Mechanisms underlying word learning in fragile X syndrome and nonsyndromic ASD

 描述（由申请人提供）：脆性X综合征是一种X连锁疾病，在男性中比女性更常见，是智力残疾的主要遗传原因，也是自闭症谱系障碍（ASD）最常见的单基因原因，多达90%的FXS男性表现出至少一些ASD遗传学，多达60%的男性患有ASD共病诊断。智力残疾、社交焦虑、ASD障碍和注意力/抑制控制困难的风险增加的综合存在使FXS患者面临语言问题的风险。然而，有证据表明，尽管有延迟的语言相对于年龄，男性与FXS是更有效的单词学习者比男性非综合征ASD的可比发展水平。这一发现令人惊讶，因为前者表现出更严重的认知障碍和更高的焦虑和过度活跃率，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并不能完全解释FXS的词汇优势。“我们假设这种词汇差异部分与以下事实有关：FXS儿童的一些支持词汇发展的基本技能比非综合征ASD儿童受损更少，即使在ASD严重程度上匹配。我们还假设，FXS患者的ASD行为学掩盖了他们对社会交往的兴趣，这种兴趣将他们与非综合征型ASD患者区分开来，并促进了早期单词学习。在拟议的项目中，我们将研究3至6岁的FXS或非综合征型ASD儿童的词汇发展，重点是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。此外，还将进行直接比较，以（1）提供先前发现的向下延伸（就年龄而言），即患有FXS的男性比智商匹配的非综合征ASD男性获得更好的词汇，（2）阐明这两种情况下词汇发展的潜在因素。FXS和非综合征型ASD之间的相似性和差异的这种深入分析，将告知我们的神经认知机制的理解，其表型和先进的模型，在典型的发展中儿童的词汇发展。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）验证以下声明：由于它们的共同病理学，使FXS受益的靶向治疗对ASD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.