【摘要】 背景 脆性X综合征（fragile X syndrome,FXS）主要致病原因是位于Xq27.3上的脆性X信使核糖核蛋白1(Fragile X Messenger Ribonucleoprotein 1,FMR1)基因5’非编码区三核苷酸序列的重复序列数（CGG）n异常增加，引起该基因启动子区域高度甲基化，从而抑制转录，导致脆性X信使核糖核蛋白（Fragile X Messenger Ribonucleoprotein,FMRP）减少或缺乏。尽管既往已有研究显示FMR1基因甲基化水平对认知功能的影响，也有研究揭示了FMRP与脑容量变化之间的潜在联系，但对于FMR1基因甲基化水平与FXS患者伴随的行为学异常以及脑容量变化的相关性，尚缺乏系统探索。目的 探讨FMR1基因甲基化水平与FXS患儿脑容量和行为表型之间的关系。设计横断面研究。方法 纳入2020年1月至2024年10月就诊于复旦大学附属儿科医院儿童保健科、基因检测FMR1(CGG)n>200、明确诊断为FXS的0～18岁男性患儿。采用格里菲斯发育量表-中文版评估患儿的发育水平；采用异常行为量表、重复刻板行为量表-修订版、中文版儿童睡眠习惯问卷评估伴随的行为学问题；扫描MRI结构成像获得患儿的脑容量；测定患儿外周血FMR1基因平均甲基化水平。采用Pearson相关分析和线性回归探索FMR1基因甲基化水平与患儿发育水平、行为学量表评分和脑容量的相关性。主要结局指标发育水平、行为学量表评分和脑容量。结果 纳入FXS患儿58例，年龄（5.9±3.4）岁。FMR1甲基化水平与全脑容量（r=-0.383）、灰质容量（r=-0.337）、白质容量（r=-0.374）均呈显著负相关（P<0.05）；多因素线性回归分析表明，FMR1甲基化水平对全脑容量（b=-1.960,t=-2.379,P<0.05）和白质容量（b=-0.820,t=-2.490,P<0.05）均具独立负向影响。FMR1甲基化水平与格里菲斯发育量表-中文版粗大运动能区的发育商（b=-0.321）、语言能区的发育商（b=-0.402）及平均发育商（b=-0.254）均呈显著负相关（P<0.05），与异常行为量表中情绪不稳/自伤攻击得分呈正相关（b=0.125,P<0.05）。结论 FMR1基因甲基化水平与全脑、灰质和白质容量存在显著相关性，并对发育水平和情绪问题的严重程度有影响。这些发现为FXS的临床诊疗和疾病管理提供了有价值的生物标志物参考。更多还原

【Abstract】 Background Fragile X syndrome(FXS) is primarily caused by a(CGG)n trinucleotide repeat expansion in the 5’ untranslated region of the FMR1 gene, resulting in promoter hypermethylation, transcriptional silencing, and consequent deficiency of FMRP. While FMR1 methylation is known to affect cognition and FMRP levels are linked to brain volume alterations, the relationship between FMR1 methylation, behavioral phenotypes, and brain structure in FXS patients requires systematic investigation. Objective To explore the correlations between FMR1 gene methylation levels and brain volumes, as well as behavioral phenotypes, in pediatric FXS patients. Design Cross-sectional study. Methods A total of 58 male children(aged 0-18 years) with genetically confirmed FXS(FMR1 CGG repeats >200) were enrolled. Developmental levels were assessed using the Griffiths Developmental Scales-Chinese Edition. Behavioral profiles were evaluated with the Aberrant Behavior Checklist(ABC), Repetitive Behavior Scale-Revised(RBS-R), and the Children’s Sleep Habits Questionnaire(CSHQ). Brain volumes were obtained from structural MRI, and peripheral blood FMR1 methylation levels were quantified. Pearson correlation and linear regression analyses were applied.Main outcome measures Developmental levels,behavioral profiles and brain volumes. Results The mean age of participants was 5.9 ± 3.4 years. FMR1 methylation levels showed significant negative correlations with total brain volume(r=-0.383,P<0.05), gray matter volume(r=-0.337,P<0.05), and white matter volume(r=-0.374,P<0.05). Multivariable linear regression confirmed that methylation level independently and negatively influenced total brain volume(b=-1.960,t=-2.379,P<0.05) and white matter volume(b=-0.820,t=-2.490,P<0.05). Furthermore, methylation levels were negatively correlated with Griffiths developmental quotients for gross motor(b=-0.321,P<0.05), language(b=-0.402,P<0.05), and overall average development(b=-0.254,P<0.05). A positive correlation was observed with the ABC Irritability/Self-injurious Aggression subscale score(b=0.125,P<0.05). Conclusion FMR1 gene methylation levels are significantly associated with global and regional brain volumes and influence the severity of developmental deficits and emotional/behavioral symptoms. These findings support the potential utility of FMR1 methylation as a biomarker for clinical assessment and management in FXS.更多还原