Di Giorgio Elisa, Benavides-Varela Silvia, Porru Annamaria, Caviola Sara, Lunghi Marco, Rigo Paola, Mioni Giovanna, Calignano Giulia, Annunziata Martina, Valenza Eloisa, Liani Valentina, Beghetti Federica, Spolaor Fabiola, Bettella Elisa, Polli Roberta, Sawacha Zimi, Murgia Alessandra
Department of Developmental Psychology and Socialisation, University of Padova, 35131 Padova, Italy.
Padova Neuroscience Center, University of Padova, 35131 Padova, Italy.
Int J Mol Sci. 2025 Jan 17;26(2):771. doi: 10.3390/ijms26020771.
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder that causes a range of developmental problems including cognitive and behavioral impairment and learning disabilities. FXS is caused by full mutations (FM) of the gene expansions to over 200 repeats, with hypermethylation of the cytosine-guanine-guanine (CGG) tandem repeated region in its promoter, resulting in transcriptional silencing and loss of gene function. Female carriers of FM are typically less impaired than males. The Activation Ratio (AR), the fraction of the normal allele carried on the active X chromosome, is thought to play a crucial modifying role in defining phenotype severity. Here, we compare the cognitive, neuropsychological, adaptive, and behavioral profile of two FXS girls (10 and 11 years old) with seemingly identical genotypic profile of FM but distinctive AR levels (70% vs. 30%). A multi-method protocol, combining molecular pathophysiology and phenotypical measures, parent reports, lab-based tasks, gait analyses, and eye-tracking was employed. Results showed that lower AR corresponds to worse performances in most (cognitive, neuropsychological, adaptive, behavioral, social, mathematical skills), but not all the considered areas (i.e., time perception and gait analysis). These observations underscore the importance of AR as a phenotypic modifying parameter in females affected with FXS.
脆性X综合征（FXS）是一种遗传性神经发育障碍，会导致一系列发育问题，包括认知和行为障碍以及学习障碍。FXS由基因扩增的完全突变（FM）引起，即重复次数超过200次，其启动子中的胞嘧啶-鸟嘌呤-鸟嘌呤（CGG）串联重复区域发生高甲基化，导致转录沉默和基因功能丧失。FM的女性携带者通常比男性受损程度轻。激活率（AR）是指活性X染色体上携带的正常等位基因的比例，被认为在定义表型严重程度方面起着关键的修饰作用。在此，我们比较了两名患有FXS的女孩（10岁和11岁）的认知、神经心理、适应性和行为特征，她们具有看似相同的FM基因型，但AR水平不同（70%对30%）。我们采用了一种多方法方案，结合分子病理生理学和表型测量、家长报告、实验室任务、步态分析和眼动追踪。结果表明，较低的AR在大多数（认知、神经心理、适应性、行为、社交、数学技能）但并非所有考虑的领域（即时间感知和步态分析）中对应着较差的表现。这些观察结果强调了AR作为FXS女性患者表型修饰参数的重要性。
