FOLATE RECHALLENGE: A PILOT STUDY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。有限的数据表明，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，那么营养调整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，我们提出了一个随机，安慰剂对照交叉试点研究两个阶段。第一阶段将重点关注AD儿童对高剂量叶酸补充剂的行为和生化反应。因为FA是一种不活跃的叶酸，需要生化转化才能变得活跃，而选择的基因型阻碍了这种转化，我们的一般假设是，FA会改善一些儿童的行为，但会加剧其他儿童的问题行为。在第二阶段，在第一阶段对FA的行为反应恶化的儿童将参加一项高剂量Metafolin补充剂的开放标签试验。这里的重点同样是参与儿童在接受研究补充剂治疗后的行为和生化结果。因为Metafolin？由于Metafolin是一种活性叶酸代谢物，不应受到叶酸途径中基因型的影响，我们对第2阶段的一般假设是Metafolin将产生行为改善，而没有行为恶化的风险。该项目的结果可能为继续研究AD儿童叶酸代谢与问题行为之间的潜在关系提供支持，可能证明需要在更大样本的受影响儿童中检查叶酸补充剂的影响。 自闭症（AD）：自闭症是一种神经发育障碍，表现为社交和沟通技能的缺陷以及重复的刻板行为。发育迟缓和/或这三个领域中至少有一个功能异常必须在3岁之前存在。大约75%被诊断患有自闭症的儿童也符合智力迟钝的标准，功能在中度受影响的范围内（智商在35？50），癫痫发作可能发生在高达25%的情况下（1）。男性被诊断患有AD的频率大约是女性的四倍。根据截至2002年的数据，监测估计表明，每150名儿童中就有1名被诊断患有自闭症谱系障碍（2）。 大多数AD患者没有确凿的原因;然而，遗传学在这种疾病发展中的影响是公认的。双胞胎研究显示，当诊断标准更窄或更宽时，双卵双胞胎的一致率约为5%，单卵双胞胎的一致率为60%至90%（3，4）。非双胞胎兄弟姐妹的复发风险在3%至5%之间（5），远高于一般人群。此外，AD还与多种遗传疾病相关，包括：结节性硬化症、Angelman综合征、Smith-Lemli Opitz综合征、唐氏综合征、MECP 2突变、22 q13缺失、15 q11-q13重复、多余等双着丝粒15 q染色体和脆性X综合征（6，7）。最近，有证据表明，更大比例的自闭症患者有从头染色体缺失或重复（8，9）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. Autistic Disorder (AD): Autism is a neurodevelopmental disorder that presents as deficits in both social and communication skills alongside repetitive, stereotypic behaviors. Developmental delays and/or abnormal functioning in at least one of these three areas must have been present prior to age 3. Approximately 75% of children diagnosed with autism also meet criteria for mental retardation, functioning in the moderately affected range (IQ between 35¿??50), and seizures may occur in up to 25% of cases (1). Males are diagnosed with AD approximately four times as often as are females. Based on data available as of 2002, surveillance estimates indicate that 1 of every 150 children is diagnosed with an autism spectrum disorder (2). There is no substantiated cause for the majority of individuals with AD; however, the influence of genetics in the development of this disorder is well established. Twin studies reveal concordance rates around 5% for dizygotic twins and between 60% and 90% for monozygotic twins when the diagnostic criteria are more narrow or more broad, respectively (3, 4). The recurrence risk for non-twin siblings is between 3% and 5% (5), which is substantially higher than that for the general population. Moreover, AD has been described in association with various genetic conditions, including: tuberous sclerosis, Angelman syndrome, Smith-Lemli Opitz syndrome, Down syndrome, MECP2 mutations, 22q13 deletion, duplications of 15q11-q13, supernumerary isodicentric 15q chromosomes, and fragile X syndrome (6, 7). More recently, there is evidence that a larger fraction of autism patients have de novo chromosomal deletions or duplications (8, 9).