D. J. H. Brock

PRENATAL DIAGNOSIS OF ANENCEPHALY THROUGH MATERNAL SERUM-ALPHAFETOPROTEIN MEASUREMENT

Abstract An anencephalic pregnancy was first diagnosed by measurement of α-feto-protein (A.F.P.) in maternal serum at 16 weeks and then 21 weeks of gestation. After confirmation of the diagnosis by amniotic-fluid A.F.P. measurement and ultrasonic and X-ray scan, the pregnancy was terminated. It is suggested that maternal serum-A.F.P. levels may be useful in the screening of large numbers of pregnancies for possible central-nervous-system malformations.

Prenatal screening for cystic fibrosis

Screening for carriers of CF (cystic fibrosis) is now possible but the best way of delivering such a service is unknown. In one model 4348 women attending antenatal clinics in an Edinburgh maternity hospital were invited to participate in a trial of prenatal screening. Mouthwash samples were tested for six CF alleles (85% of mutant genes) and when a woman was found to be a CF carrier her partner was also tested. Heterozygous couples were offered prenatal diagnosis. 609 (14%) women declined to enter the trial and another 574 (13%) were not screened, usually because of late booking. Among the remaining 3165 women there were 111 carriers of a CF gene (1 in 29). 4 of these 111 had carrier partners and these couples opted for prenatal diagnosis, the 1 pregnancy with an affected fetus being terminated. The psychological impact of screening was assessed by the general health questionnaire. There was a significant increase in stress at the time of the test result among women identified as carriers. However, this disappeared when their male partners tested normal and did not reappear later in the pregnancy. By providing time for couples to discuss the possibility of screening and by offering the test at a point (the antenatal booking clinic) at which most pregnant women are seen, this approach has advantages, provided that counselling is readily available.

Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.

Pregnancy-induced hypertension may be regarded as a manifestation of endothelial-cell dysfunction. The role of the eNOS gene in the development of a familial pregnancy-induced hypertension was evaluated by analysis of linkage among affected sisters and in multiplex families (n = 50). Markers from a 4-cM region encoding the eNOS gene showed distortion from the expected allele sharing among affected sisters (P = .001-.05), and the statistic obtained from the multilocus application of the affected-pedigree-member method also showed distortion (T[f(P)=sqrt(P)] = 3.53; P < .001). A LOD score of 3.36 was obtained for D7S505 when a best-fitting model derived from genetic epidemiological data was used, and LOD scores of 2.54-4.03 were obtained when various other genetic models were used. Estimates of recombination rate, rather than maximum LOD-score values, were affected by changes in the genetic parameters. The transmission-disequilibrium test, a model-free estimate of linkage, showed strongest association and linkage with a microsatellite within intron 13 of the eNOS gene (P = .005). These results support the localization of a familial pregnancy-induced hypertension-susceptibility locus in the region of chromosome 7q36 encoding the eNOS gene.

A Simple Method for Ranking the Affinities of Monoclonal Antibodies

Measurement of the binding of constant trace amounts of labelled antigen by increasing dilutions of culture supernatant allows the ranking of monoclonal antibodies in the order of their affinity for the antigen. The theoretical basis for this method is discussed and it is illustrated with data from a set of anti-alphafoetoprotein monoclonal antibodies. Hybridomas secreting antibodies of desired affinity for immunoassay, histochemistry or antigen purification can thus be selected at an early stage after fusion.

Psychological impact of population-based carrier testing for cystic fibrosis : 3-year follow-up

BACKGROUND The objective of this study was to show the long-term psychological effects of population-based screening for cystic fibrosis. METHODS The sample comprised all carriers (n = 435) and, for each carrier, two matched screen-negative individuals (n = 870) detected during screening programmes for cystic fibrosis in the general population and in antenatal populations carried out a median of 3 years earlier in six UK centres. Questionnaires were sent to all eligible participants, with reminders sent to non-responders. The main endpoints were understanding of test results, degree of anxiety, perceptions of health, and reproductive intentions, and behaviour. FINDINGS 746 (62%) of 1201 questionnaires were returned. Recall of the meaning of test results was accurate in 225 (80%) of 280 carriers but only 200 (43%) of 466 screen-negative individuals. 46 (16%) of 280 proven carriers believed that their result meant that they were only likely, rather than definitely, to be a carrier; 232 (50%) of 466 of those with a screen-negative result erroneously believed that the result meant that they were definitely not carriers. There was no significant difference between carriers and screen-negative individuals in degree of general anxiety, although 16% of carriers reported feeling worried about their test results. Carriers had a poorer perception of their current health than did non-carriers, even though they had been told that carrier status confers no disadvantages to their own health. There were no differences between carriers and screen-negative individuals in reproductive intentions or behaviour. INTERPRETATION We have shown that in the long-term, retention of the meaning of test results from cystic fibrosis screening is poor. Further research is needed to improve the performance of test-related counselling programmes to ensure that the main objectives of these programmes, to provide information on carrier status and to allow informed reproductive decisions, are met.

Maternal serum-alpha-fetoprotein measurements as an early indicator of low birth-weight.

In a prospective trial of 4224 pregnancies, 103 women had serum-alpha-fetoprotein (A.F.P.) above 2-3 times the median value for their stage of gestation. 10-7% of these delivered infants with birth-weights less than 2-5 kg. This was significantly greater than the rate of 4-2% for low-birth-weight infants in the general population. At higher multiples of the median serum-A.F.P. value the proportion of pregnancies leading to low-birth-weight infants was even greater. It is suggested that early identification of pregnancies with high risk of premature delivery may be an important corollary of maternal serum A.F.P. screening.

PRENATAL DIAGNOSIS OF SPINA BIFIDA AND ANENCEPHALY BY MATERNAL SERUM-ALPHA-FETOPROTEIN MEASUREMENT: A Controlled Study

Abstract In five pregnancies resulting in spina bifida and two resulting in anencephaly, the maternal serum-alpha-fetoprotein (A.F.P.) levels were found to be higher than those in fourteen control pregnancies matched for maternal age, parity, and lengt of gestation (p

Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis

Article abstract We analyzed genomic DNA from ALS patients for mutations in the apurinic/apyrimidinic endonuclease (APEX nuclease) gene. We identified three rare polymorphisms in the untranslated region of the gene and one common two-allele polymorphism (D148E). The allelic frequency D148E was significantly different in sporadic ALS patients compared with controls. A conserved amino acid change and a 4-base pair deletion were also identified in sporadic ALS patients. These data suggest that APEX nuclease may contribute to the etiology of ALS.

Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies.

Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin‐1 FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin‐1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen‐Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association. Hum Mutat 10:415–423, 1997.

Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are responsible for some cases of familial amyotrophic lateral sclerosis (ALS). We have shown that SOD1 mutations can also occur in apparently sporadic ALS. To establish how often this happens we have undertaken a study of the prevalence of SOD1 mutations in an unselected cohort of Scottish ALS patients, with both sporadic (n = 57) and familial (n = 10) disease. Single strand conformation polymorphism analysis was used to scan for new mutations, and selective restriction enzyme digestion to screen for 11 of the 20 SOD1 mutations published to date. We detected mutations in five (50%) of the familial ALS patients and also in four (7%) of the sporadic patients. One mutation, ile113thr, seems to be particularly prevalent in the Scottish population since it was detected in a total of 6/67 (9%) unrelated cases.