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

与肉碱缺乏相关的突变：自闭症谱系障碍消退的风险因素

• 批准号: 8509954
• 负责人: Robin P. Kochel
• 金额: $ 7.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509954
• 关键词: Affect; Age; Anabolism; Autistic Disorder; Behavior; Carnitine; Child; Childhood; Cognitive; Collection; DNA Sequence; Data; Development; Diagnosis; Diagnostic; Diet; Exons; Frequencies; Genes; Genetic; Genotype; Goals; Interview; Language; Lead; Life; Logistic Regressions; Methods; Mutation; Neurons; Outcome; Participant; Research Personnel; Risk; Risk Factors; Sampling; autism spectrum disorder; case control; design; experience; interest; prevent; programs; public health relevance; repository; skills; social skills; statistics

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.

描述（由申请人提供）：本研究将探讨自闭症谱系障碍（ASD）儿童回归的可能病因机制。根据定义，患有自闭症谱系障碍的儿童在出生后 3 年内会出现社交技能、语言发展异常以及受限或重复的行为/兴趣。然而，受影响儿童的自闭症谱系障碍轨迹并不统一。近三分之一的自闭症谱系障碍儿童在 1 岁至 3 岁之间经历了发育退行，或丧失了先前获得的技能，最常见的是语言和社交技能。虽然有些人重新获得了失去的技能，但那些退步的儿童到 8 岁时，认知和适应性功能结果较差。没有人知道是什么原因导致退行。在寻找 ASD 病因机制的过程中，研究人员注意到 ASD 患者的肉毒碱水平显着降低。 TMLHE 和 SLC22A5 基因突变分别导致神经元和全身肉碱缺乏。 Beaudet 实验室的新数据表明，(a) TMLHE 突变存在于至少 1/200 个 ASD 病例中，(b) SLC22A 突变存在于 1/35 个 ASD 病例中并出现消退。我们认为，患有 TMLHE 和 SLC22A5 突变的自闭症谱系障碍儿童可能会因肉碱生物合成能力下降而出现退化。本研究将使用匹配的病例对照设计来调查 TMLHE 和 SLC22A5 突变在自闭症谱系障碍和退化儿童（病例）中是否比没有退化儿童（对照）更常见。具体目标是 (1) 对 ASD 儿童的现有样本进行 TMLHE 和 SLC22A5 基因的基因分型； (2) 确定基因分型儿童的回归状态； (3)比较病例和对照之间TMLHE和SLC22A5基因的突变频率。我们假设患有自闭症谱系障碍（ASD）且出现退化的儿童比患有未退化的自闭症谱系障碍（ASD）儿童更有可能出现 TMLHE 和 SLC22A5 突变。参与者将是来自 Simons Simplex Collection 的 1200 名儿童，该集合是自闭症谱系障碍 (ASD) 儿童的遗传和表型数据存储库。回归数据将从自闭症诊断访谈修订版的技能损失项目中确定。基因分型涉及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。将使用条件逻辑回归统计来比较组间 TMLHE 和 SLC22A5 的突变频率（回归与非回归）。研究结果可能会产生通过饮食计划来预测和预防自闭症儿童退化的方法，从而增强他们的认知和适应性功能结果。