blood spot samples. This allows detection of more than 30 inborn errors of metabolism of amino acids, fatty acids, and other organic acids. In Denmark, a large-scale pilot study is being implemented to evaluate the screening potential of tandem mass spectrometry. National patient registers and medical records from clinical genetics units are used to identify cohorts of healthy infants and infants with selected inborn errors of metabolism. The neonatal screening samples of these infants are retrieved from a biobank and are assayed for amino acids and acylcarnitines using tandem mass spectrometry. This study yields decision values for neonatal screening, which will be evaluated in a subsequent 2-year prospective pilot study, offering the test to 140,000 neonates as a voluntary adjunct to the existing screening program. The organization consists of integrated units for neonatal screening and clinical genetics. The effect of the program will be assessed in terms of screening efficiency, cost and short term clinical outcome.

[Screening for carriers of cystic fibrosis. Result of a pilot study among pregnant women]. / Anlaegsbaererscreening for cystisk fibrose. Resultatet of en pilotundersøgelse blandt gravide.

Total prevention of cystic fibrosis (CF) is possible if all carrier women are found before pregnancy or early enough during pregnancy so that prenatal diagnosis can be offered. The delta 508 allele constitutes almost 90% of the mutations causing CF in the Danish population. We have examined 6599 pregnant women and found 172 carriers of delta F508. Partners of carrier women were examined for delta F508 and five other mutations. Three couples at risk and one foetus with CF were identified. Giving information to couples before and after testing is time consuming. A comprehensive questionnaire was sent to 200 non-carriers and all 172 carriers (response rate 72%). It can be concluded that the project has been very well accepted. However, the majority of carriers were shocked or very worried when they had the test result. Based on this pilot study we recommend nationwide screening for delta F508 early in pregnancy.

[Refsum's disease. Hereditary atactic polyneuritis]. / Refsum's sygdom. Heredopathia atactica polyneuritiformis.

As it is possible to prevent progression of the disease by early treatment all patients with otherwise unexplained retinitis pigmentosa should be screened for phytanic acid accumulation in the plasma.

[Neonatal screening in Denmark. Status and future perspectives]. / Neonatal screening i Danmark. Status og fremtidsperspektiver.

In Denmark, the Faroe Islands, and Greenland, comprehensive screening of newborns for phenylketonuria and congenital hypothyroidism has been carried out for 20 years. The screening programme has detected 98 and 356 patients, respectively, corresponding to incidences of 1:12,000 and 1:3,400. The future savings on health care expenditures resulting from one year of neonatal screening are estimated to be 196 million DKK in present day value, which is 28 times higher than the cost of screening. The screening samples are stored in a biobank, which is used in diagnosis of congenital diseases and infant deaths and for development of future screening methods. It is desirable to expand the existing screening programme to include a range of rare inherited metabolic diseases, which collectively are frequent. This is realistic with the advent of tandem mass spectrometry, which allows cost-effective simultaneous screening for a group of inborn errors of metabolism.

[Enzyme substitution in Gauscher disease]. / Enzymsubstitution ved mb. Gaucher.

Gaucher's disease is the most frequent inherited lysosomal storage disorder, displaying hepato-splenomegaly, thrombocytopenia, anaemia, and bone pain as characteristic features. Substitution with the modified enzyme alglucerase has revolutionized the treatment and prognosis of Gaucher's disease. Treatment in general and current trends in enzyme substitution therapy in particular are discussed.

[Gaucher disease type 1--therapeutic results of enzyme substitution]. / Mb. Gaucher type 1--behandlingsresultater ved enzymsubstitution.

Gaucher's disease is the most common inherited lysosomal storage disorder, displaying hepato-splenomegaly, thrombocytopenia, anaemia and bone pain as characteristic features. Substitution therapy with a modified enzyme alglucerase has revolutionized the treatment and prognosis of Gaucher's disease. The first Danish patients treated with alglucerase are reported.

[A follow-up study of carriers of cystic fibrosis]. / En efterundersøgelse af anlaegsbaerere for cystisk fibrose.

The aim of the present study was to assess the long-term impact of carrier screening for cystic fibrosis. The impact of being identified as a carrier for cystic fibrosis was assessed through three questionnaires measuring the emotional responses, changes in reproductive attitudes and decisions, retention of the result, and sharing of the information about the result with relatives. The questionnaires were sent to 160 women identified as carriers between 1990 and 1992 and to 200 randomly selected women with a negative result. Carriers became surprised, anxious and worried upon receipt of their result. However, this response disappeared once the partners had been tested and found negative. No sign of residual anxiety was found among carriers who answered the third questionnaire in November 1994. Carriers freely shared the information about their result with relatives, friends, and general practitioners. Few carriers changed their reproductive plans or attitudes to abortion of a foetus with CF due to the result. No decline in fertility or change in reproductive pattern were observed among carriers after testing. The imperfect sensitivity of the carrier test caused some misunderstanding in the retention of the result. This may reflect inadequacies in the information and counselling. Psychological factors are also believed to contribute to the misunderstanding of the result. The information should be improved to avoid false reassurance.