Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill.
Department of Educational Psychology, University of Minnesota, Minneapolis.
JAMA Psychiatry. 2018 May 1;75(5):505-513. doi: 10.1001/jamapsychiatry.2018.0180.
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy.
To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls.
DESIGN, SETTING, AND PARTICIPANTS: Longitudinal behavioral and brain imaging data were collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder.
Nineteen major white matter pathways were defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development.
There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004).
The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.
脆性 X 综合征（FXS）是一种遗传性神经发育障碍，也是男性智力残疾最常见的遗传原因。然而，目前尚无关于婴儿期 FXS 患儿大脑发育的发表数据。
与正常发育对照组相比，描述 FXS 患儿在 6、12 和 24 个月时白质的发育情况。
设计、地点和参与者：2008 年 8 月 1 日至 2016 年 6 月 14 日，在 2 个学术医疗中心，从 27 名 FXS 婴儿和 73 名正常发育对照组婴儿中，至少在一个时间点收集了纵向行为和脑成像数据。对照组中的婴儿没有第一或第二级亲属有智力或精神疾病，包括 FXS 和自闭症谱系障碍。
根据解剖学知识方法，在共同图谱空间中定义了 19 条主要白质通路。使用线性混合效应模型比较组间的扩散参数，包括各向异性分数。对表现出组间差异的纤维通路进行了进一步研究，与言语和非言语发育的直接测量结果相关。
27 名（22 名男性和 5 名女性）FXS 婴儿和 73 名对照组婴儿（46 名男性和 27 名女性）之间的 19 条纤维束中有 12 条存在显著差异，双侧皮质下-额部、枕部-颞部、颞部-额部和小脑-丘脑通路以及胼胝体的 6 个亚区中的 4 个纤维束的各向异性分数较低。对于这 12 条通路，组间均存在显著的主效应，但不存在年龄×组间的交互作用，这表明 FXS 婴儿的各向异性分数较低且从 6 月龄起就保持稳定。钩束的各向异性分数较低与 FXS 组的非言语发育商数较低相关（左侧钩束，F=10.06；经假发现率校正的 P=0.03；右侧钩束，F=21.8；P=0.004）。
研究结果在人类婴儿中证实了脆性 X 基因表达在白质早期发育中的重要作用。研究结果还表明，FXS 的神经发育影响在 6 个月大时就已经确立。
