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Open Biology Feb 2018Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (), a ubiquitously expressed transcriptional... (Review)
Review
Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of in the central nervous system. However, the variety of phenotypes identified in mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.
Topics: Animals; Brain; Disease Models, Animal; Disease Progression; Drug Repositioning; Female; History, 20th Century; Humans; Lipid Metabolism; Lovastatin; Methyl-CpG-Binding Protein 2; Mice; Mutation; Quality of Life; Rett Syndrome
PubMed: 29445033
DOI: 10.1098/rsob.170216 -
International Journal of Molecular... Aug 2019Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of... (Review)
Review
Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the gene, the research community's effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient's perspective and the appropriate treatment.
Topics: Animals; Gene Expression Regulation; Genetic Heterogeneity; Humans; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome; Signal Transduction
PubMed: 31409060
DOI: 10.3390/ijms20163925 -
Genes Aug 2023Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being... (Review)
Review
Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being symptomatic and supportive. This study provides a comprehensive review of the clinical features, comorbidities and multidisciplinary management of a well-characterized cohort of females with classical Rett syndrome. We aim to improve awareness and understanding of Rett syndrome amongst pediatricians, pediatric subspecialists and allied health professionals to enable early diagnosis and a streamlined enrolment approach for future clinical trials. Rett syndrome, a complex X-linked condition, affecting mainly females, is due to pathogenic variants of the gene in most affected individuals. The Rett syndrome Multidisciplinary Management clinic at The Children's Hospital at Westmead, Sydney, Australia, was established in 2000. This retrospective analysis of individuals who attended the clinic from 2000 to 2020 was performed to identify the incidence and predicted age of onset of Rett syndrome related comorbidities, disease progression and to review management principles. Data collected included age of Rett syndrome diagnosis, genotype, clinical features and medical comorbidities, such as sleep disturbance, seizures, breathing irregularities, scoliosis, mobility, hand stereotypies, hand function, constipation, feeding ability, use of gastrostomy, communication skills, QTc prolongation, anthropometry, and bruxism. Analysis of 103 girls who fulfilled the clinical diagnostic criteria for classical Rett syndrome with a pathogenic variant of the gene showed a median age of diagnosis of 3 years. The most frequent variant was c.502 C>T.
Topics: Female; Humans; Child; Child, Preschool; Male; Rett Syndrome; Retrospective Studies; Scoliosis; Constipation; Seizures
PubMed: 37628658
DOI: 10.3390/genes14081607 -
Systematic Reviews Jan 2023Rett syndrome is a rare, severe neurodevelopmental disorder. Almost all cases occur in girls, in association with spontaneous (non-inherited) mutations involving the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rett syndrome is a rare, severe neurodevelopmental disorder. Almost all cases occur in girls, in association with spontaneous (non-inherited) mutations involving the methyl-CpG-binding protein 2 gene located on the X chromosome. Diagnostic criteria for typical Rett syndrome require a period of regression, followed by recovery or stabilization, and fulfillment of all four main criteria (loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements). Our objective was to estimate the prevalence of Rett syndrome in the general population, stratified by sex.
METHODS
We conducted a search of PubMed, Embase, Web of Science, Cochrane Library, LILACS, and LIVIVO to retrieve studies published in English between Jan. 1, 2000, and June 30, 2021. Pooled prevalence with a 95% confidence interval (CI) was estimated using a random-effects meta-analysis based on a generalized linear mixed model with a logit link.
RESULTS
Ten eligible studies were identified (all in females), with a combined sample size of 9.57 million women and 673 Rett syndrome cases. The pooled prevalence estimate (random effects) was 7.1 per 100,000 females (95% CI: 4.8, 10.5, heterogeneity p < 0.001). Despite greatly variable precision of estimation, all estimates were compatible with a prevalence range of approximately 5 to 10 cases per 100,000 females based on their respective 95% CIs.
CONCLUSION
These findings may facilitate planning of therapeutic trials in this indication in terms of target sample size and accrual times.
Topics: Humans; Female; Rett Syndrome; Methyl-CpG-Binding Protein 2; Prevalence; Mutation
PubMed: 36642718
DOI: 10.1186/s13643-023-02169-6 -
Brain : a Journal of Neurology Feb 2019With the recent 50th anniversary of the first publication on Rett syndrome, and the almost 20 years since the first report on the link between Rett syndrome and MECP2... (Review)
Review
With the recent 50th anniversary of the first publication on Rett syndrome, and the almost 20 years since the first report on the link between Rett syndrome and MECP2 mutations, it is important to reflect on the tremendous advances in our understanding and their implications for the diagnosis and treatment of this neurodevelopmental disorder. Rett syndrome features an interesting challenge for biologists and clinicians, as the disorder lies at the intersection of molecular mechanisms of epigenetic regulation and neurophysiological alterations in synapses and circuits that together contribute to severe pathophysiological endophenotypes. Genetic, clinical, and neurobiological evidences support the notion that Rett syndrome is primarily a synaptic disorder, and a disease model for both intellectual disability and autism spectrum disorder. This review examines major developments in both recent neurobiological and preclinical findings of Rett syndrome, and to what extent they are beginning to impact our understanding and management of the disorder. It also discusses potential applications of knowledge on synaptic plasticity abnormalities in Rett syndrome to its diagnosis and treatment.
Topics: Humans; Methyl-CpG-Binding Protein 2; Neuronal Plasticity; Rett Syndrome; Synapses; Treatment Outcome
PubMed: 30649225
DOI: 10.1093/brain/awy323 -
Genes Jul 2021Progress in the clinical application of next-generation-sequencing-based techniques has resulted in a dramatic increase in the recognized genetic heterogeneity of the... (Review)
Review
INTRODUCTION
Progress in the clinical application of next-generation-sequencing-based techniques has resulted in a dramatic increase in the recognized genetic heterogeneity of the Rett syndrome spectrum (RSS). Our awareness of the considerable overlap with pediatric-onset epilepsies and epileptic/developmental encephalopathies (EE/DE) genes is also growing, and the presence of variable clinical features inside a general frame of commonalities has drawn renewed attention into deep phenotyping.
METHODS
We decided to review the medical literature on atypical Rett syndrome and "Rett-like" phenotypes, with special emphasis on described cases with pediatric-onset epilepsies and/or EE-DE, evaluating Neul's criteria for Rett syndrome and associated movement disorders and notable stereotypies.
RESULTS
"Rett-like" features were described in syndromic and non-syndromic monogenic epilepsy- and DE/EE-related genes, in "intellectual disability plus epilepsy"-related genes and in neurodegenerative disorders. Additionally, prominent stereotypies can be observed in monogenic complex neurodevelopmental disorders featuring epilepsy with or without autistic features outside of the RSS.
CONCLUSIONS
Patients share a complex neurodevelopmental and neurological phenotype (developmental delay, movement disorder) with impaired gait, abnormal tone and hand stereotypies. However, the presence and characteristics of regression and loss of language and functional hand use can differ. Finally, the frequency of additional supportive criteria and their distribution also vary widely.
Topics: Brain Diseases; Epilepsy; Humans; Male; Rett Syndrome
PubMed: 34440332
DOI: 10.3390/genes12081157 -
Current Opinion in Neurology Apr 2005Nearly 70 reports on Rett syndrome were published in 2004. We have selected 51 articles, including clinical reports, on pathophysiology, genotype-phenotype correlation,... (Review)
Review
PURPOSE OF REVIEW
Nearly 70 reports on Rett syndrome were published in 2004. We have selected 51 articles, including clinical reports, on pathophysiology, genotype-phenotype correlation, and clinical and basic molecular biology studies. These articles explain how mutation of the gene (MECP2) for methyl-CpG-binding protein 2 causes the particular disorders of Rett syndrome, and also induces other neurodevelopmental disorders, clarifying the situation for future studies.
RECENT FINDINGS
The role of X-chromosome inactivation has been clarified in animal experiments. New isoforms of MeCP2 have been discovered and its functional characteristics are under research. Understanding of the influence of the MECP2 mutation on other neurodevelopmental disorders has increased. However, there is no apparent progress in neurophysiological studies.
SUMMARY
Clinical studies included the pathophysiology of stereotyped movement, and cardiac and respiratory disturbances, and there were four therapeutic trials including one for epilepsy. For genotype-phenotype correlation the role of X-chromosome inactivation was looked at and its basic mechanisms were studied extensively in animals. Characteristics of mutations in the C-terminus and the biological function of the new isoform, exon 1, were introduced. In studies on related neurodevelopmental disorders, a relationship is suggested between the MECP2 gene and autism-related gene, with overlapping pathways, but this is not common to other neurodevelopmental disorders. Developmental studies suggest an important role for MeCP2 in the formation and/or maintenance of synapses, and clarify the molecular biological aspects of Rett syndrome. However, early involvement of the aminergic neurons, suggested as the basic, pathognomonic lesion of Rett syndrome, has unfortunately not been investigated with the MECP2 mutation.
Topics: Animals; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Humans; Methyl-CpG-Binding Protein 2; Repressor Proteins; Rett Syndrome
PubMed: 15791137
DOI: 10.1097/01.wco.0000162848.99154.9a -
The CRISPR Journal Aug 2022Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 () gene. The RTT is characterized by apparent... (Review)
Review
Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 () gene. The RTT is characterized by apparent normal early development followed by regression of communicative and fine motor skills. Comorbidities include epilepsy, severe cognitive impairment, and autonomic and motor dysfunction. Despite almost 60 clinical trials and the promise of a gene therapy, no cure has yet emerged with treatment remaining symptomatic. Advances in understanding RTT has provided insight into the complexity and exquisite control of expression, where loss of expression leads to RTT and overexpression leads to duplication syndrome. Therapy development requires regulated expression that matches the spatiotemporal endogenous expression of in the brain. Gene editing has revolutionized gene therapy and promises an exciting strategy for many incurable monogenic disorders, including RTT, by editing the native locus and retaining endogenous gene expression. Here, we review the literature on the currently available editing technologies and discuss their limitations and applicability to the treatment of RTT.
Topics: Brain; CRISPR-Cas Systems; Gene Editing; Humans; Rett Syndrome
PubMed: 35881862
DOI: 10.1089/crispr.2022.0020 -
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 -
Current Opinion in Neurology Apr 1995Rett syndrome is a unique and puzzling disorder noted in females, and is possibly caused by fundamental failures in critical brain connectivity during early infancy.... (Review)
Review
Rett syndrome is a unique and puzzling disorder noted in females, and is possibly caused by fundamental failures in critical brain connectivity during early infancy. Recent reports expand our understanding of the Rett syndrome phenotype, continue the pattern of inconsistent or inconclusive metabolic and genetic results, and extend observations regarding abnormal brain cytoarchitecture.
Topics: Brain; Child; Child, Preschool; Chromosomes, Human, Pair 3; Diagnosis, Differential; Diagnostic Imaging; Female; Humans; Infant; Infant, Newborn; Rett Syndrome; Translocation, Genetic; X Chromosome
PubMed: 7620591
DOI: 10.1097/00019052-199504000-00013