Análisis del crecimiento longitudinal radical

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the data collected from the environmental risk factor questionnaire. Specifically folic acid status could be evaluated based on information on maternal perinatal intake of folic acid and daily multivitamins. Other potential risk factors to consider include maternal weight, maternal diabetes, smoking and medication use during pregnancy. The two critical regions with similar evidence in favor of linkage for family 8776 suggest that there may be polygenic effects; therefore, potential gene-gene and gene-environment interactions could be studied in several NTD families.

Epigenetic mechanisms may also play a role in normal and dysregulated neural tube closure. In family 8776, epigenetic mechanisms may be involved in disrupted neural tube closure. For instance, the sex ratios for transmitting members of the family to affected children has a 5:2 female to male ratio suggesting a stronger maternal

transmission pattern. Although this observation is not statistically significant and may reflect ascertainment biases toward maternal interviews, it illustrates the potential for maternal nutritional status in family 8776 affecting imprinting mechanisms and/or

general methylation reactions that may increase the risk of having a child affected with an NTD. At this time, no imprinted genes in the 2q and 7p regions of interest were noted [253]. If future studies reveal imprinted genes in these regions they should be evaluated.

To estimate the degree of folate derivates consumed by women around the time of conception through the first month of pregnancy, a risk factor questionnaire with specific questions pertaining to folic acid, prenatal vitamins and multivitamins use was completed by NTD study participants. Although these types of questionnaires are subject to recall bias, a rough measure of maternal folic acid status at the time of neural tube closure was obtained. The folic acid questionnaire outcomes in family 8776 of the five mothers who

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had a child affected with an NTD are illustrated in Table 6.2. All five mothers reported that they took folic acid, prenatal vitamins, or multivitamins first two months of

pregnancy. Individuals 1006, 1023, and 2021 reported taking prenatal or multivitamins for an NTD-affected pregnancy before 1990 when there was less public awareness of the role of folic acid in preventing NTDs. Thus, the amount of folic acid present in the multivitamin formulations at that time may have been inadequate for full protection against NTDs. It has been additionally difficult to determine if the mothers commenced taking folic acid prior to conception or more specifically, prior to neural tube closure. To address this issue, the questionnaire has recently been changed to ask: “How far along before you knew you were pregnant?” This question is a way to better estimate the mother’s actual folic acid intake at the time of neural tube closure, and the mothers in family 8776 have not been asked this question yet. Another possible explanation is that the mothers from family 8776 had adequate folic acid consumption according to current recommendations, and this family may alternatively have genetic variant(s) conferring NTD risk that either lead to the intrauterine environment being folic acid resistant or increase the metabolism/excretion of folic acid or are completely unrelated to folic acid.

Table 6.2 Folic acid questionnaire results for family 8776 Mother Child Year Child Born FA 3m before preg? FA in first 2m of preg? PV 3m before preg? PV in first 2m of preg? MV 3m before preg? MV in first 2m of preg?

1001 1 1998 Yes yes no yes no No

1001 100 1999 Yes yes no yes no No

1006 102 1987 No no no yes yes No

1023 128 1991 No no no yes no No

1028 129 1983 No no no yes no No

2021 1075 1957 No no no no yes Yes

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Recently, autoantibodies against folate receptors to placental membranes in women who had NTD-affected pregnancies were identified that may be blocking the cellular uptake of folate [89]. It would be interesting to examine if the mothers with affected children in family 8776 also express these autoantibodies, and more generally to investigate if the autoantibodies are correlated to all NTDs or only specific form of NTDs in a larger NTD dataset. The presence of other predisposing factors for NTD

development in the presence of these autoantibodies to folate receptors is supported by the observation that two women with normal pregnancies also had autoantibodies against folate receptors. If these mothers from family 8776 demonstrate autoantibodies to folate receptors, it is possible that the chromosome 2 and 7 regions of interest may contain modifier genes that increase NTD risk in the developing fetus. Therefore, it would be additionally informative to collect serum on family members who also have children that are not affected by an NTD. Although the titer patterns of these autoantibodies is

currently unknown, such that levels may change during different stages of pregnancy or alternatively, there may be variability from one pregnancy to the next. At this time, it is unclear whether these autoantibodies are environmental triggered or genetically

determined or a combination of the two.