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Biomolecules Jun 2021Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female... (Review)
Review
Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 () gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models.
Topics: Chromatin; DNA Methylation; Epigenesis, Genetic; Epigenomics; Gene Expression; Histones; Humans; Methyl-CpG-Binding Protein 2; RNA, Untranslated; Rett Syndrome; Transcriptional Activation; Transcriptome
PubMed: 34209228
DOI: 10.3390/biom11070967 -
Neural Plasticity 2016Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety... (Review)
Review
Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss.
Topics: Animals; Brain; Cell Movement; Epigenesis, Genetic; Humans; Neuronal Plasticity; Phenotype; Rett Syndrome; Signal Transduction; Synaptic Transmission
PubMed: 26942018
DOI: 10.1155/2016/6154080 -
Dental and Medical Problems 2018Rett syndrome is a progressive pediatric neurodevelopmental disorder, predominantly affecting females, characterized by a seemingly normal prenatal and perinatal period,... (Review)
Review
Rett syndrome is a progressive pediatric neurodevelopmental disorder, predominantly affecting females, characterized by a seemingly normal prenatal and perinatal period, followed by neurodevelopmental stagnation, and then rapid regression.The purpose of this study was to provide an update of the literature on the oral aspects of Rett syndrome and their possible treatment in patients suffering from this pathology. After an electronic and manual search in MEDLINE (PubMed) and the Cochrane Library, 12 articles were found, for a total of 142 patients affected by Rett syndrome. A high prevalence of bruxism, anterior open bite, ogival palate, sucking habits, and difficulties in maintaining oral hygiene was noted. There were also oral findings related to the pharmacological treatment, which included xerostomia, glossitis, erythema multiforme, gingival hyperplasia, dysphagia, and lingual paralysis. It is important for the dentist to know what problems related to the oral cavity can be encountered in a patient diagnosed with Rett syndrome and what preventive measures can be applied.
Topics: Humans; Mouth; Mouth Diseases; Rett Syndrome
PubMed: 30648368
DOI: 10.17219/dmp/99203 -
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 -
Nature Apr 2021Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life...
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
Topics: Animals; Biomedical Enhancement; Disease Models, Animal; Electrophysiology; Female; Male; Mice; Morris Water Maze Test; Neurons; Prodromal Symptoms; Psychomotor Performance; Rett Syndrome; Rotarod Performance Test; Spatial Learning; Time Factors
PubMed: 33762729
DOI: 10.1038/s41586-021-03369-7 -
Nature Reviews. Neuroscience Jun 2018Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into... (Review)
Review
Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into RTT have greatly advanced our understanding of the function and regulation of the multifunctional protein MeCP2. Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms. These factors present challenges to the search for mechanism-based therapeutics for RTT and suggest specific approaches that may be more effective than others.
Topics: Animals; Brain; Cell Differentiation; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Humans; Methyl-CpG-Binding Protein 2; MicroRNAs; Mutation; Neurons; Rett Syndrome
PubMed: 29740174
DOI: 10.1038/s41583-018-0006-3 -
International Journal of Molecular... Oct 2019Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This... (Review)
Review
Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.
Topics: Animals; Clinical Trials as Topic; Diagnosis, Differential; Disease Management; Disease Susceptibility; Epileptic Syndromes; Humans; Methyl-CpG-Binding Protein 2; Mutation; Outcome Assessment, Health Care; Phenotype; Protein Serine-Threonine Kinases; Rett Syndrome; Spasms, Infantile; Translational Research, Biomedical
PubMed: 31618813
DOI: 10.3390/ijms20205098 -
Journal of Pediatric Gastroenterology... Oct 2013We developed recommendations for the clinical management of poor growth and weight gain in Rett syndrome through evidence review and the consensus of an expert panel of...
OBJECTIVES
We developed recommendations for the clinical management of poor growth and weight gain in Rett syndrome through evidence review and the consensus of an expert panel of clinicians.
METHODS
Initial draft recommendations were created based upon literature review and 34 open-ended questions in which the literature was lacking. Statements and questions were made available to an international, multidisciplinary panel of clinicians in an online format and a Microsoft Word-formatted version of the draft via e-mail. Input was sought using a 2-stage modified Delphi process to reach consensus. Items included clinical assessment of growth, anthropometry, feeding difficulties and management to increase energy intake, decrease feeding difficulties, and consideration of gastrostomy.
RESULTS
Agreement was achieved on 101 of 112 statements. A comprehensive approach to the management of poor growth in Rett syndrome is recommended that takes into account factors such as feeding difficulties and nutritional needs. A body mass index of approximately the 25th centile can be considered as a reasonable target in clinical practice. Gastrostomy is indicated for extremely poor growth, if there is risk of aspiration and if feeding times are prolonged.
CONCLUSIONS
These evidence- and consensus-based recommendations have the potential to improve care of nutrition and growth in a rare condition and stimulate research to improve the present limited evidence base.
Topics: Body Mass Index; Delphi Technique; Feeding Behavior; Female; Gastrostomy; Growth Disorders; Humans; Infant; Nutrition Assessment; Nutritional Requirements; Nutritional Status; Nutritional Support; Rett Syndrome; Surveys and Questionnaires; Weight Gain
PubMed: 24084372
DOI: 10.1097/MPG.0b013e31829e0b65 -
Neuropharmacology Jan 2014BDNF is the best-characterized neurotrophin in terms of its gene structure and modulation, secretion processing, and signaling cascades following its release. In... (Review)
Review
BDNF is the best-characterized neurotrophin in terms of its gene structure and modulation, secretion processing, and signaling cascades following its release. In addition to diverse features at the genetic and molecular levels, the abundant expression in several regions of the central nervous system has implicated BDNF as a potent modulator in many aspects of neuronal development, as well as synaptic transmission and plasticity. Impairments in any of these critical functions likely contribute to a wide array of neurodevelopmental, neurodegenerative, and neuropsychiatric diseases. In this review, we focus on a prevalent neurodevelopmental disorder, Rett syndrome (RTT), which afflicts 1:15,000 women world-wide. We describe the consequences of loss-of-function mutations in the gene encoding the transcription factor methyl-CpG binding protein 2 (MeCP2) in RTT, and then elaborate on the current understanding of how MeCP2 controls BDNF expression. Finally, we discuss the literature regarding alterations in BDNF levels in RTT individuals and MeCP2-based mouse models, as well as recent progress in searching for rational therapeutic interventions. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.
Topics: Animals; Brain-Derived Neurotrophic Factor; Female; Humans; Methyl-CpG-Binding Protein 2; Mice; Mutation; Rett Syndrome
PubMed: 23597512
DOI: 10.1016/j.neuropharm.2013.03.024 -
Journal of Neurodevelopmental Disorders May 2022Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common,...
BACKGROUND
Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT.
METHODS
Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019.
RESULTS
Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002).
CONCLUSION
Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care.
TRIAL REGISTRATION
NCT00299312 and NCT02738281.
Topics: Anti-Anxiety Agents; Anxiety; Female; Humans; Rett Syndrome
PubMed: 35568815
DOI: 10.1186/s11689-022-09432-2