Mutations Associated with Carnitine Deficiency: Risk Factor for Regression in ASD

描述(由申请人提供)：这项研究将探索自闭症谱系障碍(ASD)儿童回归的可能病因机制。根据定义，自闭症儿童在生命的头3年内，在社交技能、语言和受限或重复的行为/兴趣方面表现出异常的发展。然而，在受影响的儿童中，ASD的发展轨迹并不一致。近三分之一的自闭症儿童在1至3岁之间经历了发育退化或先前获得的技能的丧失，最常见的是语言和社交技能。虽然有些人恢复了失去的技能，但那些退化的儿童在8岁时认知和适应能力较差。没有人知道是什么导致了退化。在寻找ASD病因机制的过程中，研究人员注意到ASD患者的肉碱水平显著降低。基因TMLHE和SLC22A5的突变分别导致神经性和全身性肉碱缺乏。Beaudet实验室的新数据表明，(A)TMLHE突变至少存在于200例ASD病例中，(B)SLC22A存在于1/35例ASD退行性病例中。我们认为，具有TMLHE和SLC22A5突变的ASD儿童可能会因为肉碱生物合成能力降低而经历退化。这项研究将使用配对的病例对照设计来调查TMLHE和SLC22A5突变在患有ASD和回归(病例)的儿童中是否比那些没有回归(对照)的儿童更常见。具体目的是(1)对ASD儿童现有样本进行TMLHE和SLC22A5基因的基因分型；(2)确定分型儿童的回归状态；(3)比较TMLHE和SLC22A5基因突变在病例和对照组之间的频率。我们假设患有ASD和退化的儿童比那些没有退化的ASD儿童有更大的TMLHE和SLC22A5突变的几率。参与者将是来自Simons Simplex Collection的1200名儿童，Simons Simplex Collection是来自ASD儿童的遗传和表型数据的存储库。回归数据将从修订后的自闭症诊断访谈的技能损失项目中确定。基因分型包括对所有外显子进行测序，并确定两个基因中外显子的拷贝数。TMLHE和SLC22A5的突变频率将使用条件Logistic回归统计方法在不同组之间(回归组和非回归组)进行比较。这些发现可能导致通过饮食计划预测和预防自闭症儿童的回归，从而增强他们的认知和适应功能结果。

DESCRIPTION (provided by applicant): This study will explore a possible etiological mechanism for regression among children with autism spectrum disorders (ASD). By definition, children with ASD present with aberrant development in social skills, language, and restricted or repetitive behaviors/interests within the first 3 years of life. However, the trajectory of ASD is ot uniform across affected children. Nearly one third of children with ASD experience developmental regression, or a loss of previously acquired skills, most often in language and social skills, between the ages of 1 and 3. While some regain the skills lost, those who regress have poorer cognitive and adaptive-functioning outcomes by age 8. No one knows what causes regression. In the search for an ASD etiological mechanism, researchers have noted significantly reduced levels of carnitine among those with ASD. Mutations in the genes TMLHE and SLC22A5 lead to neuronal and systemic carnitine deficiency, respectively. New data from the Beaudet lab suggest that mutations in (a) TMLHE are present in at least 1/200 ASD cases and (b) SLC22A exist in 1/35 ASD cases with regression. We believe that children with ASD who have TMLHE and SLC22A5 mutations could experience regression because of reduced capacity for carnitine biosynthesis. This study will use the matched case-control design to investigate whether TMLHE and SLC22A5 mutations are more common among children with ASD and regression (cases) than those without regression (controls). Specific aims are to (1) perform genotyping for the TMLHE and SLC22A5 genes on existing samples from children with ASD; (2) ascertain regression status for genotyped children; and (3) compare the frequencies of mutations in the TMLHE and SLC22A5 genes between cases and controls. We hypothesize that children with ASD and regression will have greater odds of having mutations in TMLHE and SLC22A5 than those with ASD who have not regressed. Participants will be 1200 children from the Simons Simplex Collection, a repository of genetic and phenotypic data from children with ASD. Regression data will be ascertained from the skill-loss items of the Autism Diagnostic Interview-Revised. Genotyping involves sequencing all exons and determining copy number for exons in both genes. Frequencies of mutations for TMLHE and SLC22A5 will be compared between groups (regressed vs. nonregressed) using conditional logistic regression statistics. Findings could lead to methods for predicting and preventing regression among children with ASD through dietary programs, subsequently enhancing their cognitive and adaptive-functioning outcomes.