Noonan综合征和1型神经纤维瘤病是与Ras-丝裂原活化蛋白激酶信号通路基因中的致病变异相关的遗传条件。两者都会过度激活Ras-丝裂原激活的蛋白激酶途径的信号传导,并表现出神经精神疾病的高患病率。Further,Noonan综合征和1型神经纤维瘤病的动物模型和人类影像学研究显示两种情况下的白质异常。虽然这些发现表明Ras-丝裂原激活的蛋白激酶通路对白质的超激活作用,目前尚不清楚这些效应是综合征特异性的还是通路特异性的.为了表征Noonan综合征和1型神经纤维瘤病对人类白质微结构完整性的影响,并识别潜在的综合征特异性对个体束微结构完整性的影响,我们收集了Noonan综合征患儿(n=24)的弥散加权成像数据,神经纤维瘤病1型(n=28)和年龄和性别匹配的对照(n=31)。我们使用体素对照临床组(Noonan综合征或1型神经纤维瘤病)和对照,基于道和沿道分析。结果包括体素方面,基于束和沿束的分数各向异性,轴向扩散率,径向扩散率和平均扩散率。Noonan综合征和1型神经纤维瘤病表现出相似的模式,即部分各向异性降低和轴向扩散增加。径向扩散系数,以及相对于对照和不同空间模式的白质平均扩散系数。Noonan综合征比1型神经纤维瘤病对白质完整性的空间影响更大,通过各向异性分数测量。与1型神经纤维瘤病(d=0.4)相比,基于赛道的分析还表明Noonan综合征的效应幅度存在差异,各向异性分数总体较低。在管道层面,在相关区域中检测到Noonan综合征对分数各向异性的特定影响(上纵向,钩骨和弓形束状;P<0.012),与对照组相比,在call体中检测到1型神经纤维瘤病的特异性作用(P<0.037)。沿束分析的结果与基于束的分析的结果一致,表明影响沿受影响的束普遍存在。总之,我们发现Ras-丝裂原活化蛋白激酶通路的致病变异体与通过在发育中的脑扩散测量的白质异常相关.总的来说,Noonan综合征和1型神经纤维瘤病显示对分数各向异性和弥散标量的共同影响,以及特定的独特效果,即,Noonan综合征的颞顶额叶(半球内)和1型神经纤维瘤病的call体(半球间)。观察到的特定效应不仅证实了来自努南综合征和1型神经纤维瘤病的独立队列的先前观察结果,而且还告知了个体束的综合征特异性易感性。因此,这些发现表明了精确的潜在目标,现有药物的以大脑为中心的结果测量,如MEK抑制剂,作用于Ras-丝裂原活化蛋白激酶途径。
Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter\'s microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras-mitogen-activated protein kinase pathway.