RESUMO
Individuals with Down syndrome (DS) carry three copies of the Cystathionine ß-synthase (CßS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.
Assuntos
Síndrome de Down/genética , Ácido Fólico/sangue , Polimorfismo Genético , Adolescente , Adulto , Brasil , Criança , Pré-Escolar , Cromossomos Humanos Par 21/genética , Síndrome de Down/sangue , Feminino , Ácido Fólico/metabolismo , Frequência do Gene , Estudos de Associação Genética , Genótipo , Homocisteína/sangue , Humanos , Lactente , Modelos Lineares , Masculino , Ácido Metilmalônico/sangue , Análise de Sequência de DNA , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/genética , Adulto JovemRESUMO
The occurrence of non-mosaic double trisomy is exceptional in newborns. In this paper, a 48,XXY,+21 child, the parental origin of the extra chromosomes and the evaluation of the maternal folate metabolism are presented. The infant was born to a 13-year-old mother and presented with the typical clinical features of Down syndrome (DS). The origin of the additional chromosomes was maternal and most likely resulted from errors during the first meiotic division. Molecular analysis of 12 genetic polymorphisms involved in the folate metabolism revealed that the mother is heterozygous for the MTHFR C677T and TC2 A67G polymorphisms, and homozygous for the mutant MTRR A66G polymorphism. The maternal homocysteine concentration was 4.7 miromol/L, a value close to the one considered as a risk factor for DS in our previous study. Plasma methylmalonic acid and serum folate concentrations were 0.17 micromol/L and 18.4 ng/mL, respectively. It is possible that the presence of allelic variants for the folate metabolism and Hey concentration might have favored errors in chromosomal disjunction during gametogenesis in this young mother. To our knowledge, this is the first patient with non-mosaic Down-Klinefelter born to a teenage mother, resulting from a rare fertilization event combining an abnormal 25,XX,+21 oocyte and a 23,Y spermatozoon.
Assuntos
Alelos , Aneuploidia , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Síndrome de Down/genética , Ferredoxina-NADP Redutase/genética , Ácido Fólico/sangue , Síndrome de Klinefelter/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético/genética , Gravidez na Adolescência/genética , Aberrações dos Cromossomos Sexuais , Trissomia , Adolescente , Brasil , Análise Mutacional de DNA , Síndrome de Down/diagnóstico , Feminino , Triagem de Portadores Genéticos , Genótipo , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Homocisteína/sangue , Homozigoto , Humanos , Lactente , Síndrome de Klinefelter/diagnóstico , Masculino , Meiose , Ácido Metilmalônico/sangue , Não Disjunção Genética/genética , GravidezRESUMO
The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy concentration was higher than 4.99 micromol/L. In conclusion, the presence of three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 micromol/L are maternal risk factors for DS.
Assuntos
Síndrome de Down/genética , Ácido Fólico/metabolismo , Homocisteína/sangue , Polimorfismo Genético , Adolescente , Adulto , Alelos , Brasil , Estudos de Casos e Controles , Feminino , Ferredoxina-NADP Redutase/genética , Ferredoxina-NADP Redutase/metabolismo , Frequência do Gene , Haplótipos , Humanos , Modelos Logísticos , Idade Materna , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Mães , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Fatores de Risco , Estatística como AssuntoRESUMO
The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 mi mol/L are maternal risk factors for DS.