L. Ries

DOWN'S SYNDROME SCREENING MARKER LEVELS FOLLOWING ASSISTED REPRODUCTION

Maternal serum α‐fetoprotein (AFP), human chorionic gonadotrophin (hCG), and unconjugated oestriol (uE3) levels were examined in 1632 women who had ovulation induction and 327 who had in vitro fertilization. There was a highly statistically significant increase in hCG and reduction in uE3 among those with ovulation induction. The median levels were respectively 1·09 and 0·92 multiples of the normal gestation‐specific median (MOM) based on a total of 34 582 women. Ovulation induction appeared to have no material effect on the median AFP level but this masked a significant increase when treatment was with Clomiphene (1·05 MOM) and a significant decrease when Pergonal was used (0·93 MOM). There was a highly statistically significant reduction in uE3 among women having in vitro fertilization with a median level of 0·92 MOM. Those fertilized with a donor egg (21) had significantly higher AFP and uE3 levels than when their own egg was used. Our results were confounded by differences in gravidity, but formally allowing for this factor did not materially change the findings. None of the observed effects is great enough to warrant routine adjustment of marker levels to allow for them. Moreover, women with positive Downs syndrome screening results can be reassured that this is unlikely to be due to them having had assisted reproduction.

Genetic Analysis of Brugada Syndrome in Israel: Two Novel Mutations and Possible Genetic Heterogeneity

Idiopathic ventricular fibrillation in patients with an electrocardiogram (ECG) pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 (now frequently called Brugada syndrome) is associated with a high incidence of syncopal episodes or sudden death. The disease is inherited as an autosomal dominant trait. Mutations in SCN5A, a cardiac sodium channel gene, have been recently associated with Brugada syndrome. We have analyzed 7 patients from Israel affected with Brugada syndrome. The families of these patients are characterized by a small number of symptomatic members. Sequencing analysis of SCN5A revealed two novel mutations, G35S and R104Q, in two Brugada patients, and a possible R34C polymorphism in two unrelated controls. No mutations were detected in 5 other patients, suggesting genetic heterogeneity. Low penetrance is probably the cause for the small number of symptomatic members in the two families positive for the SCN5A mutations.

Prenatal diagnosis of a novel COL1A1 mutation in osteogenesis imperfecta type I carried through full term pregnancy

Prenatal diagnosis was performed in a family where the father has osteogenesis imperfecta (OI) type I, with a novel mutation in the COL1A1 gene: a C to T change at position c3076 (c.3076C→T) leading to a change of arginine at codon 848 to a stop codon (R848X). Prenatal diagnosis by chorionic villous sampling (CVS) was performed during the fourth pregnancy, and revealed that the fetus is a carrier of the same COL1A1 mutation. The possibility of phenotypic variability was discussed with the parents. They elected to carry the pregnancy to term, and a male child with mild OI was born. This is the first reported case where OI was diagnosed prenatally, and the parents opted to carry the pregnancy to term. It illustrates the potential use of DNA‐based analysis for early prenatal diagnosis of OI, and the complexities of genetic counselling. Copyright

EFFECT OF GRAVIDITY ON MATERNAL SERUM MARKERS FOR DOWN'S SYNDROME

The effect of gravidity on maternal serum α‐fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotrophin (hCG) levels was investigated in 27 592 women being screened for Downs syndrome. There was no difference in the median AFP level in primigravid and multigravid women, but the median hCG level in multigravid women was 5·9 per cent lower than in those tested in their first pregnancy (P<0·0001) and the median uE3 level was 3·9 per cent lower (P<0·0001). Among multigravid women, there was no material difference in hCG levels according to the number of previous pregnancies or livebirths, whereas uE3 levels declined steadily with increasing numbers. Both markers declined with advancing maternal age: for hCG this was an independent effect, but for uE3 it was due to the correlation between age and gravidity. Allowing for these effects will not greatly alter the Downs syndrome screening detection and false‐positive rates.

A missense mutation in Col1A1 in a Jewish Israeli patient with mild osteogenesis imperfecta, detected by DGGE

Abstract Osteogenesis imperfecta (OI) underlies germline mutations in either Col1A1 or Col1A2. Here we describe, for the first time, the use of the denaturing gradient gel electrophoresis (DGGE) technique for mutation analysis of the Col1A1 gene. By employing this technique, we identified a point mutation in a young Jewish Israeli patient with mild OI. The missense mutation, a G to A alteration at position 888, result in a Gly to Arg substitution at codon 79. Furthermore, the patient’s mother, who was clinically labeled as OI based solely on the fact that she has blue sclera, was found not to carry this mutation in two different tissues. We suggest that blue sclera alone should not be used as a parameter for the diagnosis of OI, and that DGGE can be effectively used for mutation analysis of the Col1A1 gene.

Heat stable and urea resistant alkaline phosphatase in maternal neutrophils from normal and Down syndrome pregnancies

Activity levels of total and placental alkaline phosphatase (AP) were determined in maternal serum and neutrophils of normal and Down syndrome pregnancies. The placental iso‐enzyme (PAP) was identified by its relative stability to urea and heat. Significant increase in the activity of all iso‐enzymes across gestational stages was observed in maternal sera of 28 normal pregnancies. However, in the neutrophil extracts of the same blood samples no differences were detected between trimesters. Another set of experiments was aimed at finding diagnostic differences of PAP activity in maternal neutrophils of normal and trisomy 21 affected pregnancies. No differences of heat stable AP activity were found in maternal samples of 19 normal and 19 Down syndrome affected pregnancies. Urea resistant AP proportions were also similar when measured after 40 minutes of exposure (13 samples in each group). However, a marginally significant increase was observed in the mean value of the Down syndrome affected samples, after 60 minutes of urea treatment. In view of the above results we conclude that neutrophil AP activity is not as yet a useful marker for the screening of trisomy 21 fetuses. Copyright