The Redox/Methylation Hypothesis of Autism

valuable clues and guidance. Moreover, awareness of the metabolic pathways of oxidative stress and redox regulation is limited within the medical community, and practitioners are not familiar with non- prescription, so-called ‘biomedical,’ treatments that could potentially address oxidative stress and impaired methylation. The result, for autistic children, is an unfortunately narrow set of treatment options within the traditional medical system. Intense behavioral approaches, such as applied behavioral analysis (ABA), can be effective, but the underlying metabolic condition goes untreated.

‘Biomedical’ treatment for autism encompasses a wide range of interventions, including nutritional supplements, antioxidants, dietary restrictions, heavy metal chelation, hyperbaric oxygen, and more. Only a very limited number of peer-reviewed clinical studies have been published to evaluate the effectiveness of these treatments. Most pertinent to the redox/methylation hypothesis are those carried out by Dr S Jill James at the University of Arkansas Children’s Hospital. In a preliminary study, significantly abnormal plasma levels of redox and methylation metabolites were documented in 20 autistic subjects, some of whom were then treated under open- label conditions with an initial regimen of folinic acid (leucovorin) and betaine (trimethylglycine), followed by the further addition of methylcobalamin (Methyl-B12).13

Plasma metabolite levels partially

normalized in response to each stage of this methylation support regimen. No data were presented for neurocognitive changes, although a brief comment claimed improvement. In a more recent study, 40 autistic subjects were treated with a combination of folinic acid and methylcobalamin for a period of three months.56

Their plasma

levels of GSH and cysteine were significantly increased, as was the ratio of GSH to GSSG, indicative of improved redox status. However, thiol metabolite levels still remained below those in the control group. A parent rating scale indicated improvement in neurocognitive status in association with improved redox status, but the results were not reported due to the potential for bias.

While these preliminary results are encouraging, more robust blinded and placebo-controlled studies are needed, including neurocognitive testing measures. Validation of the importance of oxidative stress and impaired methylation in autism hinges on documentation of clinical improvement when these metabolic conditions are corrected. At the same time, clinicians dealing with autism need to learn more about the relevant metabolic pathways, including which laboratory tests can be ordered to individually assess redox and methylation status, and what supportive treatments are available to correct abnormalities.

1. 2. 3. 4.

Yeargin-Allsopp M, Rice C, Karapurkar T, et al., Prevalence of autism in a US metropolitan area, JAMA, 2003;289:49–55.

Smalley SL, Asarnow RF, Spence MA, Autism and genetics. A decade of research, Arch Gen Psychiatry, 1988;45:953–61.

Herbert MR, Russo JP, Yang S, et al., Autism and environmental genomics, Neurotoxicology, 2006;27:671–84.

Hertz-Picciotto I, Croen LA, Hansen R, et al., The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism, Environ Health Perspect, 2006;114:1119–25.

5. 6.

Bernard S, Enayati A, Roger H, et al., The role of mercury in the pathogenesis of autism, Mol Psychiatry, 2002;7:S42–3.

Schechter R, Grether GK, Continuing increases in autism reported to California’s developmental services system:

US PSYCHIATRY

7.

Figure 2: The Redox/Methylation Hypothesis of Autism

Genetic risk factors Environmental exposures Impaired sulfur metabolism

Neuroinflammation

Oxidative stress  Methionine synthase activity  D4 receptor phospholipid methylation  Neuronal synchronization  Attention and cognition Autism

Exposure to environmental toxins promotes oxidative stress, particularly in individuals carrying genetic risk factors related to sulfur metabolism. The resultant decrease in methionine synthase activity can impair dopamine-stimulated phospholipid methylation and its role in attention and attention-based learning. Lower methionine synthase activity also decreases DNA methylation and its critical role in epigenetic regulation of gene expression during development. Autism reflects the impact of neuroinflammation, oxidative stress, and impaired methylation on the developing brain.

Summary

Increasing rates of autism suggest a causative environmental factor, which is strongly supported by the documented presence of neuroinflammation in the brain, as well as by systemic metabolic disturbances that are commonly caused by heavy metals and xenobiotics. As summarized in Figure 2, environmental exposures can interact with genetic factors in vulnerable individuals to cause oxidative stress and decrease methylation. Adverse effects of impaired methylation on gene expression in the developing brain, and on the role of dopamine-stimulated phospholipid methylation in attention, can combine to provide a molecular framework for understanding the origins of autism. This redox/methylation framework has led to novel metabolic treatment approaches, which are currently being evaluated in clinical studies. Despite ongoing controversy over the cause of the ‘autism epidemic,’ researchers and clinicians must find common ground to collaborate in an effort to bring meaningful benefit to those who are affected, as soon as possible. n

mercury in retrograde, Arch Gen Psychiatry, 2008;65:19–24.

Shannon M, Graef JW, Lead intoxication in children with

pervasive developmental disorders, J Toxicol Clin Toxicol,

1996;34:177–81.

8. Blaylock RL, Strunecka A, Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum

disorders, Curr Med Chem, 2009,16:157–70.

9.

Manev R, Manev H, Aminoglycoside antibiotics and autism: a speculative hypothesis, BMC Psychiatry 2001;1:5.

10. Connors SL, Crowell DE, Eberhart CG, Copeland J, et al., beta2-Adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins, J Child Neurol, 2005;20:876–84.

11. Masuo Y, Morita M, Oka S, Ishido M, Motor hyperactivity

caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain, Regul Pept, 2004;123:225–34.

12. D’Amelio M, Ricci I, Sacco R, Liu X, et al., Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene– environment interactions, Mol Psychiatry, 2005;10:1006–16.

13. James SJ, Cutler P, Melnyk S, et al., Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism, Am J Clin Nutr, 2004;80:1611–17.

14. James SJ, Melnyk S, Jernigan S, et al., Metabolic endophenotype and related genotypes are associated with

51

 DNA methylation Δ Gene expression Developmental delay Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68