Metabolic Endophenotype and Related Genotypes are Associated With Oxidative Stress in Children With Autism
James SJ, Melnyk S, Jernigan S, Cleves MA, HAlsted CH, Wong DH, Cutler P, Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW
American Journal of Medical Genetics Part B: Neurophsychiatric Genetics. Published Online 2006 Aug.
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. A 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 modulated these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated the plasma methionine and the ration of Sadenosylmethionine (SAM) to S-adenosylhomocysteine (ASH), 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, and indication of antioxidant capacity and redox homeostatsis, 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-methlyltransferase (COMT 472G > A), methylenetetrahydrofolate deductase (MRHFR 677C > T and 1298A > C), and glutatione-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. © 2006 Wiley-Liss, Inc.
Key Words: autism, oxidative stress, genotype, gluathione, methionine