Evidence suggests that the dimer configuration of methylenetetrahydrofolate reductase (MTHFR) enzyme might be destabilized by polymorphisms in monomers at the positions C677T and A1298C. It has been ...observed that these polymorphisms may lead to stable (CCAA, CCAC, CCCC) and unstable (CTAA, CTAC, TTAA) enzyme dimer configurations.
The aim of this study was to evaluate the association of the MTHFR enzyme dimer configuration and folate dietary intake with the stage of meiotic nondisjunction in mothers of children with maternally derived trisomy 21.
A total of 119 mothers of children with maternally derived free trisomy 21 were included in the study. The mean maternal age at the time of the birth of the child with trisomy 21 was 32.3 ± 6.4 (range 16-43) years. All mothers were Caucasian. Parental origin of trisomy 21 and meiotic stage of nondisjunction was determined using short tandem repeat markers spanning from the centromere to the telomere of chromosome 21q. The MTHFR C677T and A1298C polymorphism was evaluated by PCR-RFLP.
Increased frequency of the MTHFR genotype combinations CTAA, CTAC, and TTAA was found in the group of mothers with meiosis I (MI) nondisjunction (p = 0.007). No differences were found between study participants regarding dietary and lifestyles habits.
The risk for MI nondisjunction of chromosome 21 was 4.6-fold higher in cases who had CTAA, CTAC, and TTAA MTHFR genotype combinations and who did not used folic acid supplements in the preconception period.
Down syndrome (DS, also known as trisomy 21) most often results from chromosomal nondisjunction during oogenesis. Numerous studies sustain a causal link between global DNA hypomethylation and genetic ...instability. It has been suggested that DNA hypomethylation might affect the structure and dynamics of chromatin regions that are critical for chromosome stability and segregation, thus favouring chromosomal nondisjunction during meiosis. Maternal global DNA hypomethylation has not yet been analyzed as a potential risk factor for chromosome 21 nondisjunction. This study aimed to asses the risk for DS in association with maternal global DNA methylation and the impact of endogenous and exogenous factors that reportedly influence DNA methylation status. Global DNA methylation was analyzed in peripheral blood lymphocytes by quantifying LINE-1 methylation using the MethyLight method. Levels of global DNA methylation were significantly lower among mothers of children with maternally derived trisomy 21 than among control mothers (P = 0.000). The combination of MTHFR C677T genotype and diet significantly influenced global DNA methylation (R2 = 4.5%, P = 0.046). The lowest values of global DNA methylation were observed in mothers with MTHFR 677 CT+TT genotype and low dietary folate. Although our findings revealed an association between maternal global DNA hypomethylation and trisomy 21 of maternal origin, further progress and final conclusions regarding the role of global DNA methylation and the occurrence of trisomy 21 are facing major challenges.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study aimed to assess (i) the impact of screening consultation on male partner’s knowledge about second trimester maternal serum screening for Down syndrome and on their attitudes toward ...amniocentesis, and (ii) the concomitant effect of men’s involvement in pregnancy on both knowledge and attitudes. The study included 164 men who accompanied their partners to the screening appointment. Knowledge Questionnaire and Partner’s Involvement in Pregnancy Scale with two dimensions, support and distance, were administered. Involvement in pregnancy was determined using two factors; support and distance. Findings revealed a significant post-consultation improvement in men’s knowledge about the test, but less-educated men and those who were more distanced from partner and pregnancy were less knowledgeable even post-consultation. Compared to before the consultation, most men had a positive attitude toward amniocentesis and were willing to suggest it to their partners in case of positive test results (77 % and 42 %, respectively). The remainder would either leave the decision to their partners (20 %) or were undecided (3 %). Higher perception of distance was associated with men’s unwillingness to be involved in amniocentesis decisions, particularly before consultation. However, the consultation had considerable potential to engage men with this attitude in the decision-making process. The study highlights the need to change woman-oriented prenatal screening practices for Down syndrome to involve their male partners in the consultation.
Down syndrome (DS) is one of the most common chromosomal abnormalities associated with congenital heart defects (CHD), with approximately 40 to 60% of cases showing cardiac defects. This study ...assessed (i) the association between maternal LINE-1 methylation and the occurrence of CHDs in children with DS and (ii) the impact of endogenous maternal factors (
C677T polymorphism and maternal age) and exogenous maternal factors (cigarette smoking, alcohol intake, medication use, body mass index and dietary habits such as folate intake) on maternal LINE-1 methylation and on the occurrence of CHD in children with DS.
The study included 90 mothers of children with DS of maternal origin (49% DS-CHD
mothers/51% DS-CHD
mothers). LINE-1 DNA methylation was analyzed in peripheral blood lymphocytes by quantification of LINE-1 methylation using the MethyLight method.
C677T polymorphism genotyping was performed using PCR-RFLP.
LINE-1 methylation was not significantly different between DS-CHD
and DS-CHD
mothers (
= 0.997). Combination of
C677T genotype/diet and BMI were significant independent predictors of LINE-1 DNA methylation in DS-CHD
mothers (β -0.40,
= 0.01 and β -0.32,
= 0.03, respectively). In the analyzed multivariate model (model
= 0.028), these two factors explained around 72% of the variance in LINE-1 DNA methylation in mothers of children with DS and CHD. The group with the highest BMI (≥30 kg/m2) had significantly lower LINE-1 methylation than the group with normal BMI (Bonferroni
= 0.03) and the overweight group (Bonferroni
= 0.04). The lowest LINE-1 DNA methylation values were found in DS-CHD
mothers with the CT+TT genotype and a low-folate diet; the values were significantly lower than the values in mothers with the CC genotype and a folate-rich diet (Bonferroni
= 0.04).
Association between maternal LINE-1 methylation and CHD in children with DS was not found. Study showed that the
genotype/diet combination and BMI were significantly associated with LINE-1 methylation in mothers of children with DS-CHD
. These results highlight the need for a multifactorial approach to assess the roles of endogenous and exogenous maternal factors in maternal LINE-1 DNA methylation and the consequent pathologies in children. More extensive studies in a larger sample may help elucidate these relationships.
Background: Congenital heart defects (CHD) are present in most, but not all, cases of Down syndrome (DS). The presence of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms ...has been reported as a risk factor for CHD in DS. The aims of the present study were to assess (i) the frequency of MTHFR C677T and A1298C polymorphisms in DS individuals in the Croatian population; (ii) the relationship between the two maternal MTHFR polymorphisms and CHD‐affected DS children; and (iii) the transmission frequencies of the variant alleles of the two MTHFR polymorphisms in CHD‐affected DS.
Methods: The study population included 112 DS subjects and 221 controls. CHD were present in 48% of the DS subjects (54/112). The mothers of 107 DS individuals were available for the study; none was a periconceptional folic acid user. Allele transmission was analyzed in 34 complete parent–offspring triads.
Results: The frequencies of the allele, individual, and combined genotypes of MTHFR C677T and A1298C in DS subjects were not statistically different compared to the normal healthy Croatian controls. The maternal MTHFR polymorphisms were not found to be a risk factor for DS‐related CHD. The allele transmission of the two MTHFR polymorphisms showed no deviations from random segregation.
Conclusions: Because the fetus is lost in a great proportion of trisomy 21 pregnancies, both maternal and fetal, not only live‐born MTHFR C677T and A1298C, as well as maternal nutrition and lifestyle during pregnancy, should be analyzed to asses the impact on CHD in DS.
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Objectives We sought to evaluate pregnant women’s knowledge about features of second-trimester screening for Down syndrome and to assess whether knowledge and educational level influence their ...attitude toward amniocentesis before receiving test results. Methods Pregnant Caucasian women ( n = 300) <35 years old with no personal or family history of Down syndrome were surveyed. Women were randomized to 2 groups. One group of women ( n = 150) were surveyed by questionnaire before consultation with specially trained midwives; the other group of women ( n = 150) were surveyed after consultation. The questionnaire consisted of 3 sections: 1) participants’ demographic data, 2) knowledge about prenatal screening for Down syndrome, and 3) readiness to undergo amniocentesis if there was an increased risk of Down syndrome. Results Women surveyed after consultation had greater total knowledge scores than those surveyed before consultation ( p < .001). A statistically significant difference in knowledge scores in relation to educational levels was observed only in women who were surveyed before consultation ( p = .007). Significantly more women were prepared to accept amniocentesis in the group surveyed after consultation (74%) than before consultation (53%; p < .001). Conclusion Knowledge gained during a prescreening consultation influenced pregnant women’s attitudes toward further diagnostic investigation. A smaller proportion of women who were indecisive was observed in the group surveyed after prescreening consultation. Indecisiveness was not affected by poor knowledge about screening, but rather by difficulty in knowing how they will feel and what they will do if their screening result is positive.
The aims of the present study were to assess (1) the parental origin of trisomy 21 and the stage in which nondisjunction occurs and (2) the relationship between altered genetic recombination and ...maternal age as risk factors for trisomy 21. The study included 102 cases with Down syndrome from the Croatian population. Genotyping analyses were performed by polymerase chain reaction using 11 short tandem repeat markers along chromosome 21q. The vast majority of trisomy 21 was of maternal origin (93%), followed by paternal (5%) and mitotic origin (2%). The frequencies of maternal meiotic I (MI) and meiotic II errors were 86% and 14%, respectively. The highest proportion of cases with zero recombination was observed among those with maternal MI derived trisomy 21. A higher proportion of telomeric exchanges were presented in cases with maternal MI errors and cases with young mothers, although these findings were not statistically significant. The present study is the first report examining parental origin and altered genetic recombination as a risk factor for trisomy 21 in a Croatian population. The results support that trisomy 21 has a universal genetic etiology across different human populations.
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