Cerebral Folate Deficiency in Autism Spectrum Disorders

THE IMPORTANCE OF FOLATE Folic acid (vitamin B9, also known as folate) is a water-soluble B vitamin that is essential for numerous physiological systems of the body. Folate derives its name from the Latin word folium, which means leaf, to signify that the main natural source of this vitamin is from leafy vegetables. However, in the modern western diet, the main source of folate is from folate-forti!ed foods. Folic acid is the inactive, oxidized form of the folate compounds. "e main active form of folate in the body is 5-methyltetrahydrofolate (5-MTHF). Folic acid is converted to dihydrofolate and then to tetrahydrofolate (THF) by the enzyme dihydrofolate reductase. "is reaction, which requires niacin (vitamin B3), can be inhibited by certain medications. 5-MTHF is also converted to THF by the enzyme methylenetetrahydrofolate reductase (MTHFR). 5-MTHF is then converted back to THF through a cobalamin (vitamin B12) dependent enzyme called methionine synthase, a process that recycles methionine from homocysteine. Folate is important for the de novo synthesis of purine and pyrimidine nucleic acids that are the molecules from which DNA and RNA are produced. DNA stores the genetic code and needs to be duplicated when a cell divides and replicates. "us, folate is extremely important during cell replication, especially prior to birth during the development of the embryo and fetus. It is also essential during early life when cells are growing quickly. "e folate cycle interacts with the methionine cycle as well as the tetrahydrobiopterin production and salvage pathways. De!ciencies in folates can lead to abnormalities in these pathways. "e methionine cycle is essential for the methylation of DNA, a process that is important in controlling gene expression. Tetrahydrobiopterin is essential for the production of nitric oxide, a substance critical for the regulation of blood #ow and for the production of the monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine. Production of these neurotransmitters and nitric oxide converts tetrahydrobiopterin to dihydropterin. "e conversion of tetrahydrobiopterin back to dihydropterin again requires conversion of 5-MTHF to THF. In addition, tetrahydrobiopterin is produced de novo using the precursor purine guanosine triphosphate, a substance that requires THF to be produced. Several disorders have been linked to folate de!ciency. For example, since blood cells need to be constantly replenished, a lack of folate commonly leads to anemia, an insu$ciency of red blood cells. Folate de!ciency during pregnancy leads to fetal neural tube defects such as spina bi!da. CEREBRAL FOLATE DEFICIENCY IN AUTISM SPECTRUM DISORDERS