Payne Jonathan M, Haebich Kristina M, Mitchell Rebecca, Bozaoglu Kiymet, Giliberto Emma, Lockhart Paul J, Maier Alice, Velasco Silvia, Ball Gareth, North Kathryn N, Hocking Darren R
Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
Mol Psychiatry. 2025 Apr;30(4):1676-1688. doi: 10.1038/s41380-024-02863-4. Epub 2024 Dec 5.
BACKGROUND/OBJECTIVES: Dysregulation of molecular pathways associated with mechanistic target of rapamycin (mTOR) and elevated rates of neurodevelopmental disorders are implicated in the genetic syndromes neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Noonan syndrome (NS). Given shared molecular and clinical features, understanding convergent and divergent implications of these syndromes on brain development may offer unique insights into disease mechanisms. While an increasing number of studies have examined brain volumes in these syndromes, the effects of each syndrome on global and subcortical brain volumes are unclear. Therefore, the aim of the current study was to conduct a systematic review and meta-analysis to synthesize existing literature on volumetric brain changes across TSC, FXS, NF1, and NS. Study outcomes were the effect sizes of the genetic syndromes on whole brain, gray and white matter, and subcortical volumes compared to typically developing controls.
SUBJECTS/METHODS: We performed a series of meta-analyses synthesizing data from 23 studies in NF1, TSC, FXS, and NS (pooled N = 1556) reporting whole brain volume, gray and white matter volumes, and volumes of subcortical structures compared to controls.
Meta-analyses revealed significantly larger whole brain volume, gray and white matter volumes, and subcortical volumes in NF1 compared to controls. FXS was associated with increased whole brain, and gray and white matter volumes relative to controls, but effect sizes were smaller than those seen in NF1. In contrast, studies in NS indicated smaller whole brain and gray matter volumes, and reduced subcortical volumes compared to controls. For individuals with TSC, there were no significant differences in whole brain, gray matter, and white volumes compared to controls. Volumetric effect sizes were not moderated by age, sex, or full-scale IQ.
This meta-analysis revealed that dysregulation of mTOR signaling across pre- and post-natal periods of development can result in convergent and divergent consequences for brain volume among genetic syndromes. Further research employing advanced disease modeling techniques with human pluripotent stem cell-derived in vitro models is needed to further refine our understanding of between and within syndrome variability on early brain development and identify shared molecular mechanisms for the development of pharmaceutical interventions.
背景/目的：与雷帕霉素作用靶点（mTOR）相关的分子通路失调以及神经发育障碍发病率升高与1型神经纤维瘤病（NF1）、结节性硬化症（TSC）、脆性X综合征（FXS）和努南综合征（NS）等遗传综合征有关。鉴于这些综合征具有共同的分子和临床特征，了解它们对大脑发育的趋同和差异影响可能为疾病机制提供独特见解。虽然越来越多的研究已考察这些综合征中的脑容量，但每种综合征对全脑和皮层下脑容量的影响尚不清楚。因此，本研究的目的是进行系统综述和荟萃分析，以综合现有关于TSC、FXS、NF1和NS脑容量变化的文献。研究结果是与典型发育对照相比，这些遗传综合征对全脑、灰质和白质以及皮层下容量的效应大小。
对象/方法：我们进行了一系列荟萃分析，综合了来自NF1、TSC、FXS和NS的23项研究（汇总样本量N = 1556）的数据，这些研究报告了与对照相比的全脑容量、灰质和白质容量以及皮层下结构的容量。
荟萃分析显示，与对照相比，NF1患者的全脑容量、灰质和白质容量以及皮层下容量显著更大。与对照相比，FXS患者的全脑、灰质和白质容量增加，但效应大小小于NF1患者。相反，NS的研究表明，与对照相比，全脑和灰质容量较小，皮层下容量减少。对于TSC患者，与对照相比，全脑、灰质和白质容量无显著差异。容量效应大小不受年龄、性别或全量表智商的影响。
这项荟萃分析表明，在发育的产前和产后阶段，mTOR信号通路失调可导致遗传综合征之间脑容量出现趋同和差异的后果。需要进一步开展研究，采用先进的疾病建模技术和人多能干细胞衍生的体外模型，以进一步完善我们对综合征间和综合征内早期脑发育变异性的理解，并确定药物干预开发的共同分子机制。
