Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism

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Abstract

Autism is a complex neurodevelopmental disorder that usually presents in early childhood and that is thought to be influenced by genetic and environmental factors. Although abnormal metabolism of methionine and homocysteine has been associated with other neurologic diseases, these pathways have not been evaluated in persons with autism. The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism. Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.

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Most cited references 45

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Prevalence of Autism in a US Metropolitan Area

Marshalyn Yeargin-Allsopp, Catherine Rice, Tanya Karapurkar … (2003)

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Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation.

P. Yi, S Melnyk, M Pogribna … (2000)

S-Adenosylmethionine and S-adenosylhomocysteine (SAH), as the substrate and product of essential cellular methyltransferase reactions, are important metabolic indicators of cellular methylation status. Chronic elevation of SAH, secondary to the homocysteine-mediated reversal of the SAH hydrolase reaction, reduces methylation of DNA, RNA, proteins, and phospholipids. High affinity binding of SAH to the active site of cellular methyltransferases results in product inhibition of the enzyme. Using a sensitive new high pressure liquid chromatography method with coulometric electrochemical detection, plasma SAH levels in healthy young women were found to increase linearly with mild elevation in homocysteine levels (r = 0.73; p < 0.001); however, S-adenosylmethionine levels were not affected. Plasma SAH levels were positively correlated with intracellular lymphocyte SAH levels (r = 0.81; p < 0.001) and also with lymphocyte DNA hypomethylation (r = 0.74, p < 0.001). These results suggest that chronic elevation in plasma homocysteine levels, such as those associated with nutritional deficiencies or genetic polymorphisms in the folate pathway, may have an indirect and negative effect on cellular methylation reactions through a concomitant increase in intracellular SAH levels.

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Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation.

F Bove, M Yeargin-Allsopp, P Decoufle … (2001)

This study determined the prevalence of autism for a defined community, Brick Township, New Jersey, using current diagnostic and epidemiologic methods. The target population was children who were 3 to 10 years of age in 1998, who were residents of Brick Township at any point during that year, and who had an autism spectrum disorder. Autism spectrum disorder was defined as autistic disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), and Asperger disorder. The study used 4 sources for active case finding: special education records, records from local clinicians providing diagnosis or treatment for developmental or behavioral disabilities, lists of children from community parent groups, and families who volunteered for participation in the study in response to media attention. The autism diagnosis was verified (or ruled out) for 71% of the children through clinical assessment. The assessment included medical and developmental history, physical and neurologic evaluation, assessment of intellectual and behavioral functioning, and administration of the Autism Diagnostic Observation Schedule-Generic. The prevalence of all autism spectrum disorders combined was 6.7 cases per 1000 children. The prevalence for children whose condition met full diagnostic criteria for autistic disorder was 4.0 cases per 1000 children, and the prevalence for PDD-NOS and Asperger disorder was 2.7 cases per 1000 children. Characteristics of children with autism in this study were similar to those in previous studies of autism. The prevalence of autism in Brick Township seems to be higher than that in other studies, particularly studies conducted in the United States, but within the range of a few recent studies in smaller populations that used more thorough case-finding methods.