How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis

Richard Deth*, Christina Muratore, Jorge Benzecry, Verna Ann Power-Charnitsky, Mostafa Waly

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

210 Citations (Scopus)


Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. We review the metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks.

Original languageEnglish
Pages (from-to)190-201
Number of pages12
Issue number1
Publication statusPublished - Jan 2008
Externally publishedYes


  • Arsenic
  • Attention
  • Attention-deficit hyperactivity disorder (ADHD)
  • D4 dopamine receptor
  • Folic acid
  • Heavy metal
  • Lead
  • Mercury
  • Neuronal synchronization
  • Oxidative stress
  • Pesticide
  • Phospholipid methylation
  • Thimerosal
  • Vitamin B
  • Xenobiotic

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology


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