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Frontiers in Neurology 2021is one of the most common epilepsy genes. About 80% of gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More... (Review)
Review
is one of the most common epilepsy genes. About 80% of gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More than 1,800 mutations have been identified in . Although it is known that is the main cause of DS and genetic epilepsy with febrile seizures plus (GEFS+), there is a dearth of information on the other related diseases caused by mutations of . The aim of this study is to systematically review the literature associated with and other non-DS-related disorders. We searched PubMed and SCOPUS for all the published cases related to gene mutations of until October 20, 2021. The results reported by each study were summarized narratively. The PubMed and SCOPUS search yielded 2,889 items. A total of 453 studies published between 2005 and 2020 met the final inclusion criteria. Overall, 303 studies on DS, 93 on GEFS+, three on Doose syndrome, nine on the epilepsy of infancy with migrating focal seizures (EIMFS), six on the West syndrome, two on the Lennox-Gastaut syndrome (LGS), one on the Rett syndrome, seven on the nonsyndromic epileptic encephalopathy (NEE), 19 on hemiplegia migraine, six on autism spectrum disorder (ASD), two on nonepileptic -related sudden deaths, and two on the arthrogryposis multiplex congenital were included. Aside from DS, also causes other epileptic encephalopathies, such as GEFS+, Doose syndrome, EIMFS, West syndrome, LGS, Rett syndrome, and NEE. In addition to epilepsy, hemiplegic migraine, ASD, sudden death, and arthrogryposis multiplex congenital can also be caused by mutations of .
PubMed: 35002916
DOI: 10.3389/fneur.2021.743726 -
Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease.Biomolecules Jan 2021Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected... (Review)
Review
Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry mutation(s) in the Methyl-CpG-Binding Protein 2 ( gene. While the majority of RTT patients have mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 ( and . Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA () and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and .
Topics: Animals; Brain-Derived Neurotrophic Factor; Epigenesis, Genetic; Homeostasis; Humans; Methyl-CpG-Binding Protein 2; Rett Syndrome; Signal Transduction
PubMed: 33429932
DOI: 10.3390/biom11010075 -
Brain Sciences Jun 2020Rett syndrome is a rare genetic disorder that affects brain development and causes severe mental and physical disability. This systematic review analyzes the most recent... (Review)
Review
Rett syndrome is a rare genetic disorder that affects brain development and causes severe mental and physical disability. This systematic review analyzes the most recent evidence concerning the role of physical therapy in the management of individuals with Rett syndrome. The review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A total of 17319 studies were found in the main scientific databases. Applying the inclusion/exclusion criteria, 22 studies were admitted to the final phase of the review. Level of evidence of the included studies was assessed using the Oxford Centre for Evidence-Based Medicine-Levels of Evidence guide. Nine approaches to physical therapy for patients with Rett syndrome were identified: applied behavior analysis, conductive education, environmental enrichment, traditional physiotherapy with or without aids, hydrotherapy, treadmill, music therapy, computerized systems, and sensory-based treatment. It has been reported that patients had clinically benefited from the analysed approaches despite the fact that they did not have strong research evidence. According to the results, a multimodal individualized physical therapy program should be regularly recommended to patients with Rett syndrome in order to preserve autonomy and to improve quality of life. However, more high-quality studies are needed to confirm these findings.
PubMed: 32630125
DOI: 10.3390/brainsci10070410 -
Nature Oct 2020Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing....
Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.
Topics: Adaptive Immunity; Animals; Female; Heterochromatin; Immunity, Innate; Intellectual Disability; Methyl-CpG-Binding Protein 2; Mice; Mutation; Neurons; Phenotype; Rett Syndrome
PubMed: 32698189
DOI: 10.1038/s41586-020-2574-4 -
Nature Neuroscience Oct 2021Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases...
Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.
Topics: Adult; Benzothiazoles; Brain; Calcium Signaling; Child, Preschool; Epilepsy; Female; Humans; Induced Pluripotent Stem Cells; Methyl-CpG-Binding Protein 2; Nerve Net; Neurogenesis; Neuroimaging; Neurons; Rett Syndrome; Single-Cell Analysis; Synapses; Toluene; Transcriptome
PubMed: 34426698
DOI: 10.1038/s41593-021-00906-5 -
Nature Neuroscience Sep 2022Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across...
Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across disorders, is not known. In this study, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down syndromes). ND astrocytes increase release of Igfbp2, a secreted inhibitor of insulin-like growth factor (IGF). IGF rescues neuronal deficits in many NDs, and we found that blocking Igfbp2 partially rescues inhibitory effects of Rett syndrome astrocytes, suggesting that increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified that increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett syndrome astrocytes reverses inhibitory effects on neurite outgrowth. This work provides a resource of astrocyte-secreted proteins in health and ND models and identifies novel targets for intervention in diverse NDs.
Topics: Animals; Astrocytes; Mice; Neurodevelopmental Disorders; Neurogenesis; Neurons; Rett Syndrome
PubMed: 36042312
DOI: 10.1038/s41593-022-01150-1 -
Brain : a Journal of Neurology Nov 2021MECP2 gene transfer has been shown to extend the survival of Mecp2-/y knockout mice modelling Rett syndrome, an X-linked neurodevelopmental disorder. However,...
MECP2 gene transfer has been shown to extend the survival of Mecp2-/y knockout mice modelling Rett syndrome, an X-linked neurodevelopmental disorder. However, controlling deleterious overexpression of MECP2 remains the critical unmet obstacle towards a safe and effective gene therapy approach for Rett syndrome. A recently developed truncated miniMECP2 gene has also been shown to be therapeutic after AAV9-mediated gene transfer in knockout neonates. We show that AAV9/miniMECP2 has a similar dose-dependent toxicity profile to that of a published second-generation AAV9/MECP2 vector after treatment in adolescent mice. To overcome that toxicity, we developed a risk-driven viral genome design strategy rooted in high-throughput profiling and genome mining to rationally develop a compact, synthetic microRNA target panel (miR-responsive auto-regulatory element, 'miRARE') to minimize the possibility of miniMECP2 transgene overexpression in the context of Rett syndrome gene therapy. The goal of miRARE is to have a built-in inhibitory element responsive to MECP2 overexpression. The data provided herein show that insertion of miRARE into the miniMECP2 gene expression cassette greatly improved the safety of miniMECP2 gene transfer without compromising efficacy. Importantly, this built-in regulation system does not require any additional exogenous drug application, and no miRNAs are expressed from the transgene cassette. Although broad applications of miRARE have yet to be determined, the design of miRARE suggests a potential use in gene therapy approaches for other dose-sensitive genes.
Topics: Animals; Genetic Therapy; Humans; Injections, Spinal; Methyl-CpG-Binding Protein 2; Mice; Mice, Knockout; MicroRNAs; Protein Engineering; Regulatory Elements, Transcriptional; Rett Syndrome
PubMed: 33950254
DOI: 10.1093/brain/awab182 -
Molecular Therapy : the Journal of the... Sep 2023The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major...
The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett syndrome gene therapy vectors to date. Our team designed a new truncated methyl-CpG-binding protein 2 (MECP2) promoter allowing widespread expression of MECP2 in mice and non-human primates after a single injection into the cerebrospinal fluid without causing overexpression symptoms up to 18 months after injection. Additionally, this new vector is highly efficacious at lower doses compared with previous constructs as demonstrated in extensive efficacy studies performed by two independent laboratories in two different Rett syndrome mouse models carrying either a knockout or one of the most frequent human mutations of Mecp2. Overall, data from this multicenter study highlight the efficacy and safety of this gene therapy construct, making it a promising candidate for first-in-human studies to treat Rett syndrome.
Topics: Humans; Mice; Animals; Rett Syndrome; Primates; Genetic Therapy; Mutation
PubMed: 37481701
DOI: 10.1016/j.ymthe.2023.07.013 -
International Journal of Molecular... Sep 2023A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented... (Review)
Review
A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented previously in healthy individuals but also in those who suffer from various brain disorders. Sex-based differences concerning some features such as the risk, prevalence, age of onset, and symptomatology have been confirmed in a range of neurological and neuropsychiatric diseases. The mechanisms responsible for the establishment of sex-based differences between men and women are not fully understood. The present paper provides up-to-date data on sex-related dissimilarities observed in brain disorders and highlights the most relevant features that differ between males and females. The topic is very important as the recognition of disparities between the sexes might allow for the identification of therapeutic targets and pharmacological approaches for intractable neurological and neuropsychiatric disorders.
Topics: Humans; Male; Female; Sex Characteristics; Brain; Brain Diseases
PubMed: 37834018
DOI: 10.3390/ijms241914571