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. ? ? ?
|James, S J; Shpyleva, S; Melnyk, S et al. (2014) Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. Transl Psychiatry 4:e460|
|James, S J; Shpyleva, Svitlana; Melnyk, Stepan et al. (2013) Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Transl Psychiatry 3:e232|
|Frye, Richard E; Melnyk, Stepan; Fuchs, George et al. (2013) Effectiveness of methylcobalamin and folinic Acid treatment on adaptive behavior in children with autistic disorder is related to glutathione redox status. Autism Res Treat 2013:609705|
|Melnyk, Stepan; Fuchs, George J; Schulz, Eldon et al. (2012) Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord 42:367-77|
|Rose, S; Melnyk, S; Pavliv, O et al. (2012) Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry 2:e134|
|Rose, Shannon; Melnyk, Stepan; Trusty, Timothy A et al. (2012) Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res Treat 2012:986519|
|James, S Jill; Melnyk, Stepan; Jernigan, Stefanie et al. (2010) A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism. Am J Med Genet B Neuropsychiatr Genet 153B:1209-20|
|James, S Jill; Rose, Shannon; Melnyk, Stepan et al. (2009) Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J 23:2374-83|
|James, S Jill; Melnyk, Stepan; Fuchs, George et al. (2009) Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr 89:425-30|
|James, S Jill; Jill James, S; Melnyk, Stepan et al. (2008) Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J Autism Dev Disord 38:1966-75|
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