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Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.

Abstract

The inverse association between maternal folate status and incidence of infants born with neural tube defects (NTD's) was recognized over twenty years ago and led the US health agencies in the early 1990s to recommend that women of childbearing age consume 400 microg of folic acid each day. The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's. However, this same time period directly coincides with what many feel is the apparent beginning and continuous increase in the prevalence of Autism and related Autism Spectrum Disorders (ASD's) in the US. Are these similar time frames of changes in maternal folate status and possible Autism prevalence a random event or has improved maternal (and fetal) folate status during pregnancy played a role? It is not only plausible but highly likely. A particular polymorphic form to a key enzyme required to activate folate for methylation in neurodevelopment, 5-methylenetetrahydrofolate reductase (MTHFR), demonstrates reduced activity under low or normal folate levels but normal activity under conditions of higher folate nutritional status. A consequence of the presence of the polymorphic form of this enzyme during normal or reduced folate status are higher plasma homocysteine levels than noncarriers and the combination of these factors have been shown in several studies to result in an increase rate of miscarriage via thrombotic events. However, the incidence of hyperhomocysteinemia in the presence of the polymorphism is reduced under the common condition of enhanced folate status and thereby masks the latent adverse effects of the presence of this enzyme form during pregnancy. Of great importance is that this polymorphism, although common in the normal population, is found in significantly higher frequency in Autisic individuals. It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates. This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period. If these numbers have increased then so have the absolute number of infants that after birth fail to maintain the higher folate status experienced in utero thus leading to an increased number of cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well as other methionine cycle enzymes related to folate metabolism and methylation at birth as part of newborn screening programs could determine which newborns need be monitored and maintained on diets or supplements that ensure adequate folate status during this critical postnatal neurodevelopment period.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    University of Massachusetts Lowell, Clinical Laboratory and Nutritional Sciences, Lowell, MA 01854, United States. Eugene_Rogers@uml.edu

    Source

    Medical hypotheses 71:3 2008 Sep pg 406-10

    MeSH

    Autistic Disorder
    Female
    Folic Acid
    Homocysteine
    Humans
    Methylenetetrahydrofolate Reductase (NADPH2)
    Neural Tube Defects
    Polymorphism, Genetic
    Pregnancy
    Selection, Genetic

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    18514430

    Citation

    Rogers, Eugene J.. "Has Enhanced Folate Status During Pregnancy Altered Natural Selection and Possibly Autism Prevalence? a Closer Look at a Possible Link." Medical Hypotheses, vol. 71, no. 3, 2008, pp. 406-10.
    Rogers EJ. Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link. Med Hypotheses. 2008;71(3):406-10.
    Rogers, E. J. (2008). Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link. Medical Hypotheses, 71(3), pp. 406-10. doi:10.1016/j.mehy.2008.04.013.
    Rogers EJ. Has Enhanced Folate Status During Pregnancy Altered Natural Selection and Possibly Autism Prevalence? a Closer Look at a Possible Link. Med Hypotheses. 2008;71(3):406-10. PubMed PMID: 18514430.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link. A1 - Rogers,Eugene J, Y1 - 2008/06/02/ PY - 2008/03/29/received PY - 2008/03/29/revised PY - 2008/04/01/accepted PY - 2008/6/3/pubmed PY - 2008/10/28/medline PY - 2008/6/3/entrez SP - 406 EP - 10 JF - Medical hypotheses JO - Med. Hypotheses VL - 71 IS - 3 N2 - The inverse association between maternal folate status and incidence of infants born with neural tube defects (NTD's) was recognized over twenty years ago and led the US health agencies in the early 1990s to recommend that women of childbearing age consume 400 microg of folic acid each day. The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's. However, this same time period directly coincides with what many feel is the apparent beginning and continuous increase in the prevalence of Autism and related Autism Spectrum Disorders (ASD's) in the US. Are these similar time frames of changes in maternal folate status and possible Autism prevalence a random event or has improved maternal (and fetal) folate status during pregnancy played a role? It is not only plausible but highly likely. A particular polymorphic form to a key enzyme required to activate folate for methylation in neurodevelopment, 5-methylenetetrahydrofolate reductase (MTHFR), demonstrates reduced activity under low or normal folate levels but normal activity under conditions of higher folate nutritional status. A consequence of the presence of the polymorphic form of this enzyme during normal or reduced folate status are higher plasma homocysteine levels than noncarriers and the combination of these factors have been shown in several studies to result in an increase rate of miscarriage via thrombotic events. However, the incidence of hyperhomocysteinemia in the presence of the polymorphism is reduced under the common condition of enhanced folate status and thereby masks the latent adverse effects of the presence of this enzyme form during pregnancy. Of great importance is that this polymorphism, although common in the normal population, is found in significantly higher frequency in Autisic individuals. It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates. This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period. If these numbers have increased then so have the absolute number of infants that after birth fail to maintain the higher folate status experienced in utero thus leading to an increased number of cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well as other methionine cycle enzymes related to folate metabolism and methylation at birth as part of newborn screening programs could determine which newborns need be monitored and maintained on diets or supplements that ensure adequate folate status during this critical postnatal neurodevelopment period. SN - 0306-9877 UR - https://www.unboundmedicine.com/medline/citation/18514430/Has_enhanced_folate_status_during_pregnancy_altered_natural_selection_and_possibly_Autism_prevalence_A_closer_look_at_a_possible_link_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-9877(08)00163-1 DB - PRIME DP - Unbound Medicine ER -