title: How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02468, United States. r.deth@neu.edu
authors.forename: Richard
authors.initials: R
authors.lastname: Deth
authors.forename: Christina
authors.initials: C
authors.lastname: Muratore
authors.forename: Jorge
authors.initials: J
authors.lastname: Benzecry
authors.forename: Verna-Ann
authors.initials: VA
authors.lastname: Power-Charnitsky
authors.forename: Mostafa
authors.initials: M
authors.lastname: Waly
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000209:etiology* / Q000235:genetics*; D004777:Environment; D006801:Humans; D008745:Methylation; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050638:Receptors, Dopamine D4 / Q000235:genetics; D013455:Sulfur / Q000378:metabolism
chemical_list: D050638:Receptors, Dopamine D4; D013455:Sulfur