TY - JOUR
T1 - How environmental and genetic factors combine to cause autism
T2 - A redox/methylation hypothesis
AU - Deth, Richard
AU - Muratore, Christina
AU - Benzecry, Jorge
AU - Power-Charnitsky, Verna Ann
AU - Waly, Mostafa
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - Arsenic
KW - Attention
KW - Attention-deficit hyperactivity disorder (ADHD)
KW - D4 dopamine receptor
KW - Folic acid
KW - Heavy metal
KW - Lead
KW - Mercury
KW - Neuronal synchronization
KW - Oxidative stress
KW - Pesticide
KW - Phospholipid methylation
KW - Thimerosal
KW - Vitamin B
KW - Xenobiotic
UR - http://www.scopus.com/inward/record.url?scp=37849037738&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37849037738&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2007.09.010
DO - 10.1016/j.neuro.2007.09.010
M3 - Review article
C2 - 18031821
AN - SCOPUS:37849037738
SN - 0161-813X
VL - 29
SP - 190
EP - 201
JO - NeuroToxicology
JF - NeuroToxicology
IS - 1
ER -