Mechanisms underlying word learning in fragile X syndrome and nonsyndromic ASD

 描述(申请人提供)：脆性X综合征是一种X连锁疾病，男性比女性更常见，是导致智力残疾的主要遗传原因，也是导致自闭症谱系障碍(ASD)的最常见单基因原因，多达90%的FXS男性患者至少表现出一些ASD症状，高达60%的男性患者需要同时诊断为ASD。智力障碍、社交焦虑、自闭症症状的存在，以及注意力/抑制控制困难的高风险，都会使FXS患者面临语言问题的风险。然而，有证据表明，尽管语言相对于年龄有延迟，但患有FXS的男性比发育水平相当的非综合征性ASD男性更有效地学习单词。这一发现令人惊讶，因为前者表现出更严重的认知障碍，更高的焦虑和多动率，这些特征可能会阻碍单词学习过程。此外，ASD严重程度的差异似乎不能完全解释FXS的“词汇优势”。我们假设，这种词汇差异在一定程度上与以下事实有关：支持词汇发展的一些基本技能在FXS儿童中的受损程度低于非综合征性ASD儿童，即使ASD的严重程度与之匹配也是如此。我们还假设，FXS患者的ASD症状学掩盖了他们对社交的兴趣，这将他们与非综合征性ASD患者区分开来，并促进早期单词学习。在这项拟议的项目中，我们将考察患有FXS或非综合征ASD的3-6岁儿童的词汇发展，重点放在支持词汇发展的基本技能和可能成为词汇发展障碍的挑战性行为上。此外，还将进行直接比较，以(1)提供(就年龄而言)先前的研究结果，即患有FXS的男性比患有非综合征ASD的智商匹配的男性获得更好的词汇，以及(2)阐明这两种情况下词汇发展的潜在因素。对FXS和非综合征性ASD之间的异同进行深入的分析将有助于我们理解其表型背后的神经认知机制，以及典型发育儿童的词汇发展的高级模式。此外，需要对这两种疾病的发展轨迹进行直接比较，以(1)开发最佳治疗方法和(2)证实这样的说法，即由于这两种疾病的症状相同，使FXS受益的靶向治疗对ASD也同样有益。

 DESCRIPTION (provided by applicant): Fragile X syndrome, an X-linked disorder that is more common in males than females, is the leading inherited cause of intellectual disability and the most common single-gene cause of autism spectrum disorder (ASD), with as many as 90% of males with FXS demonstrating at least some ASD symptomatology and up to 60% of males warranting a comorbid diagnosis of ASD. The combined presence of intellectual disability, social anxiety, ASD symptomatology, and heighted risk for attentional/inhibitory control difficulties place individuals with FXS at risk for language problems. However, evidence suggests that, despite having delays in language relative to age, males with FXS are more efficient word learners than are males with nonsyndromic ASD of comparable developmental levels. This finding is surprising given that the former display more severe cognitive impairments and higher rates of anxiety and hyperactivity, characteristics likely to impede the word learning process. Moreover, differences in ASD severity do not appear to fully explain this FXS "lexical advantage." We hypothesize that this lexical difference is, in part, related to the fact that some of the foundational skills supporting lexical development are less impaired in children with FXS than in nonsyndromic ASD, even when matched on ASD severity. We also hypothesize that ASD symptomatology in individuals with FXS masks an interest in social interaction that distinguishes them from individuals with nonsyndromic ASD and facilitates early word learning. In the proposed project, we will examine lexical development in 3- to 6-year-olds with FXS or nonsyndromic ASD, with a focus on the foundational skills supporting lexical development and on the challenging behaviors that may serve as barriers to lexical development. In addition, direct comparisons will be made to (1) provide a downward extension (in terms of age) of previous findings that males with FXS achieve better vocabularies than do IQ-matched males with nonsyndromic ASD and (2) elucidate the factors underlying lexical development in these two conditions. Such in-depth analyses of the similarities and differences between FXS and nonsyndromic ASD will inform our understanding of the neurocognitive mechanisms underlying their phenotypes and advance models of lexical development in typically developing children. In addition, this direct comparison of the developmental trajectories of these two disorders is needed to (1) develop optimal treatment approaches and (2) verify the claim that, because of their shared symptomatology, targeted treatments benefitting FXS will be equally beneficial for ASD.