One possibility for achieving maximum folate benefit without the risk of anti-folate effects is through supplementation with a form of folate, Metafolin, that can serve directly as a methyl donor. Metafolin is the L-form isomer of 5- methyltetrahydrofolate (5-MTHF) and, presumably, a more active compound than folic acid or folinic acid (leucovorin). Metafolin has been approved for use in the U.S. as a dietary supplement since 2001. While studies around the globe have tested the safety of 5-MTHF at doses up to 17mg, there have not yet been any studies to examine its efficacy as a therapeutic agent in specific neurodevelopmental disorders. However, folinic acid (5,10- MTHF), which immediately precedes 5-MTHF in the folate-metabolism cycle, has been investigated repeatedly as a potential therapeutic agent for this population. In one such study, James et al. examined the biochemical effects of folinic acid supplementation in conjunction with betaine and vitamin B12 on the biochemical outcomes of children with imbalanced metabolic profiles. This team initially discovered that, compared with a control group, children with AD had significantly lower baseline concentrations of methionine, S-adenosylmethionine (SAM), and homocysteine and significantly higher concentrations of S-adenosylhomocysteine (SAH) and adenosine--a metabolic profile that is consistent with impaired capacity for methylation. Following supplementation with the study treatments, the metabolic imbalance within the AD group was normalized. This same research team recently published results from an extension of this work in which they assessed levels of folate-related metabolites and genotypes for select enzymes. Approximately 50% of children with AD had severely abnormal metabolic profiles; additionally, "...several susceptibility alleles that perturb a common metabolic pathway were increased among the autistic children. The hypothesis that a genetic component of autism could involve multiple susceptibility alleles that interact to create a fragile, environmentally sensitive metabolic imbalance is worthy of further pursuit," (electronic copy; no page number available).