Abstract
Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) pregnancies but is unlikely to prevent pregnancy-related complications in the presence of folate receptor autoantibodies (FRAb). In pregnancy, these autoantibodies can block folate transport to the fetus and in young children, folate transport to the brain. These antibodies are prevalent in neural tube defect pregnancies and in developmental disorders such as cerebral folate deficiency (CFD) syndrome and autism spectrum disorder (ASD). In the latter conditions, folinic acid treatment has shown clinical improvement in some of the core ASD deficits. Early testing for folate receptor autoantibodies and intervention is likely to result in a positive outcome. This review discusses the first identification of FRAb in women with a history of neural tube defect pregnancy and FRAb’s association with sub-fertility and preterm birth. Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folinic acid with overall improvements in speech, language and social interaction. The diagnosis of folate receptor autoimmune disorder by measuring autoantibodies against FRα in the serum provides a marker with the potential for treatment and perhaps preventing the pathologic consequences of folate receptor autoimmune disorder.
Highlights
Folate, an umbrella term used for metabolically active forms of folic acid (B9), is an essential B-complex vitamin necessary for basic cellular metabolism including, but not limited to, essential cellular DNA synthesis, repair and methylation including regulation of synthesis and metabolism of monoamine neurotransmitters
No abnormalities of the FRα gene are found in autism spectrum disorder (ASD), but a majority of these children are positive for folate receptor autoantibodies (FRAb) and have low cerebro-spinal fluid (CSF) folate [11,12]
An emerging culprit of folate transport disruption is folate receptor autoimmune disorder, where autoantibodies against the FRα can interfere with folate transport to the fetus; it has been associated with subfertility, difficulty in conceiving, miscarriage and neural tube defects in the fetus [16,17,45,46]
Summary
An umbrella term used for metabolically active forms of folic acid (B9), is an essential B-complex vitamin necessary for basic cellular metabolism including, but not limited to, essential cellular DNA synthesis, repair and methylation including regulation of synthesis and metabolism of monoamine neurotransmitters. One of its most characterized roles is facilitating single carbon transfer to homocysteine to form methionine This reaction is critical for maintaining intracellular Sadenosyl methionine, an essential compound for methylation reactions. No abnormalities of the FRα gene are found in ASD, but a majority of these children are positive for FRAb and have low CSF folate [11,12]. This is a priori proof that FRα is the primary transporter of folate into the brain under physiologic folate status
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