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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 -
Neuroscience and Biobehavioral Reviews Sep 2019
Topics: Child; Developmental Disabilities; Humans; Mutation; Rett Syndrome
PubMed: 31283952
DOI: 10.1016/j.neubiorev.2019.06.038 -
Human Genomics Sep 2023Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). MeCP2 is a multi-functional protein...
BACKGROUND
Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2). MeCP2 is a multi-functional protein involved in many cellular processes, but the mechanisms by which its dysfunction causes disease are not fully understood. The duplication of the MECP2 gene causes a distinct disorder called MECP2 duplication syndrome (MDS), highlighting the importance of tightly regulating its dosage for proper cellular function. Additionally, some patients with mutations in genes other than MECP2 exhibit phenotypic similarities with RTT, indicating that these genes may also play a role in similar cellular functions. The purpose of this study was to characterise the molecular alterations in patients with RTT in order to identify potential biomarkers or therapeutic targets for this disorder.
METHODS
We used a combination of transcriptomics (RNAseq) and proteomics (TMT mass spectrometry) to characterise the expression patterns in fibroblast cell lines from 22 patients with RTT and detected mutation in MECP2, 15 patients with MDS, 12 patients with RTT-like phenotypes and 13 healthy controls. Transcriptomics and proteomics data were used to identify differentially expressed genes at both RNA and protein levels, which were further inspected via enrichment and upstream regulator analyses and compared to find shared features in patients with RTT.
RESULTS
We identified molecular alterations in cellular functions and pathways that may contribute to the disease phenotype in patients with RTT, such as deregulated cytoskeletal components, vesicular transport elements, ribosomal subunits and mRNA processing machinery. We also compared RTT expression profiles with those of MDS seeking changes in opposite directions that could lead to the identification of MeCP2 direct targets. Some of the deregulated transcripts and proteins were consistently affected in patients with RTT-like phenotypes, revealing potentially relevant molecular processes in patients with overlapping traits and different genetic aetiology.
CONCLUSIONS
The integration of data in a multi-omics analysis has helped to interpret the molecular consequences of MECP2 dysfunction, contributing to the characterisation of the molecular landscape in patients with RTT. The comparison with MDS provides knowledge of MeCP2 direct targets, whilst the correlation with RTT-like phenotypes highlights processes potentially contributing to the pathomechanism leading these disorders.
Topics: Humans; Rett Syndrome; Multiomics; Mental Retardation, X-Linked; RNA Processing, Post-Transcriptional
PubMed: 37710353
DOI: 10.1186/s40246-023-00532-1 -
Current Opinion in Pediatrics Jun 2024We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs,... (Review)
Review
PURPOSE OF REVIEW
We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying).
RECENT FINDINGS
We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound.
SUMMARY
Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.
Topics: Child; Humans; Deep Brain Stimulation; Friedreich Ataxia; Genetic Therapy; Movement Disorders; Precision Medicine; Rett Syndrome; Tourette Syndrome
PubMed: 38655812
DOI: 10.1097/MOP.0000000000001354 -
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 -
The Lancet. Diabetes & Endocrinology Aug 2023Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene,...
BACKGROUND
Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype.
METHODS
In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation.
FINDINGS
Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice.
INTERPRETATION
We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process.
FUNDING
Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.
Topics: Animals; Child; Female; Humans; Male; Mice; Brazil; Cohort Studies; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Puberty, Precocious; Rett Syndrome
PubMed: 37385287
DOI: 10.1016/S2213-8587(23)00131-6 -
Cell Reports Dec 2023A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their...
A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIβ (TOP2β) in mouse neurons. We profile neuronal TOP2β activity genome wide, detecting enrichment at regulatory regions and gene bodies of long genes, including MeCP2-regulated genes. We show that loss and overexpression of MeCP2 alter TOP2β activity at MeCP2-regulated genes. These findings uncover a mechanism of TOP2β inhibition by MeCP2 in neurons and implicate TOP2β dysregulation in disorders caused by MeCP2 disruption.
Topics: Animals; Mice; Methyl-CpG-Binding Protein 2; Neurons; Rett Syndrome
PubMed: 38096051
DOI: 10.1016/j.celrep.2023.113538 -
Brain and Behavior Jul 2022The onset of severe, drug-resistant seizures in early childhood is characteristic of the rare epileptic disorders Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS),... (Review)
Review
INTRODUCTION
The onset of severe, drug-resistant seizures in early childhood is characteristic of the rare epileptic disorders Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and CDKL5 deficiency disorder (CDD) and is frequently observed in the rare genetic conditions tuberous sclerosis complex (TSC) and Rett syndrome (RTT). High-quality treatment guidelines are needed for optimal management of these conditions. This review aimed to assess content, availability, and development of treatment guidelines for these disorders in the Nordics region (Denmark, Finland, Iceland, Norway, and Sweden).
METHODS
A targeted literature review (TLR) was therefore conducted in November/December 2020 by manually searching online rare disease and guideline databases in addition to relevant health technology assessment and regulatory agency websites to identify pharmacological treatment guidelines for DS, LGS, TSC, RTT, and CDD. Search terms for each disorder were translated to identify country-specific guidelines. Treatment recommendations, geographical focus, and guideline development methodology was extracted into a predetermined extraction grid.
RESULTS
Most of the 24 eligible guidelines identified (16/24; 66%) were specific to particular countries; Sweden was the most represented (7/24 [29%] guidelines), while no guidelines were identified for Iceland. Guideline development methodologies were heterogeneous, including systematic literature reviews/TLRs and expert consultation; several methodologies did not report details on the evidence sources used (7/24 [29%] guidelines). Treatment recommendation availability was variable across disorders, ranging from 126 treatment recommendations (LGS) to none (RTT, CDD).
CONCLUSION
Comprehensive, consensus-based treatment guidance developed via international collaboration within the Nordics region is necessary to optimize patient care in these five rare epileptic conditions.
Topics: Child, Preschool; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Rett Syndrome; Spasms, Infantile
PubMed: 35765698
DOI: 10.1002/brb3.2622 -
European Journal of Paediatric... Sep 2020Rett syndrome (RTT) is neurodevelopmental disorder affecting approximately 1:10000-15000 live female births, commonly associated with MECP2 gene mutations. Hand... (Review)
Review
UNLABELLED
Rett syndrome (RTT) is neurodevelopmental disorder affecting approximately 1:10000-15000 live female births, commonly associated with MECP2 gene mutations. Hand stereotypies and gait disturbance, as well as spasticity and dystonia, were noted in RTT since first descriptions. This review aimed to explore the prevalence of reported movement disorders in RTT.
DATA SOURCES AND EXTRACTION
Pubmed and Embase databases for papers describing features of movement disorders in RTT. Papers were selected if included description of case report, cohort or case-series of patients with RTT including descriptions of clinical features of their movement disorder. Papers were divided into 3 epochs - i) Pre-1999,ii) 2000-2009, and iii) 2010 onwards.
RESULTS
32 studies (13 in the first, 10 in the second and 9 in the third epochs) reported on movement disorders in RTT. Hand stereotypies were almost universal, diminishing but not disappearing over time. Gait disturbance and ataxia/tremor were also very common (>50% cases). Hypertonia was also often reported, increasing with age. In earlier descriptions spasticity was commonly described, with greater reference to dystonia/rigidity in more recent reports. Myoclonus and choreoathetosis were uncommonly reported.
CONCLUSIONS
Movement disorders beyond hand stereotypies are common in RTT, most notably tremor. Hypertonia is frequently seen in RTT, increasing in prevalence with age, with apparent changes in nomenclature over time, (i.e early epoch spasticity, late epoch dystonia). Dystonia was specifically reported in 229/417 cases. Further work is required to explore the relative contribution of dystonia and rigidity to hypertonia in RTT, as well as the impact of these impairments when present.
Topics: Adult; Female; Humans; Male; Motor Disorders; Movement Disorders; Prevalence; Rett Syndrome
PubMed: 32807681
DOI: 10.1016/j.ejpn.2020.06.020 -
Genes, Brain, and Behavior Jan 2022
Topics: Genetic Therapy; Humans; Methyl-CpG-Binding Protein 2; Phenotype; Rett Syndrome
PubMed: 34053173
DOI: 10.1111/gbb.12754