title: Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.
abstract: Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202, USA. jamesjill@uams.edu
authors.forename: S Jill
authors.initials: SJ
authors.lastname: James
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jernigan
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
authors.forename: Charles H
authors.initials: CH
authors.lastname: Halsted
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wong
authors.forename: Paul
authors.initials: P
authors.lastname: Cutler
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bock
authors.forename: Marvin
authors.initials: M
authors.lastname: Boris
authors.forename: J Jeffrey
authors.initials: JJ
authors.lastname: Bradstreet
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Baker
authors.forename: David W
authors.initials: DW
authors.lastname: Gaylor
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005260:Female; D005787:Gene Frequency; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008715:Methionine / Q000097:blood* / Q000378:metabolism; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*; D058978:Reduced Folate Carrier Protein; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood; D014155:Transcobalamins / Q000235:genetics
chemical_list: D017931:DNA Primers; D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D014155:Transcobalamins; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002394:Catechol O-Methyltransferase; D005982:Glutathione Transferase