In my last two posts (prompted by a query from Sheila, a woman who is homozygous for the MTHFR C677T polymorphism and had a baby with Down syndrome) we have tried to make a case for an association of abnormalities in folic acid/methylation metabolism and increased risk for having a baby with Down syndrome based on the worldwide medical literature. The overall sense is that such an association exists but that the expression of risk is variable and may depend on variations in genetic polymorphisms, geographical locations, dietary habits and perhaps other unknown factors. The presumption at the outset has been that these genetic polymorphisms increase the risk for Down syndrome by increasing (primarily) maternal risk for nondisjunction during meiosis. However, in my reading of the limited literature on this subject, it seems the actual cause may not be quite as simple as that and there may be other reasons we see more Down syndrome babies in mothers who carry these polymorphisms.
One of the first questions that should be asked under these circumstances is if these same metabolic abnormalities increase the risk for trisomies associated with nondisjunction of chromosomes other than chromosome 21. The only study I could find that addressed this issue was published in 2001 by Hassold and colleagues (Am J Hum Genet 2001;69:434-9). These investigators “analyzed maternal polymorphisms at MTHFR and MTRR in 93 cases of sex chromosome trisomy, 44 cases of trisomy 18, and 158 cases of autosomal trisomies 2, 7, 10, 13, 14, 15, 16, or 22, and compared the distributions of genotypes to those of control populations.” The only significant association they found was between the MTHFR polymorphism and the risk for having a trisomy 18 pregnancy.
Another intriguing area of inquiry is related to the survival and ultimate development of the Down syndrome conceptuses themselves. Most (80% or more) trisomy 21 babies do not survive the first trimester. We do not understand why some of these babies survive, and others do not, nor why some of these babies have severe malformations and/or mental deficiencies whereas others are not so profoundly affected. Could it be that these metabolic abnormalities of folic acid/methylation metabolism confer some ‘selective advantage’ to survival of these conceptuses? In other words, could there be a greater likelihood of survival among those babies that actually inherit these polymorphisms? If there is, then it might just appear that there is an association between maternal carrier status for these polymorphisms (that are very widespread in the population) and babies with Down syndrome.
At least one article might support this idea. In 2002, Hobbs and colleagues (Am J Med Genet 2002;113:9-14) examined the transmission frequencies of the C677T MTHFR polymorphism from heterozygous parents (parents that had both one ‘normal’ and one C677T allele) to their children with Down syndrome. They found that the C677T allele “was transmitted to children with Down syndrome (who survived pregnancy) at a significantly higher rate than would be expected based on Mendelian inheritance patterns…” Without going into detail, the authors hypothesized that the ‘beneficial effect’ of the MTHFR polymorphism might be in limiting the the ‘overactivity’ that results from 3 (rather than just two) copies of other folate-dependent enzymes whose genes reside on chromosome 21.
Of course, there is also the possibility that some of these babies do better simply because of better maternal nutritional status, which raises the prospects for improving outcome by folic acid and other supplementation. If you look back at my first post on this subject, Sheila was taking high doses of folic acid and other vitamins to help her achieve a successful pregnancy; her baby not only had no heart abnormalities, she apparently is doing quite well developmentally for a baby with Down Syndrome. With the well-documented benefit of folic acid in the reduction of neural tube defects, the growing evidence of the importance of folic acid in the development of the fetal heart, and the high prevalence of MTHFR and other folic acid/methylation polymorphisms among women in the general population, it appears we now have another good reason for insuring an adequate intake of folic acid prior to conception and during early pregnancy. If either (or both) the risk of having a baby with Down syndrome could be reduced, or the developmental outcome of these babies could be improved, by simply increasing the supplementation of folic acid in all reproductive age women, there could be a significant impact on pregnancy outcome and long-term costs of medical care.