The other day I received a comment from Sheila on my post related to MTHFR mutations and fetal cardiovascular malformations. She reported that she had had a history of recurrent pregnancy losses (x 4) and during her ‘work-up’ for the same was found to have a low-positive level of IgM anticardiolipin antibodies and was also found to be homozygous (two copies) for the C677T MTHFR mutation. Her “homocysteine levels are normal” (but I am not told if these were done before or after she began folic acid supplementation) and karyotyping (presumably hers and her partners) “also came back normal.” She finally succeeded in carrying a pregnancy, after being treated with Foltex, prenatal vitamins, and Lovenox, only to deliver a baby at term with Down syndrome (trisomy 21). She notes that the baby “has no cardiac problems and is actually developing very well.” Her primary question to me was “Are these blood disorders (MTHFR mutation and Down syndrome) related?”
Well, Sheila, thanks for writing and you get the prize for the most intriguing question of the month! First let me review why folate metabolism and the methylenetetrahydrofolate reductase (MTHFR) gene are important. MTHFR is an enzyme that requires folic acid to convert homocysteine to methionine (an important amino acid) and when this does not occur, homocysteine can accumulate. As we briefly discussed in that previous post, when this occurs in a developing embryo as the result of either folate deficiency or certain mutations in the MTHFR gene, this may have a ‘toxic’ effect, increasing the risk for neural tube defects and certain cardiovascular abnormalities. This same biochemical pathway is also essential for the production of a substance called S-adeneosyl methionine that is an essential intermediate in pathways that add methyl (CH3) groups to nucleic acids (DNA; RNA), proteins, neurotransmitters, and phospholipids, a process that plays an important regulatory role in the biological functions of each of these.
Down syndrome results from the presence of 3 copies of chromosome 21. In 90-95% of cases, the extra chromosome is maternal in origin and results from a failure of normal chromosomal segregation (nondisjunction)during meiosis. This produces one egg (ova) that has 24 chromosomes (22 different chromosomes + 2 copies of chromosome 21) and one egg that has only 22 chromosomes (with no copies of chromosome 21). If the first egg is fertilized by a normal sperm containing 23 different chromosomes, we end up with a baby that has 47 chromosomes rather than 46, and in this case Down syndrome. If the second egg is fertilized, the embryo that is produced has only 45 chromosomes and is nonviable if it has only one copy of chromosome 21 (from the father). Although the risk for trisomy 21 increases with maternal age, most children with Down syndrome are actually born to women less than 30 years of age.
“On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation,” James and colleagues (Am J Clin Nutr 1999;70:429-30) hypothesized in 1999 that young women with the most common MTHFR mutation (C677T) might be at greater risk for having a baby with Down syndrome than their peers who do not have the mutation. In this study, they evaluated the frequency of the C677T mutation, plasma homocysteine levels, and lymphocyte methotrexate cytotoxicity as indicators of functional folate status in 57 mothers of Down syndrome children and 50 matched controls. Findings of significantly higher levels of plasma homocysteine and increased sensitivity of lymphocytes to methotrexate cytotocity in the women with Down syndrome babies supported their hypothesis that abnormal folate and methyl metabolism might contribute to the risk for trisomy 21. Indeed, the women with the C677T MTHFR mutation in this small study had a 2.6-fold higher risk for having a baby with Down syndrome than those who did not.
A subsequent study published by Hobbs and colleagues the next year (Am J Hum Genet 2000;67:623-30) confirmed the preliminary results above. In a cohort of 157 women with Down syndrome babies and 150 matched controls, these investigators not only looked at the prevalence of the C677T MTHFR mutation (technically ‘polymorphism’), but also the prevalence of a common mutation (A66G) in the methionine synthase reductase (MTRR) gene, another enzyme essential for normal folate metabolism. The presence of the C677T MTHFR mutation was associated with a 1.9-fold greater risk, the presence of the homozygous A66G MTRR mutation a 2.57-fold risk, and the presence of both polymorphisms a 4.08-fold risk for having a baby with Down syndrome….(to be continued)