FOLATE RECHALLENGE: A PILOT STUDY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 新的证据表明，自闭症(AD)可能与叶酸代谢异常有关，叶酸代谢异常是一个通过促进DNA甲基化的甲基供体的形成来影响基因表达的过程。有限的数据显示，一些AD儿童在叶酸(FA)治疗后表现出行为改善，而另一些则表现出恶化的效果。如果行为恶化与叶酸代谢异常有关，那么营养改善可以使这些过程正常化，并导致临床改善。为了解决这一前提，我们提出了一项随机、安慰剂对照的交叉试验研究，分两个阶段进行。第一阶段将关注阿尔茨海默病儿童对大剂量叶酸补充的行为和生化反应。因为FA是一种需要生化转化才能活跃的不活跃的叶酸，而选择的基因型会阻碍这种转化，我们的一般假设是FA会改善一些儿童的行为，但会加剧另一些儿童的问题行为。在第二阶段，在第一阶段对FA有更差行为反应的儿童将参加一项高剂量Metaflin补充剂的开放标签试验。这里的重点同样是参与研究的儿童在接受研究补充治疗后的行为和生化结果。由于Metaflin是一种活跃的叶酸代谢物，不应受叶酸途径中的基因类型的影响，因此我们对第二阶段的一般假设是，Metaflin将产生行为改善，而不会有行为恶化的风险。该项目的结果可能为继续研究阿尔茨海默病儿童叶酸代谢和问题行为之间的潜在关系提供支持，可能证明有必要在更大的受影响儿童样本中检查叶酸补充的效果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT New evidence suggests that autistic disorder (AD) may be associated with abnormalities in folate metabolism, which is a process that affects genetic expression by facilitating the formation of methyl donors for DNA methylation. Limited data show that some children with AD show behavioral improvements with folic acid (FA) therapy, while others show a worsening effect. If behavioral worsening is linked with abnormalities in folate metabolism, then nutritional modifications could normalize these processes and result in clinical improvements. To address this premise, we propose a randomized, placebo-controlled crossover pilot study with two phases. The first phase will focus on the behavioral and biochemical responses of children with AD to high-dose folic acid supplementation. Because FA is an inactive folate that requires biochemical conversion to become active, and select genotypes impede this conversion, our general hypothesis is that FA will yield behavioral improvements in some children but exacerbate problem behaviors in others. During the second phase, children who had a worsened behavioral response to FA during phase 1 will participate in an open-label trial of high-dose Metafolin¿ supplementation. The focus here would similarly be on the behavioral and biochemical outcomes of participating children following treatment with the study supplement. Because Metafolin¿ is an active folate metabolite that should not be affected by genotypes in the folate pathway, our general hypothesis for phase 2 is that Metafolin¿ would yield behavioral improvements without the risk for behavioral worsening. Results from this project may provide support for continued study of the potential relationship between folate metabolism and problem behaviors among children with AD, potentially justifying the need to examine effects of folate supplementation among a larger sample of affected children.