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: 7270396
• 负责人: Sandra Jill James
• 金额: $ 36.74万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270396
• 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 Intervention; Environment; Environmental Risk Factor; Epigenetic Process; Exhibits; Exogenous Factors; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genome; 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; Thinking; Toddler; Translational Research; Translations; Withdrawal; autistic behaviour; autistic children; base; behavior rating scale; behavior test; case control; clinical Diagnosis; cost; design; early childhood; endophenotype; gene interaction; improved; insight; multidisciplinary; novel; pediatrician

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，CDC报告的美国儿童患病率约为1/166，未来社会成本估计每年高达430亿美元。尽管迫切需要揭示自闭症的生物学基础，但研究进展缓慢。虽然遗传和环境因素都被认为与此有关，但迄今为止还没有可重复的确定。自闭症的代谢基础受到的研究关注要少得多，尽管慢性生化失衡往往是复杂疾病发展的主要因素。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，通过它可以查看基因和环境的相互影响，并确定相关的易感因素。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，这可能部分导致自闭症的发展和临床表现。我们进一步假设，异常的代谢谱将与基因多态性的频率增加，功能上影响蛋氨酸和谷胱甘肽代谢。目的1将确定代谢物失衡的严重程度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的生化测试是否具有阳性预测价值，以支持行为诊断。目标2将前瞻性地研究在行为测试之前，是否可以在高危幼儿中检测到异常代谢谱，以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的证据，增加对氧化应激的脆弱性，和/或DNA低甲基化。使用代谢谱作为选择候选基因的表型图，Aim 4将确定自闭症是否与影响甲硫氨酸和谷胱甘肽代谢的特定遗传多态性、基因-基因和基因-代谢物相互作用相关。从这项建议中获得的知识将为自闭症儿童的诊断和临床管理增加一个新的代谢维度。与自闭症风险增加相关的代谢内表型的鉴定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转化为早期发现和改善诊断，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。