Comprehensive Volumetric Analysis of Mecp2-Null Mouse Model for Rett Syndrome by T2-Weighted 3D Magnetic Resonance Imaging

Akaba, Yuichi; Shiohama, Tadashi; Komaki, Yuji; Seki, Fumiko; Ortuğ, Alpen; Sawada, Daisuke; Uchida, Wataru; Kamagata, Koji; Shimoji, Keigo; Aoki, Shigeki; Takahashi, Satoru; Suzuki, Takeshi; Natsume, Jun; Takahashi, Emi

doi:10.3389/fnins.2022.885335

Cited by 6 publications

(4 citation statements)

References 68 publications

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“…The decreased gray matter volume in parietal lobes with age may explain the pain insensitivity and decreased proprioception with impaired hand functional use in individuals with RTT. Although the previous study demonstrated relative sparing of the occipital lobe compared with other lobes in RTT [ 9 ], our study also demonstrated a reduction in the volume of the left occipital lobe with age, consistent with a previous study on visual abnormality in RTT and a recent MRI study using a mouse model [ 1 , 29 ].…”

Section: Discussionsupporting

confidence: 92%

“…The parietal lobe is implicated in tactile information processing and sensorimotor integration and may be essential for proper hand functional use [ 9 ]. The finding of decreased volume in parietal lobes was also consistent with a recent MRI study in an Mecp2 -null mouse model [ 1 ], showing the decreased brain volume in the somatosensory area. The decreased gray matter volume in parietal lobes with age may explain the pain insensitivity and decreased proprioception with impaired hand functional use in individuals with RTT.…”

Section: Discussionsupporting

confidence: 91%

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Developmental change of brain volume in Rett syndrome in Taiwan

Jan,

Wong,

Hsu

et al. 2024

J Neurodevelop Disord

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Objective Rett syndrome (RTT) is characterized by neurological regression. This pioneering study investigated the effect of age on brain volume reduction by analyzing magnetic resonance imaging findings in participants with RTT, ranging from toddlers to adults. Methods Functional evaluation and neuroimaging were performed. All scans were acquired using a Siemens Tim Trio 3 T scanner with a 32-channel head coil. Results The total intracranial volume and cerebral white matter volume significantly increased with age in the control group compared with that in the RTT group (p < 0.05). Cortical gray matter volume reduction in the RTT group continued to increase in bilateral parietal lobes and left occipital lobes (p < 0.05). The differences in cortical gray matter volume between typically developing brain and RTT-affected brain may tend to continuously increase until adulthood in both temporal lobes although not significant after correction for multiple comparison. Conclusions A significant reduction in brain volume was observed in the RTT group. Cortical gray matter volume in the RTT group continued to reduce in bilateral parietal lobes and left occipital lobes. These results provide a baseline for future studies on the effect of RTT treatment and related neuroscience research.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Developmental change of brain volume in Rett syndrome in Taiwan

Jan,

Wong,

Hsu

et al. 2024

J Neurodevelop Disord

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“…More recent MRI studies using voxelbased methods have provided evidence of selective alterations in related brain regions such as cerebellum, occipital cortex, and anterior frontal lobe for the gray matter, as well as the corpus callosum and fibers in the frontal area for the white matter (Carter et al, 2008;Mahmood et al, 2010;Shiohama et al, 2019). MRI studies on Mecp2-null(KO) mice showed overlapping brain areas with decreased volume, supporting the hypothesis of regional brain reduction in RTT (Saywell et al, 2006;Akaba et al, 2022). In accordance with the previous studies, our results also exhibited more regional reductions in gray matter volume and more regional alterations in white matter parameters in girls with RTT.…”

Section: Discussionmentioning

confidence: 92%

Brain structural alterations in young girls with Rett syndrome: A voxel-based morphometry and tract-based spatial statistics study

Mei²,

Li³

et al. 2022

Front. Neuroinform.

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function variants in the MECP2 gene, currently with no cure. Neuroimaging is an important tool for obtaining non-invasive structural and functional information about the in vivo brain. Multiple approaches to magnetic resonance imaging (MRI) scans have been utilized effectively in RTT patients to understand the possible pathological basis. This study combined developmental evaluations with clinical severity, T1-weighted imaging, and diffusion tensor imaging, aiming to explore the structural alterations in cohorts of young girls with RTT, idiopathic autism spectrum disorder (ASD), or typical development. Voxel-based morphometry (VBM) was used to determine the voxel-wised volumetric characteristics of gray matter, while tract-based spatial statistics (SPSS) was used to obtain voxel-wised properties of white matter. Finally, a correlation analysis between the brain structural alterations and the clinical evaluations was performed. In the RTT group, VBM revealed decreased gray matter volume in the insula, frontal cortex, calcarine, and limbic/paralimbic regions; TBSS demonstrated decreased fractional anisotropy (FA) and increased mean diffusivity (MD) mainly in the corpus callosum and other projection and association fibers such as superior longitudinal fasciculus and corona radiata. The social impairment quotient and clinical severity were associated with these morphometric alterations. This monogenic study with an early stage of RTT may provide some valuable guidance for understanding the disease pathogenesis. At the same time, the pediatric-adjusted analytic pipelines for VBM and TBSS were introduced for significant improvement over classical approaches for MRI scans in children.

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“…Given that DNMT3A has critical roles both embryonically (Kaneda et al, 2004; Okano et al, 1999) and in early postnatal development (Lavery et al, 2020; Stroud et al, 2017), we next assessed if onset of brain volume phenotypes occurs during early development or arises progressively. This is especially important because previous studies have demonstrated transcriptional overlap between DNMT3A and MeCP2 disorders, and MeCP2 mutants have progressive decrease in brain volume which may be phenocopied in DNMT3A mutants (Akaba et al, 2022; Allemang-Grand et al, 2017; Christian et al, 2020). We therefore imaged DNMT3A mutant mice early in postnatal development, after any embryonic actions of DNMT3A and before postnatal DNMT3A or MeCP2 are highly expressed.…”

Section: Resultsmentioning

confidence: 99%

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

Christian

Zhang

et al. 2023

Preprint

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Phenotypic heterogeneity is a common feature of monogenic neurodevelopmental disorders that can arise from differential severity of missense variants underlying disease, but how distinct alleles impact molecular mechanisms to drive variable disease presentation is not well understood. Here, we investigate missense mutations in the DNA methyltransferase DNMT3A associated with variable overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity in neurodevelopmental disease. We generate a DNMT3A P900L/+ mouse model mimicking a disease mutation with mild-to-moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. We show that the P900L mutation leads to disease-relevant overgrowth, obesity, and social deficits shared across DNMT3A disorder models, while the R878H mutation causes more extensive epigenomic disruption leading to differential dysregulation of enhancers elements. We identify distinct gene sets disrupted in each mutant which may contribute to mild or severe disease, and detect shared transcriptomic disruption that likely drives common phenotypes across affected individuals. Finally, we demonstrate that core gene dysregulation detected in DNMT3A mutant mice overlaps effects in other developmental disorder models, highlighting the importance of DNMT3A-deposited methylation in neurodevelopment. Together, these findings define central drivers of DNMT3A disorders and illustrate how variable disruption of transcriptional mechanisms can drive the spectrum of phenotypes in neurodevelopmental disease.

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Comprehensive Volumetric Analysis of Mecp2-Null Mouse Model for Rett Syndrome by T2-Weighted 3D Magnetic Resonance Imaging

Cited by 6 publications

References 68 publications

Developmental change of brain volume in Rett syndrome in Taiwan

Developmental change of brain volume in Rett syndrome in Taiwan

Brain structural alterations in young girls with Rett syndrome: A voxel-based morphometry and tract-based spatial statistics study

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

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