How environmental and genetic factors combine to cause autism

A redox/methylation hypothesis

Richard Deth, Christina Muratore, Jorge Benzecry, Verna A. Power-Charnitsky, Mostafa Waly

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

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
JournalNeuroToxicology
Volume29
Issue number1
DOIs
Publication statusPublished - Jan 2008

Fingerprint

Methylation
Autistic Disorder
Oxidation-Reduction
Oxidative stress
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
Oxidative Stress
Sulfur
Metabolism
Dopamine
Dopamine D4 Receptors
Detoxification
Poisons
Genetic Polymorphisms
Vitamin B 12
Polymorphism
Folic Acid
Phospholipids
Synchronization
Neural networks
Membranes

Keywords

  • 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)
  • Cellular and Molecular Neuroscience
  • Toxicology

Cite this

How environmental and genetic factors combine to cause autism : A redox/methylation hypothesis. / Deth, Richard; Muratore, Christina; Benzecry, Jorge; Power-Charnitsky, Verna A.; Waly, Mostafa.

In: NeuroToxicology, Vol. 29, No. 1, 01.2008, p. 190-201.

Research output: Contribution to journalArticle

Deth, Richard ; Muratore, Christina ; Benzecry, Jorge ; Power-Charnitsky, Verna A. ; Waly, Mostafa. / How environmental and genetic factors combine to cause autism : A redox/methylation hypothesis. In: NeuroToxicology. 2008 ; Vol. 29, No. 1. pp. 190-201.
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