Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial

Figure 2

Pathophysiology of autism based on our findings showing the impact of reactive oxygen species (ROS) at different levels of intermediary metabolism and the consequences of brain 5-methyl-tetrahydrofolate (5-methyl THF) deficiency due to FRα autoimmunity. ROS inhibits B-methionine synthase (B-MS) activity and stimulates cystathionine-beta-synthase (CBS) activity, shifting the homocysteine accumulation from the methionine cycle into the transsulfuration pathway with increased production of the natural antioxidant glutathione. Superoxide anions also react with NO at the level of NO-synthase (NOS1) to form peroxynitrite instead of NO, which predisposes to apoptosis and nitrosylation of tyrosine and cysteine. Nitrosative stress affects activity of tryptophan- (TPH2) and tyrosine hydroxylases (TH), the rate-limiting enzymes for serotonin and dopamine synthesis. In addition ROS catabolize 5-methyl-THF and impair folate uptake and transcellular transport across the choroid plexus and placental barriers due to interaction with FRα and RFC1 folate transporters. FRα autoantibodies also impair folate transport to the fetus and brain and predispose to brain folate deficiency with reduction of SAM production and SAM-dependent methyl-transfer reactions, reduced purine and thymidine synthesis with diminished GTP and BH4 production, which is the common cofactor of the enzymes TH, TPH2 and NOS1. Reduction of the activated methyl-group donor SAM down regulates DNA methylation and affects posttranslational modifications of histones (methylation and trimethylation of histones), thereby impeding the homeostatic balance between gene transcription and silencing. In addition folate deficiency is accompanied by overexpression of histone deacetylases, which further leads to abnormal gene silencing. The shutdown in expression of specific sets of genes will affect neuronal growth, pruning and differentiation. Abbreviations: GTPCH: GTP-cyclohydrolase I; cyst: cysteine; tyr: tyrosine; MTHFR: methylene-tetrahydrofolate reductase; RFC1: reduced folate carrier-1.