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T K Eskes

Publications and source records attributed to T K Eskes.

At least 19 recordsLinked to original sources
PubMed1998

Neural tube defects, vitamins and homocysteine.

Folic acid (multivitamins) reduce the recurrence and occurrence of neural tube defects (NTDs). Vitamin profiles seem not suitable to identify women at risk for NTDs. A subset of these women have hyperhomocysteinaemia and a mutation of the gene for thermolabile methylenetetrahydrofolate reductase (MTHFR). From studies with the rat embryo in vitro, it can be concluded that the de- and remethylation cycle of methionine, being folate and vitamin B12 dependent, is crucial for embryonic and fetal growth probably via generation of DNA, proteins and polyamines. Nutrition for the embryo is also supplied by the follicular fluid, the yolk sac, the extraembryonic coelomic cavity and the amniotic fluid.

Animals↗
PubMed1998

From birth to conception. Open or closed.

In this valedictory address the research of the Nijmegen homocysteine team on birth defects and vascular disease is presented. Hyperhomocysteinemia was found in women with neural tube defect (NTD) offspring, other birth defects and vascular disease. Raised homocysteine levels in the blood plasma can be explained by lack of B-vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase genes or both. Genetic mutations were found on the first chromosome (677 C-->T and 1298 A-C) and can explain up to 50% of the NTD protective effect of folic acid. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects and vascular problems like placental abruption, infarcts and fetal growth retardation. One of the most exciting medical findings of the last years is that folic acid can prevent NTD defects. This might also hold for other birth defects and vascular disease.

Congenital Abnormalities↗
PubMed1998

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.

Adenine↗
PubMed1998

Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages.

To determine the effects of daily supplementation of 0.5 mg folic acid on homocysteine and folate concentrations, we investigated 49 women with a history of unexplained recurrent miscarriages. A methionine loading test (including the vitamin concentrations of concern) was used preceding and after 2 mo of folic acid intake. Subsequently, these effects were studied after stratification for C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism. Folic acid supplementation (for 2 mo) reduced the median fasting and delta (after-load minus fasting) total plasma homocysteine (tHcy) concentrations 27% (P < 0.001) and 14% (P < 0.05), respectively. Median serum and red cell folate concentrations increased 275 and 70%, respectively (P < 0.01). The homocysteine-lowering effect was most marked in women with the highest tHcy concentrations at baseline. All MTHFR-genotypes (homozygous T/T, n = 8; heterozygous T/C, n = 23; wild type C/C, n = 18) had a different response to the supplementation. After 2 mo, homozygous women showed the greatest decline in median fasting (-41%; P < 0.01) tHcy concentrations, but the lowest absolute increase in serum folate concentration (+26 nmol/L; P < 0.05). In conclusion, 2 mo of daily supplementation of 0. 5 mg folic acid in women with a history of unexplained recurrent miscarriages caused, in general, substantially reduced tHcy concentrations. This effect was most distinct in women with the highest tHcy concentrations at baseline and in women homozygous for the 677 C-->T mutation of the MTHFR-gene.

Abortion, Habitual↗
PubMed1998

Open or closed? A world of difference: a history of homocysteine research.

This article presents the research of the Nijmegen homocysteine team on birth defects and vascular disease. Hyperhomocysteinemia was found in women who gave birth to offspring with neural tube defects (NTDs) and other birth defects and in women with vascular disease. Elevated homocysteine levels in the blood plasma can be explained by lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) genes, or both. Genetic mutations were found on the first chromosome (677 C T and 1298 A-C) and can explain up to 50% of the protective effect of folic acid against NTDs. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects, and vascular problems such as placental abruption, infarcts, and fetal growth retardation. One of the most exciting medical findings of recent years is that folic acid can prevent NTDs. This might also hold true for other birth defects and vascular disease.

Animals↗
PubMed1997

Folates and the fetus.

It is proven that folic acid supplied in the periconceptional period can lower the recurrence and occurrence rate of neural tube defects (NTDs). Our research team on prevention of birth defects could demonstrate that folic acid preventable NTDs are partly based on hyperhomocystinemia and a genetic predisposition (mutation of the methylenetetrahydrofolate-reductase gene (MTHF-R)). Reduced activity of the folate methylation cycle seems to be an attractive working hypothesis in the aetiology of NTDs. This genetic metabolic defect can be overcome by treatment with folic acid and/or vitamin B12.

Anemia, Megaloblastic↗
PubMed1997

Prenatal diagnosis and treatment of congenital Toxoplasma gondii infections: an experimental study in rhesus monkeys.

The efficacy of treatment in fetuses in whom congenital Toxoplasma gondii infection has ben established has been investigated using rhesus monkeys as a model for humans. A polymerase chain reaction has been developed for the detection of Toxoplasma gondii. Using this polymerase chain reaction congenital infection can be established within 2 days of receiving an amniotic fluid sample. The polymerase chain reaction has subsequently been used to monitor the effect of treatment on fetal infection. The results show that early treatment with the combination of pyrimethamine and sulfadiazine was clearly effective in reducing the number of parasites in the infected fetus. The parasite was no longer detectable in the amniotic fluid 10 to 13 days after treatment was started. Spiramycin, on the other hand, has to be administered for at least 3 weeks to achieve the same effect. Moreover, pharmacokinetic studies revealed that spiramycin does not reach the brain. Pyrimethamine and sulfadiazine are able to pass the blood-brain barrier. Pyrimethamine appears to accumulate in the brain tissue and reaches concentrations which are also effective in vitro.

Amniotic Fluid↗
PubMed1997

Abruptio placentae. A "classic" dedicated to Elizabeth Ramsey.

The syndrome of abruptio placentae was originally described in 1997. Total hysterectomy was advocated by Couvelaire in 1991. The placenta is fixed to the uterine wall by anchoring villi. When spiral arteries lack the physiologic trophoblast invasion, like in case of maternal hypertension placental infarcts/abruption might occur. Infusion of thromboplastic material induces disseminated intravascular coagulation. The uterus "en bois" representing hypertonicity and polysystolia probably safe-guard the entrance of further thromboplastic material into the maternal circulation. Prompt restoration of the intravascular volume with full blood avoids hysterectomy. Preventive measures are avoidance of the supine position, cocaine and smoking. Treatment of hyperhomocysteinemia probably can prevent vascular damage.

Abruptio Placentae↗
PubMed1997

Low-sodium diet in pregnancy: effects on blood pressure and maternal nutritional status.

In ninety-four Dutch nulliparous women the effects of a low-Na diet in pregnancy on blood pressure, energy and nutrient intake, Ca metabolism, Zn and Mg status and body composition were studied longitudinally. The women were randomly divided into an intervention group (n 41), which used a low-Na diet (mean urinary Na excretion 61 mmol/24 h) from week 14 of pregnancy until delivery and a control group (n 53; mean urinary Na excretion 142 mmol/24 h). No effect of the diet on blood pressure was observed. The use of a low-Na diet resulted in significantly reduced intakes of energy, protein, carbohydrates, fat, Ca, Zn, Mg, Fe and cholesterol. However, the women on the low-Na diet appeared to be able to adapt quite well to the reduced intake since Ca, Zn and Mg homeostasis was maintained. In the case of Ca and Mg this was probably due to the observed reduced urinary excretions of these nutrients. Non-significant reductions in weight gain (1.5 kg) and fat-mass gain (0.9 kg) over pregnancy were found in the women on the low-Na diet. No significant effects of the diet on birth weight or placental weight were observed.

Adult↗
PubMed1997

Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis.

The common 677C-->T mutation (+) in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme, has been associated with spina bifida neural tube defects (NTD). We combined all known Dutch control groups, a total of 1273 individuals, and found a prevalence of the 677C-->T mutation of 8.4%. When compared with the frequencies in 55 SB patients and to mothers with a child with SB their parents, this gave an OR of 1.9 [95% CI 1.1-3.3] for mothers and an OR of 1.5 [95% CI 0.74-3.1] for patients. The frequency of this mutation and its associated risk for NTD may be population-dependent. However, the frequencies of the 677C-->T mutation in different national and international control groups are almost all in the same range. We therefore combined the observed frequencies of the 677C-->T mutation in all reported studies. The mutation was present in 9.2% of controls, resulting in ORs for all reported NTD patients and their parents of: 1.7 [95% CI: 1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and NTD patients (combined prevalence 16.4%), respectively, vs. all international controls. This meta-analysis confirms that the 677C-->T mutation is a genetic risk factor for NTD.

Female↗
PubMed1997

Altered folate and vitamin B12 metabolism in families with spina bifida offspring.

Folic acid intake reduces the risk of neural tube defects (NTDs). Although the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for NTDs, it only partly explains the elevated homocysteine levels in mothers of children with NTDs. We measured vitamin B12, folate and homocysteine in patients with spina bifida (SB), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozygosity for the 677C-->T mutation causes decreased plasma folate and increased red-cell folate (RCF) and plasma homocysteine levels, we excluded individuals homozygous for that mutation. The remaining SB patients and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B12 levels. Red-cell folate was the same in all groups, suggesting that dietary folate intake and its uptake was normal. Risk of SB was increased at the 25th percentile of plasma folate and at the 75th percentile of homocysteine values in SB patients and their parents, and at the 5th and 25th percentiles of vitamin B12 in mothers with SB-affected offspring. This underlines the functional importance of homocysteine remethylation to methionine. There was no correlation between vitamin B12 and homocysteine or RCF. In combination with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data do not support a major involvement of methionine synthase in the aetiology of SB. Our data rather favour the involvement of genetic variation at loci coding for the formation of 5-methyltetrahydrofolate, such as MTHFR, methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.

Adolescent↗
PubMed1997

Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease.

Elevated homocysteine (Hcy) levels are observed in two apparently unrelated diseases: neural-tube defects (NTD) and premature vascular disease. Defective human methionine synthase (MS) could result in elevated Hcy levels. We sequenced the coding region of MS in 8 hyperhomocysteinaemic patients (4 NTD patients and 4 patients with pregnancies complicated by spiral arterial disease, SAD). We identified only one mutation resulting in an amino acid substitution: an A-->G transition at bp 2756, converting an aspartic acid (D919) into a glycine (G). We screened genomic DNA for the presence of this mutation in 56 NTD patients, 69 mothers of children with NTD, 108 SAD patients and 364 controls. There was no increased prevalence of the GG and AG genotypes in NTD patients, their mothers or SAD patients. The D919G mutation does not seem to be a risk factor for NTD or vascular disease. We then examined the mean Hcy levels for each MS genotype. There was no correlation between GG- or AG-genotype and Hcy levels. The D919G mutation is thus a fairly prevalent, and probably benign polymorphism. This study, though limited, provides no evidence for a major involvement of MS in the aetiology of homocysteine-related diseases such as NTD or vascular disease.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1997

Maternal and fetal levels of methionine and homocysteine in early human pregnancy.

OBJECTIVE: To investigate methionine metabolism during normal human embryonic development by measuring levels of methionine and total homocysteine in samples of maternal serum, extra-embryonic coelomic fluid, and amniotic fluid. DESIGN: Cross-sectional observational study. SETTING: Collaboration between St Bartholomew's Hospital, London, and the University Hospital of Nijmegen in The Netherlands. PARTICIPANTS: Twenty-three women with uncomplicated pregnancies between 8 and 12 weeks of gestation before surgical termination of an ultrasonographically normal fetus. METHODS: Maternal serum samples were collected prior to surgery. Samples of extra-embryonic fluid and amniotic fluids were obtained by transvaginal ultrasound-guided coelocentesis and amniocentesis. Methionine was measured using an amino acid analyser and total homocysteine by high performance liquid chromatography. RESULTS: Levels of methionine were four times higher in extra-embryonic coelomic fluid and twice as high in amniotic fluid compared with maternal serum. In contrast, the total homocysteine concentrations were much lower in both extra-embryonic coelomic fluid and amniotic fluid than in maternal serum. All differences were significant (P < or = 0.01). CONCLUSIONS: The comparatively high concentrations of methionine in extra-embryonic coelomic fluid and amniotic fluid, and the concomitant low levels of total homocysteine in these fluids, suggest a role for methionine metabolism during early human pregnancy.

Amniotic Fluid↗
PubMed1996

Decreased methylene tetrahydrofolate reductase activity due to the 677C-->T mutation in families with spina bifida offspring.

Periconceptional folate intake reduces both the occurrence and recurrence risk of neural tube defects. Plasma homocysteine levels can be elevated in mothers of a child with a neural tube defect, suggesting a dysfunctional folate metabolism. Very recently we showed that a common 677C-->T mutation in the 5,10-methylene tetrahydrofolate reductase gene, causing thermolability of the enzyme, is a risk factor for spina bifida offspring. Restriction enzyme analysis of the genomic 5,10-methylene tetrahydrofolate reductase polymerase chain reaction fragment revealed a significantly higher prevalence of a +/+ genotype among spina bifida patients and their mothers. The risk for spina bifida offspring is the strongest if both the mother and her child have the mutation in the homozygous state. Enzymatic analysis showed that homozygosity for the 677C-->T mutation causes a decreased 5,10-methylene tetrahydrofolate reductase activity, resulting in elevated plasma homocysteine and red blood cell folate levels and lowered plasma folate and cysteine values. This extended study demonstrates that a nucleotide substitution in the coding region of 5,10-methylene tetrahydrofolate reductase, resulting in reduced activity and an impaired homocysteine and folate metabolism, is a genetic risk factor for spina bifida.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗