Metabolic Biomarkers of Autism: Predictive Potential and Genetic Susceptibility

Summary

Principal Investigator: SANDRA JAMES
Abstract: Autism is a behaviorally-defined neurodevelopmental disorder with a CDC-reported prevalence of approximately 1 in 166 children in the US and future societal costs estimates up to $43 billion per year. Despite the urgency to uncover the biologic basis of autism, research progress has been slow. Although both genetic and environmental factors are thought to be involved, none as yet have been reproducibly identified. The metabolic basis for autism has received much less research attention despite the fact that chronic biochemical imbalance is often a primary factor in the development of complex disease. 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. Based on our recent discovery that children with autism exhibit abnormal methionine and glutathione metabolism, we hypothesize that the observed metabolic imbalance results in increased oxidative stress and impaired methylation capacity that may contribute, in part, to the development and clinical manifestations of autism. We further hypothesize that the abnormal metabolic profile will be associated with increased frequency of genetic polymorphisms that functionally affect methionine and glutathione metabolism. Aim 1 will determine whether the severity and specificity of metabolite imbalance is associated with quantitative measures of cognition and behavior and whether the metabolic profile has positive predictive value as a biochemical test for autism to support the behavioral diagnosis. Aim 2 will prospectively investigate whether the abnormal metabolic profile is detectable in high risk toddlers before the behavioral testing is possible as a means to expedite early intervention and treatment strategies to improve outcome. Mechanistic Aim 3 will establish whether cells from autistic children exhibit evidence of oxidative damage, increased vulnerability to oxidative stress, and/or DNA hypomethylation. Using the metabolic profile as a phenotypic map for the selection of candidate genes, Aim 4 will determine whether autism is associated with specific genetic polymorphisms, gene-gene and gene- metabolite interactions that affect methionine and glutathione metabolism. The knowledge gained from this proposal will add a new metabolic dimension to the diagnosis and clinical management of children with autism. The identification of a metabolic endophenotype associated with increased risk of autism will provide new insights into treatment options and new directions for translational research. The public health significance of this proposal is the clinical translation of these findings into early detection and improved diagnosis, better understanding of autism-related pathology, and new targeted intervention strategies to improve the health and clinical outcome of children with autism.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, Arkansas 72202, USA
    Am J Med Genet B Neuropsychiatr Genet 141:947-56. 2006
  2. pmc Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
    J Autism Dev Disord 38:1966-75. 2008
  3. pmc Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain
    S Rose
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Transl Psychiatry 2:e134. 2012
  4. pmc Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum
    S J James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Transl Psychiatry 3:e232. 2013
  5. pmc Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism
    S Jill James
    Department of Pediatrics and Biostatistics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Am J Clin Nutr 89:425-30. 2009
  6. pmc Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, 1120 Marshall St, Little Rock, AR 72202, USA
    FASEB J 23:2374-83. 2009
  7. pmc A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
    Am J Med Genet B Neuropsychiatr Genet 153:1209-20. 2010
  8. pmc Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism
    Stepan Melnyk
    Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
    J Autism Dev Disord 42:367-77. 2012

Scientific Experts

  • SANDRA JAMES
  • S Rose
  • Stepan Melnyk
  • Jill J Fussell
  • S Bai
  • George J Fuchs
  • O Pavliv
  • R E Frye
  • Maya Lopez
  • ELDON SCHULZ
  • Stephen G Kahler
  • David W Gaylor
  • Shannon Rose
  • Oleksandra Pavliv
  • S Melnyk
  • Jayne Bellando
  • T G Nick
  • Lisa Seidel

Detail Information

Publications8

  1. pmc Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, Arkansas 72202, USA
    Am J Med Genet B Neuropsychiatr Genet 141:947-56. 2006
    ..We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism...
  2. pmc Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
    J Autism Dev Disord 38:1966-75. 2008
    ..Studies are underway to determine whether the abnormal profile in parents reflects linked genetic polymorphisms in these pathways or whether it simply reflects the chronic stress of coping with an autistic child...
  3. pmc Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain
    S Rose
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Transl Psychiatry 2:e134. 2012
    ....
  4. pmc Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum
    S J James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Transl Psychiatry 3:e232. 2013
    ....
  5. pmc Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism
    S Jill James
    Department of Pediatrics and Biostatistics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, Little Rock, AR 72202, USA
    Am J Clin Nutr 89:425-30. 2009
    ..Metabolic abnormalities and targeted treatment trials have been reported for several neurobehavioral disorders but are relatively understudied in autism...
  6. pmc Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children s Hospital Research Institute, 1120 Marshall St, Little Rock, AR 72202, USA
    FASEB J 23:2374-83. 2009
    ..These results suggest that the autism LCLs exhibit a reduced glutathione reserve capacity in both cytosol and mitochondria that may compromise antioxidant defense and detoxification capacity under prooxidant conditions...
  7. pmc A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism
    S Jill James
    Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
    Am J Med Genet B Neuropsychiatr Genet 153:1209-20. 2010
    ..Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism...
  8. pmc Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism
    Stepan Melnyk
    Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
    J Autism Dev Disord 42:367-77. 2012
    ..Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism...