Methyl B12 and Autism Spectrum Disorders: Any Clues to Etiology?

To The Editor:

Hendren et al. (2016) have recently published their findings that methyl B12 supplementation versus placebo improved symptoms of autism spectrum disorder (ASD). The authors further demonstrated that these clinical improvements were significantly correlated with increases in transmethylation metabolism, representing improvements in methylation capacity among ASD subjects. Those with the lowest baseline methionine status seem to show the most improvement from methyl B12 treatment. Although the authors cite limitations with sample sizes and laboratory testing, these findings are made notable given the recent finding that brain levels of methyl B12 are reduced in autism, schizophrenia, and aging (Zhang et al. 2016). Together, these studies demonstrate that central methyl B12 deficiency may be a marked metabolic abnormality in ASD, which can be ameliorated with treatment. As insightful as their findings were, Hendren et al. (2016) did not offer any explanation as to why methyl B12 treatment exerted clinical and metabolic improvements. A reasonable question that could be generated from their work is whether the improvements from vitamin B12 treatment offer any insight regarding ASD etiology.

The author of this correspondence has previously been the first to suggest that exposure to the environmental air pollutant, nitrous oxide (N₂O), may be the leading etiology to the development of offspring ASD and related neuropathological outcomes (Fluegge, 2016). As already discussed, N₂O irreversibly inhibits vitamin B12, inhibiting the action of methionine synthase and, therefore, reducing methylation capacity and potentially contributing to altered fatty acid profiles in ASD subjects through its action on B12 or other known targets (Fluegge, 2016).

Rucklidge et al. (2014) published results from a randomized placebo-controlled trial wherein 64 adults with diagnosed attention-deficit hyperactivity disorder (ADHD) were treated with micronutrients or placebo for a period of 8 weeks. The authors noted that micronutrient supplementation did increase levels of serum nutrient biomarkers, including vitamin B12, which may have contributed to positive neuropsychiatric outcomes associated with micronutrient supplementation. However, baseline vitamin B12 status was not associated with either baseline or outcome psychiatric endpoints in the ADHD subjects, suggesting that serum measures of such biomarkers and reference range comparisons may not be adequate in assessing the effect of micronutrient treatment on psychiatric outcomes in adult ADHD subjects. The findings of Zhang et al. (2016) showing markedly decreased methylcobalamin and methionine synthase activity in the brain of subjects with neuropathology (i.e., ASD) implicate aberrant central methyl B12 status as a possible neural mediator in the early fetal programming of an ASD phenotype.

Given these findings, larger human trials with the use of age- and sex-matched control participants are needed to more comprehensively characterize the nutritional profiles (i.e., B12 status) of subjects with neurodevelopmental disorders. It is recommended here that future research be focused on the role of central methyl B12 status in neurodevelopmental conditions and whether methyl B12 treatment directly improves CNS methylation capacity. If so, as suspected, it may be important to recognize environmental N₂O, a compound that targets central methyl B12 and promotes neurodegeneration, as a principal etiology of neurodevelopmental disorders such as ASD and ADHD.