Serum copper, zinc, calcium and magnesium levels in mothers with offspring affected by neural tube defects: a case-control study

Background: Neural tube defects (NTDs) are important causes of infant mortality, which result from a complex interaction between genetics and environmental factors such as trace elements, which play and crucial role in the epigenetic regulation in the embryo fetal developmental program. Objectives: To measure the maternal serum levels of copper, zinc, calcium and magnesium in mothers with offspring affected by NTDs, and to examine a possible relationship between the serum concentrations of these micronutrients and occurrence of NTDs. Design: Case-controls study. Subjects and Methods: Maternal serum blood samples were obtained from 72 healthy pregnant women and 36 mothers who had NTDs affected offspring, including those alive, stillbirths and elective pregnancy' termination at Centro Provincial de Genetica in Villa Clara. Copper, zinc, calcium and magnesium levels in serum were measured by flame atomic absorption spectrometry and were compared between the two groups of mothers. Results: Serum zinc levels were determined to be significantly lower in the study group compared with the control group, while copper levels were significant elevated in the study group (all p values < .05). There was a negative correlation between serum zinc levels and serum copper levels. However, no association between calcium and magnesium serum levels and increased risk for the development of NTDs was observed. Conclusions: High maternal serum levels of copper and lower level of zinc during pregnancy were associated with NTDs in offspring. If folic acid supplementation is given, additional zinc supplementation should be considered for the further decrease in the recurrence risk of NTDs(AU)

Polimorfismo C677T del gen de la metilentetrahidrofolato reductasa en madres de niños afectados con defectos del tubo neural / C677T polymorphism of the methylentetrahydrofolate reductase gene in mothers of children affected with neural tube defects.

Los defectos del tubo neural (DTN) son las alteraciones congénitas más frecuentes del sistema nervioso central. El mecanismo de transmisión hereditario de los DTN aislados es multifactorial, se debe a la interacción de factores ambientales y genéticos. El polimorfismo 677C>T del gen de la metilentetrahidrofolato reductasa (MTHFR) ha sido implicado como factor de riesgo para DTN. El objetivo de este trabajo fue investigar la asociación del polimorfismo 677C>T del gen de la MTHFR como factor de riesgo en los DTN. Se analizaron muestras de ADN de 52 madres con antecedente de al menos un hijo con DTN y de 119 madres controles. A través de la reacción en cadena de la polimerasa se amplificó un fragmento de 198 pb, el cual se sometió a digestión con la enzima HinfI. La frecuencia alélica de la MTHFR en los grupos problema y control fue de 51,92% y 34,45%; para el alelo T y 48,08% y 65,55%; para el C respectivamente. Se encontró diferencia significativa entre las frecuencias del alelo T y del alelo C (p: 0,002), así como entre las frecuencias genotípicas (p: 0,007) al ser comparadas en ambos grupos. El odds ratio (OR) para el genotipo TT vs CC se estimó como OR: 4,9 [IC 95%: 1,347-6,416] p: 0,002; CT+TT vs CC: OR: 2,9 [IC 95%: 1,347-6,416] p: 0,005; TT vs CT+CC: OR: 2,675 [IC 95%: 1,111-6,441] p: 0,024. Los presentes datos aportan una asociación significativa entre el polimorfismo 677C>T de la MTHFR y riesgo aumentado en las madres con antecedente de hijos con DTN.

Neural tube defects (NTD) are the most common congenital anomalies of the central nervous system, with a multifactorial pattern of inheritance, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene 677C>T polymorphism has been implicated as a risk factor for NTD. The main objective of this research was to investigate the association of the 677C>T polymorphism of the MTHFR gene as a genetic risk factor for NTD. Molecular analysis was performed in DNA samples from 52 mothers with antecedent of NTD offspring and from 119 healthy control mothers. Using the Polymerase Chain Reaction, a 198 bases pairs fragment was digested with the restriction enzyme HinfI. 677T MTHFR allele frequencies for the problem and the control groups were 51.92% and 34.45%, respectively, and 677C MTHFR allele frequencies were 48.08% and 65.55%, respectively. There were significant differences in allele (p: 0.002) and genotype (p: 0.007) frequencies between these two groups. The odds ratio (OR) to the TT genotype vs the CC genotype was estimated as OR: 4.9 [95% CI: 1,347-6.416] p: 0.002; CT+TT vs CC: OR: 2.9 [95% CI: 1.347-6.416] p: 0.005; TT vs CT+CC: OR: 2.675 [95% CI: 1,111-6.441] p: 0.024. The data presented in this study support the relationship between MTHFR 677C>T polymorphism and risk in mothers with antecedent of NTD offspring.

Malformaciones Congénitas: Aspectos Generales y Genéticos / Congenital Malformations: General and Genetic Aspects

Los defectos del desarrollo se pueden deber a malformaciones congénitas, deformaciones o disrupciones. El 10% de las malformaciones se atribuyen a causas ambientales el 25% a factores genéticos y el 65% a factores desconocidos probablemente de orden multifactorial. Existe un período de mayor susceptibilidad frente a los teratógenos que corresponde a la etapa donde se están formando la mayoría de los órganos y sistemas. La ingestión de plantas teratogénicas puede dar lugar a anomalías congénitas en los fetos de animales. Los pesticidas como DDT, la contaminación de las aguas por mercurio y los disruptores endocrinos afectan la embriogénesis de las distintas especies del reino animal. También se consideran como factores causantes de malformaciones a los agentes ambientales infecciosos y a algunos medicamentos. Los agentes físicos como los aumentos de temperatura, las condiciones de hipoxia y las radiaciones afectan a distintos organismos, desde los peces al ser humano. La genética de las malformaciones ha sido difícil de establecer, principalmente porque la mayor parte de ellas se caracteriza por presentar manifestaciones fenotípicas diversas, que en muchos casos aparentemente no están relacionadas y que son variables para los individuos afectados. Por otra parte, los estudios realizados indican que frecuentemente, en la determinación genética de las malformaciones participan varios genes y las interacciones de éstos con el ambiente, aunque determinaciones monogénicas se han podido establecer para unos pocos casos. Ilustramos aquí estos dos tipos contrastantes de determinación genética, a través de la descripción de los factores genéticos que estarían involucrados en los defectos del tubo neural y en el síndrome de CHARGE, respectivamente.

Developmental defects may be due to congenital malformations, deformations or disruptions; 10% of malformations are caused by environmental factors, 25% by genetics factors and 65% are due to unknown multifactorial problems. There is a developmental period of greater susceptibility to teratogens, which corresponds to the stages when most organs and systems are being formed. Ingestions of teratogenics plants may result in congenital anomalies in animal foetuses. Pesticide such as DDT, water contamination with the Hg and the endocrine disrupters affect embryogenesis of different animal species. As factors that provoke malformations there are environmental agents, infections and some drugs. Physical agents such as increased temperature, hypoxic conditions and radiation, affect different organisms from fishes to human. Genetic of malformations have been difficult to establish, mainly because most of them are characterized by diverse phenotypic aspects, apparently not related and variable for the different affected organisms. On the other hand, studies realized indicate that frequently in the genetic determination of malformations several genes and their interactions with the environment are involved, although it has been possible to establish monogenic determination for a few cases. Here we contrast these two types of genetic determination, describing the genetic factors involved in the neural tube defects and the CHARGE syndrome, respectively.

Effect of maternal Tp53 gene G412C polymorphism on neural tube defects: A study from North India.

Context: Tumor protein 53 (tp53) is one of the candidate gene proposed for neural tube defects, which affects central nervous system during early embryonic development, on the basis of mouse models. Aims: The present study is an attempt to unfold the possible role of tp53 G412C polymorphism in the incidence of neural tube defect (NTDs) in humans. Settings and Design: Case-control study was carried out in government hospitals of Delhi, India. Materials and Methods: Subjects comprised of 100 mothers of NTD children and 100 matched control mothers. Information on some environmental exposures was collected along with blood samples. After DNA extraction, the genotyping of tp53 G412C polymorphism was carried out by PCR-RFLP method. Statistical Analysys: Fisher Exact or Chi square test, binary logistic model, and odds ratio (95% confidence interval) calculations were used to evaluate effect of risk factors on NTDs using SPSS v17.0. Results: The 'CC' genotype of tp53 G412C showed protective effect towards the development of anencephaly and/or encephalocele (OR: 0.44; 95% CI: 0.19-1.00); however, no significant difference among overall NTD cases and controls was observed (P>0.05). Further segregation of all subjects based on 2 different communities, Hindus and Muslims, the association of 'CC' genotype of the polymorphism with reduced NTD risk was observed among Hindu community (OR: 0.33; 95% CI: 0.13-0.79). Conclusion: The study highlights the selective advantage provided by maternal 'CC' genotype, thereby reducing risk of cephalic NTDs, probably due to the lower apoptotic activity of the protein, however, more specifically in the presence of community-specific microenvironment.

Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects.

Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C→T is associated with a 2–4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A→C transition at position 1298. The 1298A→C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C→T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs.

Estudios genéticos sobre espina Bífida en Chile: por dónde comenzar?: [revisión] / Genetic studies of spina bifida in Chile: where do we start?: [review]

Neural tube defects (NTDs) are a group of congenital anomalies that affect the central nervious system. Spina Bifida (SB) is the most frecuent NTD in live births andi t is usually associated to disease, disability; and mortality. NTDs are considered as a multifactorial disease. Women who use folic acid periconceptionally are at a 50-70% reduced risk for NTD-affected pregnancies. More than 80 candidates genes to SB are been studied, someones related to folic acid metabolic pathway. MTHFR gene is the gene more studied in NTDs. Its allele 677T is asóciate to higher risk to NTD. It is important to study polymorphisms in MTHFR gene in Chile because Chilean population has dfferent ethnic origen from others previous studied populations.

Congenital malformations in newborns of consanguineous and non-consanguineous parents

To find out the pattern of different congenital malformation [CM] and to compare the proportion of congenital malformations between consanguineous and non-consanguineous parents. This observational study was done in Countess of Dufferin Fund Hospital, [CDF] Hyderabad from July 2006 to June 2008. All newborns with congenital anomaly at birth were included. Complete examination of the newborn after birth and relevant investigations were done. Babies with malformations whose parents were consanguineous were compared with babies having CM whose parents were non-consanguineous. Maternal age, parity, singletons, multiple births, still births and neonatal death were also recorded. Overall prevalence of congenital malformations was 15.7 / 1000 births. Central nervous system anomalies were the commonest [51%]. Congenital malformations in the newborns of consanguineous parents were significantly higher than in the newborns of non-consanguineous parents. Still births and neonatal deaths were commoner in the newborns of consanguineous parents. The results of this study show that parental consanguinity is associated with increased congenital malformations; neural tube defect is the most common anomaly seen

Consumo de fumonisinas y daños a la salud humana / Fumonisin intake and human health

Las fumonisinas son una familia de micotoxinas que contaminan al maíz, alteran el metabolismo de los esfingolípidos y del folato, se asocian con defectos del tubo neural y están catalogadas por la Agencia Internacional de Investigación en Cáncer (IARC por sus siglas en inglés) como posibles carcinógenos humanos. Debido a que en México los derivados de maíz constituyen una parte importante de la dieta y existe alta prevalencia de población genéticamente susceptible a la deficiencia de folato, en este ensayo se presentan las evidencias mundiales y nacionales de la exposición a fumonisinas y la relevancia que para México representa la evaluación de esta exposición.

Fumonisins are mycotoxins that contaminate maize, disrupt the folate and sphingolipid metabolism, are associated with neural tube defects, and are considered by the International Agency for Research on Cancer (IARC) as possible human carcinogens. Since maize-based foods are significant components of the Mexican diet and there is a high prevalence of genetic susceptibility for folate deficiency among Mexicans, this essay presents international and national evidence of fumonisin exposure and the relevance that such exposure represents for Mexico.

Reservas de ácido fólico intraeritrocitario en madres y recién nacidos con defectos del tubo neural comparado con un grupo control sano / Folic acid stores in mothers and infants with neural tube defects compared with a healthy control group

Introducción: la prevalencia de los defectos del tubo neural, especialmente la anencefalia, espina bifida y encefalocele, se presentan mayormente en poblaciones que presentan deficiencias nutricionales. Pocos estudios de países en desarrollo han estudiado la relación de los niveles de ácido fólico sérico e intraeritrocitario en la madre y el recién nacido que presenta DTN. El ácido fólico intraeritrocitario es un marcador del depósito celular de este folato...

Methionine synthase polymorphisms (MTR 2756 A>G and MTR 2758 C>G) frequencies and distribution in the Jordanian population and their correlation with neural tube defects in the population of the northern part of Jordan.

BACKGROUND: The human methionine synthase gene (MTR) is located on chromosome 1q43; it is of 105.24 kb and is made up of 33 exons. Methionine synthase is a cytoplasmic enzyme that requires methylcobalamin for activity and catalyzes the remethylation of homocysteine to methionine. In this reaction, the methyl group of 5-methyltetrahydrofolate is transferred to the enzyme bond cob(I) alamin to generate methylcobalamin, followed by the transfer of the methyl group to homocysteine to reform methionine. MATERIALS AND METHODS: The frequencies of the polymorphisms of MTR 2756A>G and MTR 2758C>G have been determined in this study in a sample of 491 individuals collected from all regions of Jordan and representing the Jordanian population. The different alleles and genotypes at the two polymorphic sites were identified using the Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) analysis. RESULTS: Showed that the percentages of the polymorphic alleles at the MTR 2756 position in the north, middle and south regions were 90.38, 92.65 and 83.69%, respectively, for the MTR 2756A allele, and were 9.61, 7.34 and 16.30%, respectively, for the MTR 2756G allele, with overall percentages in the whole Jordanian population of 90.73 and 9.27% for the MTR 2756A and MTR 2756G alleles, respectively. The percentages of the genotype MTR 2756AA were 82.90% in the northern region, 86.72% in the middle region and 71.73% in the southern region, and an overall percentage of MTR 2756AA in the whole Jordanian population was 83.50%. The frequencies of MTR 2756AG genotype in the northern, middle and southern regions were 14.95, 11.84 and 23.91%, respectively, with an overall percentage of 14.46% in the whole Jordanian population. The percentages of the genotype MTR 2756GG in the northern, middle and southern regions were 2.13, 1.42 and 4.34%, respectively, with an overall percentage of 2.04% in the whole Jordanian population. Only the wild type allele (C) of the MTR 2758C>G polymorphism was detected in this study. In addition, the association of MTR 2756A>G and MTR 2758C>G polymorphisms with the development of neural tube defects (NTDs) was examined using 17 cases of mothers from the northern part of Jordan, who gave birth to NTD affected children during the period of this study. Results showed no association between these two examined polymorphisms and the increase in maternal risk for giving birth to NTD children. CONCLUSION: results of this study recommend that examination should be done on larger populations to arrive at better conclusions. Also, more studies on gene–gene interaction should be done to examine the associations with NTDs.

Nutri-genetic determinants of neural tube defects in India.

Justification: Neural tube defects (NTDs) are one of the commonest birth defects with a high incidence in India. However, few studies have systematically looked into the etio-pathogeneis of NTDs, which mainly includes nutritional deficiencies and genetic predisposition. Efforts are afoot for universal food fortification with folic acid in the hope of preventing NTDs, without factual evidence of folate deficiency in the target population. Evidence acquisition: We conducted a review of Indian literature on NTDs focusing on the role of folate and vitamin B12 nutrition and common genetic polymorphisms in 1-carbon metabolism. We performed a literature search of Medline and Indian Medlars (www. indmed.nic.in) for articles using following search terms: Neural tube defect and India, published up to November 2008, on human subjects. We did not include individual case reports and case series describing surgical and medical management, genetic syndromes where NTD was only one of the features or unusual associations of NTDs with other clinical findings. Results: Absence of a nationally representative large study, lack of interventional studies and methodological differences were conspicuous during this review. Larger studies are, therefore, urgently needed to delineate gene-nutrient interactions in association with NTDs in India. We urge that caution should be exercised before widespread folic acid fortification of food, without addressing the issue of concurrent B12 deficiency.

Defecto del cierre del tubo neural: acrania: a propósito de un caso / Neural tube defect closing: acrania: a purpose of a case

Las malformaciones congénitas son un problema poco frecuente; considerando todas las malformaciones en conjunto, éstas se presentan en menos del 2 por ciento de los recién nacidos. Los defectos del cierre del tubo neural: anencefalia, espina bifida, acrania y meningocele, al igual que la mayoría de las malformaciones congénitas, son un grupo de afecciones de etiología multifactorial, producto de la interacción de factores genéticos y ambientales. Los factores genéticos actúan en un sistema poligenético, en el que se tienen que considerar los riesgos de recurrencia, cálculos de heredabilidad, la frecuencia de consanguineidad y las variaciones raciales, los factores ambientales, las infecciones virales, agentes físicos como la hipertemia (fiebre), deficiencia o alteraciones del metabolismo del ácido fólico, así como la exposición a diversas substancias químicas.

Defectos de cierre del tubo neural. Prevención de ocurrencia y recurrencia. Recomendaciones útiles / Neural tube closure defects. Occurrence and recurrence prevention useful recommendations

Los defectos de cierre del tubo neural (DCTN) son anomalías congénitas multifactoriales originadas por interacción entre factores genéticos y ambientales. El principal factor ambiental es el ácido fólico, relacionado con la sintesis de ADN y ARN y transformación de homocisteína en metionina. El principal factor genético es el gen para la enzima MTHFR (cr1p36.3), que permite al folato alcanzar su forma activa. Su polimorfismo más frecuente es C677T, codificante de variante termolábil. En homocigocis para C677T, disminuyen acción reductasa de MTHFR y folato disponible para proliferación celular (malformaciones congénitas) y aumenta homocisteína circulante (trombosis ateriovenosas, accidentes cardio y cerebrovascular). El presente trabajo investiga factores ambientales y genéticos, en niños con espina bífida (DCTN más frecuente) y sus madres en niños y madres de la población general. Desarrolla estudio de caso-control mediante búsqueda bibliográfica (participación de variable estudiadas); entrevistas a casos y controles (influencia de factores ambientales y familiares) y trabajo especifico de laboratorio (polimorfismo C677T). Realiza trabajo descriptivo para cada variable y trabajo analítico comparando casos y controles. Resultados y conclusiones coinciden con la literatura y fundamentarían la utilidad de la prevención primaria: suplementación con folatos a mujeres en edad fértil. No obstante, dado que para algunas variables los resultados no alcanzaron significancia estadística, su validez deberia corroborarse mediante estudios posteriores.

Malformación congénita: anencefalia a propósito de un caso / Congenital malformation: anencefalia a purpose of a case

La Anencefalia es uno de los defectos congénitos del sistema nervioso central, dado por la ausencia de huesos craneales y tejido encefálico. Este tubo neutral suele cerrarse alrededor de 28 días después de iniciarse el período de crecimiento. El origen de este tipo de malformación es multifactorial asociado principalmente a las deficiencias de folatos por parte de la gestante, igualmente se presume que la exposición a sustancias tóxicas y el consumo de drogas de abuso también se asocian a este tipo de alteración teratogénica. Se presentan en 1-2 de cada 1000 nacidos vivos. El diagnóstico es principalmente dado por estudio ecográfico a partir de la semana 14 de gestación, también se emplea la titulación de alfafetoproteínas y el estudio de líquido anmiótico. Lamentablemente la Anencefalia no tiene tratamiento ya que de sobrevivir al parto el producto vivirá menos de 12 horas. Es preciso que durante el control de la gestación el médico indique la ingesta de ácido fólico y multivitaminicos principalmente B12. Se presenta el caso de una paciente femenina de 27 años de edad, II gestas I para 0 abortos, quien consulta por presentar hallazgo ecográfico que evidencia alteración del cráneo, con una edad gestacional de 24 semanas, por eco, con un embarazo no controlado, refiere antecedente de consumo de drogas por parte de la pareja; igualmente niega ingesta de folatos, hierro o complejo B durante la gestación, refiere trabajar en una empresa productora de alimentos derivados de la papa. Razón por la cual acude a este centro donde se valora y se ingresa para discutir caso; se ingresa con el diagnóstico de embarazo de 25 semanas + 1 día por eco traspolado y ARO por malformación fetal: Anencefalia, no evidenciando alteración al examen físico obstétrico. En sala de hospitalización se realiza eco obstétrico que evidencia malformación fetal anencefalia y se decide trasladar a sala de parto para interrupción del embarazo, se induce trabajo de parto.

Ácido fólico en la prevención de defectos del tubo neural, problemas coronarios, accidentes vasculares cerebrales, cáncer alzheimer, osteoporosis y posiblemente del síndrome de hiperlaxitud articular / Folicacid in the prevention of neural tube defects, coronary problems, cerebral vascular accidents, alzheimer´s disease, osteoporosis, certain cancers and possibly of the joint hypermobility

Se revisa la importancia de la carencia de ácido fólico y los polimorfismos de la metilentetrahidrofofato-reductasa en la génesis no sólo de los defectos del tubo neural, sino también de problemas coronarios, AVE, Alzheimer, ciertos tipos de cáncer, osteoporosis y la posibilidad de que también influya en la génesis del síndrome de hiperlaxitud articular.

Factores de riesgo maternos asociados a anencefalia / Maternal risk factors associated to anencephaly

Introducción. La anencefalia tiene factores de riesgo genéticos, ambientales y maternos. Objetivo. Identificar factores de riesgo maternos para anencefalia. Diseño. Estudio de casos y controles, pareado de base institucional. Sitio. Departamento de Gineco-Obstetricia y Pediatría de un Hospital de Seguridad Social, de segundo nivel. Participantes. 69 Pacientes embarazadas atendidas en su parto, 23 casos y 46 controles. Intervenciones. Se aplicó cuestionario preelaborado que contenía los factores de riesgo más consistentes, a cada una de las pacientes con hijos anencefálicos (casos), y posteriormente a dos madres con hijos normales, que constituyeron los controles. Mediciones. Se analizaron los datos obtenidos en tablas 2 x 2 contrastando las diferencias con prueba de x2, y se midió la asociación con la razón de momios (OR). Se dio como significativo el resultado mayor de 1.5 con IC95 por ciento por arriba de 1. Resultados. La incidencia de anencefalia fue de 2.82/1 000 n.v. No se encontró asociación con la edad materna, paridad, patología gestacional, exposición a altas temperaturas, ocupación de la madre, exposición a agentes químicos o físicos. Se encontró asociación de protección con la ingesta de fármacos durante la gestación, principalmente multivitamínicos. Conclusiones. La incidencia es alta, constituye un problema de salud pública. La probabilidad de anencefalia fue menor en las madres que ingirieron multivitamínicos durante la gestación.

Neural tube defects: prevention by folic acid and other vitamins.

Folic acid has been demonstrated in clinical trials to reduce significantly the recurrence (and probably occurrence) of neural tube defects (NTD). In the U.K., there has been no decline in prevalence of NTD since the publication of the findings with folic acid. This article examines a series of questions relating to the action of folic acid, with emphasis on the use of mouse models as a source of experimental information which cannot easily be obtained by direct study of humans. Several mouse genetic NTD models exhibit sensitivity to prevention by folic acid, whereas other mice which develop morphologically similar NTD are resistant. Folic acid normalises neurulation in the sensitive mouse strains, providing evidence for a direct effect on the developing embryo, not on the pregnant female: Mouse studies do not support the proposed action of folic acid in encouraging the in utero demise of affected fetuses (i.e. terathanasia). Polymorphic variants of several folate-related enzymes have been shown to influence risk of NTD in humans and an inherited abnormality of folate metabolism has been demonstrated in one mouse NTD model. However, the biochemical basis of the action of folic acid in preventing NTD remains to be determined in detail. NTD in one folate-resistant mouse strain can be prevented by myo-inositol, both in utero and in vitro, raising the possibility of a therapeutic role also in humans. Gene-gene interactions seem likely to underlie the majority of NTD, suggesting that poly-therapy involving folic acid and other agents, such as myo-inositol, may prove more effective in preventing NTD than folic acid treatment alone.