Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome

Pozzi, Elisa; Vergani, Patrizia; Dalprà, Leda; Combi, Romina; Silvestri, Daniela; Crosti, Francesca; Dell'Orto, Mariagrazia; Valsecchi, Maria Grazia

doi:10.1016/j.ajog.2008.12.046

Cited by 29 publications

(26 citation statements)

References 27 publications

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“…One study showed that vitamin B12 and folate deficiency contributed to high levels of homocysteine in those mothers who gave birth to children with aneuploidy and it also implicated as risk factor for aneuploidy births [29,30]. In my study, all mothers showed serum B12 and folate levels within normal reference ranges inferring to the dietary adequacy Homozygous TT (mutant) -30% of normal enzyme activity 0% 0% 0% (Table 2).…”

Section: Discussionmentioning

confidence: 62%

Methyl Tetra Hydro Folate Reductase Enzyme Polymorphism in the Mothers with Previous Autosomal Aneuploidy Birth in the Indigenous African Population of Northern Region of South Africa

Duma¹,

Khine²

2017

J Down Syndr Chr Abnorm

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IntroductionAneuploidy is a genetic disorder where the total number of chromosomes is either less or more than the normal diploid number of 46, XX or 46, XY [1]. The most common aneuploidies in South Africa caused by autosomal chromosomal abnormalities include Down syndrome (Trisomy 21), Edward syndrome (Trisomy 18) and Patau syndrome (Trisomy 13). Globally the incidence for Down syndrome is about 1 in 650 to 1000 live births [2], Edward syndrome is 1 in 6000 live birth [3], and Patau is between 1 in 5000 to 29000 live birth [4]. Currently the prevalence rate is 1 out of 500 live birth for Down syndrome in South Africa with 1886 new cases diagnosed every year [5] and for Edward syndrome the prevalence is 1 in 4000 live birth and Patau is 1 in 8889 live birth [6,7]. The aetiology of these autosomal aneuploidies are believed to be due to non-disjunction of chromosome in maternal ovum during meiosis which is thought to be a sporadic, incidental event usually associated with older age group mothers. Notably, there is an increased incidence of aneuploidy babies has been observed in younger age group mothers with less than 35 years of age in South African black population [8].There were studies done in the Middle East families with recurrence aneuploidy births to determine if there is a genetic link. Krishna Murthy and Farag reported two unrelated Kuwaiti families each having 3 siblings with trisomy 21 as a result the researchers suggested that some genetic predisposition and gonadal mosaicism could be the underlying cause of recurrent aneuploidy in the younger mothers, thus increasing the risk of recurrence of such pregnancies [9]. There were studies that found that a particular polymorphism of one of these genes Methylenetetrahydrofolate reductase (MTHFR) might be a maternal risk factor for having child with Aneuploidy or Down syndrome and that a significant increase in plasma homocysteine levels exists in mothers of the children with Aneuploidy or Down syndrome [10,11].Increased homocysteine may result from dietary deficiency of folate and or vitamin B12 or from genetic polymorphism of Methylenetetrahydrofolate reductase (MTHFR). These genes encode the enzymes involved in the transfer of methyl group from sulpha containing amino acids (homocysteine and cysteine). Decreased transfer results in decrease methylation of DNA around the centromere region of chromosome 21, 18 and 13 proposed to be leading to aneuploidy. This hypothesis has led many researchers to further explore the evidence between DNA methylation of chromosome 21, 18, 13 in the unfertilized ovum but due to invasive nature of method involved in acquiring the pre-implementation studies, it has not been proven [10,[12][13][14][15][16].Indirect evidence of younger mothers having high level of plasma homocysteine with or without genetic polymorphisms would be the closest link to identifying the risk of recurrence aneuploidy in the AbstractBackground and purpose of the study: Aneuploidy births are highly prevalent in our population and some families, recurre...

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Section: Discussionmentioning

confidence: 62%

Methyl Tetra Hydro Folate Reductase Enzyme Polymorphism in the Mothers with Previous Autosomal Aneuploidy Birth in the Indigenous African Population of Northern Region of South Africa

Duma¹,

Khine²

2017

J Down Syndr Chr Abnorm

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“…Downregulated or decelerated synthesis of methionine has been reported as a pathogenic mechanism causing dementia in DS (Regland and Gottfries, 1992). Pozzi et al (2009), in a study of factors affecting centromeric hypomethylation in the pathogenesis of DS, reported a correlation between polymorphisms in the methionine synthetase-reductase (MTRR) A66G and DS. A recent study reported that the MTRR c.66A>G polymorphism could be a risk factor for DS in newborn children (Coppedè et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

Yq¹,

T²,

Wy³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify disrupted pathways related to Down syndrome (DS), and DS-associated congenital heart defects (DS-CHD). The gene expression profile and pathway data of 10 human DS patients and 5 control samples in E-GEOD-1789 were recruited and analyzed by the individualized pathway aberrance score (iPAS) method, consisting of the data processing, gene-level statistics, pathway-level statistics, and significant measurement steps. The pre-processing step identified 12,493 genes and 1022 pathways (4269 genes). The pathway significant analysis identified eight pathways (adjusted P value <0.1) that differed between the disease and control samples. The cross-presentation of particulate exogenous antigen (phagosomes) and methionine salvage pathways showed the most significant differences among these. The gene expression levels of key pathway genes, such as CYBB and ADI1, were higher in disease samples than in normal controls. Based on our results, we predicted that the cross-presentation of particulate exogenous antigens (phagosomes) and the methionine salvage pathway could be good indicators of DS-CHD.

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“…The MTR 2756 A→G polymorphism has been associated with increased maternal risk for DS in the presence of AG or GG genotypes, as well as when combined with polymorphisms MTRR 66 A→G (MTR 2756AG/MTRR 66AG) (Bosco et al, 2003) and MTHFR 677 C→T (MTHFR 677TT/MTR 2756AA). In addition, the allele MTR 2756 G proved to be more frequent, both in homozygosis and heterozygosis, in DS mothers as compared to mothers of individuals without the syndrome (Pozzi et al, 2009). Concerning its influence on Hcy concentrations, studies have shown conflicting results, since some have associated the MTR 2756 A allele to increased Hcy concentration (Fredriksen et al, 2007;Harmon et al, 1999), while others found the same association, but with the polymorphic 2756 G alelle (Feix et al, 2001;Fillon-Emery et al, 2004).…”

Section: Folate Metabolism Genomic Stability and Maternal Risk For mentioning

confidence: 91%

“…In addition to the MTHFR gene, other genetic polymorphisms involved in the folate pathway seem to modulate the maternal risk for bearing a child with DS (Bosco et al, 2003;J.M. Biselli et al, 2008a;Meguid et al, 2008;Pozzi et al, 2009;Sadiq et al, 2011;Scala et al, 2006;Wang et al, 2008) as well as the concentrations of metabolites involved in the folate pathway (Ananth et al 2007;Barbosa et al, 2008;Cheng et al, 2010;Devos et al, 2008). The MTR 2756 A→G polymorphism has been associated with increased maternal risk for DS in the presence of AG or GG genotypes, as well as when combined with polymorphisms MTRR 66 A→G (MTR 2756AG/MTRR 66AG) (Bosco et al, 2003) and MTHFR 677 C→T (MTHFR 677TT/MTR 2756AA).…”

Section: Folate Metabolism Genomic Stability and Maternal Risk For mentioning

confidence: 99%

“…As to the MTRR 66 A→G polymorphism, some studies have supported an independent role for this polymorphism in the maternal risk for DS in the presence of the homozygous MTRR 66 GG genotype (Hobbs et al, 2000;Pozzi et al, 2009;Wang et al, 2008). Most of the studies have associated this polymorphism with the risk of DS and increased Hcy concentration when combined to other polymorphisms, such as MTHFR 677 C→T (Hobbs et al, 2000;Martínez-Frías et al, 2006;O'Leary et al, 2002;Yang et al, 2008).…”

Section: Folate Metabolism Genomic Stability and Maternal Risk For mentioning

confidence: 99%

See 1 more Smart Citation

Abnormal Folate Metabolism and Maternal Risk for Down Syndrome

Pavarino¹,

Zampieri²,

Biselli³

et al. 2011

Genetics and Etiology of Down Syndrome

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Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome

Cited by 29 publications

References 27 publications

Methyl Tetra Hydro Folate Reductase Enzyme Polymorphism in the Mothers with Previous Autosomal Aneuploidy Birth in the Indigenous African Population of Northern Region of South Africa

Methyl Tetra Hydro Folate Reductase Enzyme Polymorphism in the Mothers with Previous Autosomal Aneuploidy Birth in the Indigenous African Population of Northern Region of South Africa

Identification of altered pathways in Down syndrome-associated congenital heart defects using an individualized pathway aberrance score

Abnormal Folate Metabolism and Maternal Risk for Down Syndrome

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