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Objectives: Ataxic-rigid gait is a characteristic gait pathology in patients with Rett syndrome (RTT). In the present study, we aimed to quantitatively evaluate gait pathology in patients with RTT using three-dimensional gait analysis (3DGA). Methods: We performed 3DGA in 11 patients with RTT ranging from 5 to 18 years (median age, 9 years) and in 33 age-matched healthy female controls. We compared the results of 3DGA, including spatiotemporal gait parameters and comprehensive indices of gait kinematics, such as the Gait Deviation Index (GDI) and Gait Profile Score (GPS), between the two groups. The GPS consists of nine sub-indices called Gait Variable Scores (GVSs). Decline in GDI or elevation of GPS and GVS indicated greater abnormal gait pathology. Results: The patients demonstrated significantly slower walking speed, lower step length/length of the lower extremities, lower cadence, wider step width, and higher coefficient of variation of step length than the controls. Moreover, the patients had a lower GDI and higher GPS than the controls. The patients also exhibited higher GVSs for eight out of nine gait kinematics, particularly the sagittal plane in the pelvis, hip, knee, and ankle joint; coronal plane in the pelvis and hip joint; and horizontal plane in the pelvis than the controls. Conclusions: Quantitative evaluation of gait pathology in patients with RTT is possible using 3DGA. We found that in addition to ataxic-rigid gait, abnormalities in the coronal plane of the pelvis and hip joint and the horizontal plane of the pelvis were prominent.

To clarify the relationship between structural and functional changes in the brains of patients with Rett syndrome (RTT) using multimodal magnetic resonance imaging (MRI).Nine subjects with typical RTT (RTTs) and an equal number of healthy controls (HCs) underwent structural MRI, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI). The measurements obtained from each modality were statistically compared between RTTs and HCs and examined for their correlation with the clinical severity of RTTs.Structural MRI imaging revealed volume reductions in most cortical and subcortical regions of the brain. Remarkable volume reductions were observed in the frontal and parietal lobes, cerebellum, and subcortical regions including the putamen, hippocampus, and corpus callosum. DTI analysis revealed decreased white matter integrity in broad regions of the brain. Fractional anisotropy values were greatly decreased in the superior longitudinal fasciculus, corpus callosum, and middle cerebellar peduncle. Rs-fMRI analysis showed decreased functional connectivity in the interhemispheric dorsal attention network, and between the visual and cerebellar networks. The clinical severity of RTTs correlated with the volume reduction of the frontal lobe and cerebellum, and with changes in DTI indices in the fronto-occipital fasciculus, corpus callosum, and cerebellar peduncles.Regional volume and white matter integrity of RTT brains were reduced in broad areas, while most functional connections remained intact. Notably, two functional connectivities, between cerebral hemispheres and between the cerebrum and cerebellum, were decreased in RTT brains, which may reflect the structural changes in these brain regions.

Summary Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running., Graphical Abstract, Highlights • Prenatal VPA treatment caused an untimely enhancement of embryonic neurogenesis • Prenatal VPA treatment has the long-term effect of impairing adult neurogenesis • Reduced level of adult neurogenesis is associated with cognitive functional impairments • Voluntary running can ameliorate the persistent detrimental effects caused by VPA, Nakashima and colleagues show that prenatal VPA exposure in mice produced comparable postnatal cognitive functional impairments in children from epileptic mothers. VPA enhances embryonic neurogenesis, which then leads to depletion of the neural precursor cell pool, resulting in a decreased level of adult hippocampal neurogenesis. They further show that voluntary running could reinstate the neurogenesis and restore cognitive functions.

SummaryRett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations. Although emerging evidence suggests that MeCP2 deficiency is associated with dysregulation of mechanistic target of rapamycin (mTOR), which functions as a hub for various signaling pathways, the mechanism underlying this association and the molecular pathophysiology of RTT remain elusive. We show here that MeCP2 promotes the posttranscriptional processing of particular microRNAs (miRNAs) as a component of the microprocessor Drosha complex. Among the MeCP2-regulated miRNAs, we found that miR-199a positively controls mTOR signaling by targeting inhibitors for mTOR signaling. miR-199a and its targets have opposite effects on mTOR activity, ameliorating and inducing RTT neuronal phenotypes, respectively. Furthermore, genetic deletion of miR-199a-2 led to a reduction of mTOR activity in the brain and recapitulated numerous RTT phenotypes in mice. Together, these findings establish miR-199a as a critical downstream target of MeCP2 in RTT pathogenesis by linking MeCP2 with mTOR signaling.