Metabolic Biomarkers of Autism: Predictive Potential and Genetic Susceptibility

自闭症的代谢生物标志物：预测潜力和遗传易感性

• 批准号: 7867943
• 负责人: Sandra Jill James
• 金额: $ 35.11万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867943
• 关键词: Achievement; Affect; Algorithms; Arkansas; Attention; Autistic Disorder; Basic Science; Behavior; Behavioral; Biochemical; Biological Markers; Candidate Disease Gene; Cells; Child; Chronic; Clinical; Clinical Management; Cognition; Communication; Complex; DNA; Databases; Development; Diagnosis; Dietary Intervention; Dimensions; Disease; Early Diagnosis; Early treatment; Environment; Environmental Risk Factor; Epigenetic Process; Exhibits; Exogenous Factors; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Glutathione Metabolism Pathway; Health; Impairment; Individual; Intervention; Knowledge; Lymphocyte; Maps; Measures; Metabolic; Metabolite Interaction; Methionine; Methylation; Molecular; Neurodevelopmental Disorder; Outcome; Oxidative Stress; Pathology; Phenotype; Population; Predictive Value; Predisposition; Prevalence; Public Health; Reporting; Research; Research Personnel; Risk; Severities; Social Behavior; Specificity; Speech; Testing; Toddler; Translational Research; Translations; Withdrawal; autistic behaviour; autistic children; base; behavior rating scale; behavior test; case control; cost; design; early childhood; endophenotype; gene interaction; genome-wide; high risk; improved; insight; multidisciplinary; novel; oxidative damage; pediatrician; treatment strategy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：自闭症是一种行为定义的神经发育障碍，据 CDC 报告，美国每 166 名儿童中就有 1 人患有自闭症，未来的社会成本估计高达每年 430 亿美元。尽管揭示自闭症的生物学基础迫在眉睫，但研究进展却很缓慢。尽管遗传和环境因素被认为都参与其中，但尚未得到可重复的鉴定。尽管慢性生化失衡往往是复杂疾病发展的主要因素，但自闭症的代谢基础受到的研究关注却少得多。个体的代谢表型反映了内源和外源因素对基因型的影响。因此，它提供了一个窗口，通过该窗口可以观察基因和环境的相互作用影响并识别相关的易感因素。基于我们最近发现自闭症儿童表现出异常的蛋氨酸和谷胱甘肽代谢，我们假设观察到的代谢失衡导致氧化应激增加和甲基化能力受损，这可能在一定程度上导致自闭症的发展和临床表现。我们进一步假设异常的代谢特征将与功能性影响蛋氨酸和谷胱甘肽代谢的遗传多态性频率增加有关。目标 1 将确定代谢失衡的严重性和特异性是否与认知和行为的定量测量相关，以及代谢谱作为自闭症生化测试是否具有阳性预测价值以支持行为诊断。目标 2 将前瞻性地调查在行为测试之前是否可以在高风险幼儿中检测到异常代谢特征，作为加快早期干预和治疗策略以改善结果的手段。机制目标 3 将确定自闭症儿童的细胞是否表现出氧化损伤、氧化应激脆弱性增加和/或 DNA 低甲基化的证据。使用代谢谱作为选择候选基因的表型图，目标 4 将确定自闭症是否与影响蛋氨酸和谷胱甘肽代谢的特定遗传多态性、基因-基因和基因-代谢物相互作用有关。从该提案中获得的知识将为自闭症儿童的诊断和临床管理增加新的代谢维度。鉴定与自闭症风险增加相关的代谢内表型将为治疗选择和转化研究提供新的见解。该提案的公共卫生意义在于将这些发现临床转化为早期检测和改进诊断、更好地了解自闭症相关病理学以及新的有针对性的干预策略，以改善自闭症儿童的健康和临床结果。

项目成果

Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain.

• DOI: 10.1038/tp.2012.61
• 发表时间: 2012-07-10
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Rose S;Melnyk S;Pavliv O;Bai S;Nick TG;Frye RE;James SJ
• 通讯作者: James SJ

Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism.

• DOI: 10.1155/2012/986519
• 发表时间: 2012
• 期刊: Autism research and treatment
• 作者: Rose S;Melnyk S;Trusty TA;Pavliv O;Seidel L;Li J;Nick T;James SJ
• 通讯作者: James SJ

Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.

• DOI: 10.1038/tp.2014.87
• 发表时间: 2014-10-07
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: James SJ;Shpyleva S;Melnyk S;Pavliv O;Pogribny IP
• 通讯作者: Pogribny IP

Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum.

• DOI: 10.1038/tp.2013.8
• 发表时间: 2013-02-19
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: James SJ;Shpyleva S;Melnyk S;Pavliv O;Pogribny IP
• 通讯作者: Pogribny IP

Effectiveness of methylcobalamin and folinic Acid treatment on adaptive behavior in children with autistic disorder is related to glutathione redox status.

• DOI: 10.1155/2013/609705
• 发表时间: 2013
• 期刊: Autism research and treatment
• 作者: Frye RE;Melnyk S;Fuchs G;Reid T;Jernigan S;Pavliv O;Hubanks A;Gaylor DW;Walters L;James SJ
• 通讯作者: James SJ