Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110-1093, USA.
Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110-1093, USA.
J Neurodev Disord. 2021 Mar 20;13(1):10. doi: 10.1186/s11689-021-09359-0.
Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs.
We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1 mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point.
Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1 mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood.
These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics.
运动障碍，如异常步态，是许多神经发育障碍（NDD）的一个被低估但具有特征性的表型，包括威廉姆斯综合征（WS）和神经纤维瘤病 1 型（NF1）。与认知表型相比，步态表型在人类和模式生物中都可以更容易且可比地进行评估，并且由明确的中枢神经系统回路控制。在 NDD 之间发现共同的步态表型可能表明存在共同的细胞和分子缺陷，并突出简单的结果变量，以潜在地量化 NDD 中的纵向治疗效果。
我们使用 DigiGait 测定法在两种不同的小鼠 NDD 模型中对步态进行了特征描述：完全缺失（CD）小鼠，其模拟杂合性缺失的整个 WS 基因座；以及 Nf1 小鼠，其模拟 NF1 患者来源的杂合性种系 NF1 突变。纵向数据在四个发育时间点（出生后第 21-30 天）和一个早期成年时间点收集。
与野生型同窝对照相比，两种模型在发育过程中都显示出明显相似的空间、时间和姿势步态异常。发育中的 CD 小鼠也显示出变异性指标的显著降低。在 Nf1 小鼠中观察到的多种发育中的步态异常在成年早期持续存在，包括步幅长度增加和步频降低，而 CD 模型中的发育异常在成年后基本得到解决。
这些发现表明，NDD 中受影响的步态亚成分在疾病之间存在重叠，以及一些疾病特异性特征，这些特征可能随着发育过程而变化。我们纳入空间、时间和姿势步态测量也为其他 NDD 模型的步态特征描述提供了模板，并为研究电路或纵向治疗提供了平台。
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