American Journal of Clinical Nutrition 2004 80(December):1611-1617. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism
S Jill James, Paul Cutler, Stepan Melnyk, Stefanie Jernigan, Laurette Janak, David W Gaylor and James A Neubrander
Background : 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.
Objective: The purpose of this study was to evaluate plasma concentrations of metabolites in the methionine transmethylation and transsulfuration pathways in children diagnosed with autism.
Design: 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.
Results: 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.
Conclusions: An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.
Experimental Biology 2005. April 2. San Diego. Abstract Low plasma methionine, cysteine, and glutathione levels are associated with increased frequency of common polymorphisms affecting methylation and glutathione pathways in children with autism
S. Jill James, Stepan Melnyk, Stefanie Jernigan. Pediatrics, University of Arkansas for Medical Sciences, 1120 Marshall St. , Slot 512.40B, Little Rock , AR , 72202
Autism is a complex neurodevelopmental disorder that is thought to involve both genetic and environmental factors. The 10-fold increase in the prevalence of autism in the last 15 years is a major public health concern. Although abnormal thiol metabolism has been associated with other neurologic diseases, 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 90 autistic and 45 control children using HPLC with electrochemical detection. Polymorphic variants in transcobalamin II (TCII), methylene- tetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), catecholamine-O-methyltransferase (COMT), and glutathione-S-transferase (GST) M1/T1 were evaluated in 233 autistic children and 183 controls. The results indicated that mean levels of methionine, cysteine, total glutathione, and the ratio of oxidized to reduced glutathione were significantly decreased among the autistic children. The frequency of MTHFR 677CT/1298AG heterozygosity, TCII 776GG, COMT 1947GG, and the GST M1/T1 double null genotype was increased in the autistic children relative to controls. We hypothesize that an increased vulnerability to oxidative stress (environmental and/or intracellular) may contribute to the development and clinical manifestations of autism.
Supported by the Autism Research Institute, San Diego , CA