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Frontiers in Genetics 2024The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities... (Review)
Review
The emergence of new genetic tools has led to the discovery of the genetic bases of many intellectual and developmental disabilities. This creates exciting opportunities for research and treatment development, and a few genetic disorders (e.g., spinal muscular atrophy) have recently been treated with gene-based therapies. is found on the X chromosome and regulates the transcription of thousands of genes. Loss of gene product leads to Rett Syndrome, a disease found primarily in females, and is characterized by developmental regression, motor dysfunction, midline hand stereotypies, autonomic nervous system dysfunction, epilepsy, scoliosis, and autistic-like behavior. Duplication of causes MECP2 Duplication Syndrome (MDS). MDS is found mostly in males and presents with developmental delay, hypotonia, autistic features, refractory epilepsy, and recurrent respiratory infections. While these two disorders share several characteristics, their differences (e.g., affected sex, age of onset, genotype/phenotype correlations) are important to distinguish in the light of gene-based therapy because they require opposite solutions. This review explores the clinical features of both disorders and highlights these important clinical differences.
PubMed: 38410154
DOI: 10.3389/fgene.2024.1332469 -
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 -
Frontiers in Pediatrics 2023The Rett Syndrome Behaviour Questionnaire (RSBQ), which is completed by the caregiver, is one of the most widely used efficacy measures in clinical studies of Rett... (Review)
Review
The Rett Syndrome Behaviour Questionnaire (RSBQ), which is completed by the caregiver, is one of the most widely used efficacy measures in clinical studies of Rett syndrome (RTT) due to its specificity to the core features of RTT. As healthcare providers participate in routine healthcare assessments of individuals with RTT in clinical practice, there is a need for these providers to understand the psychometric properties of the RSBQ and how it relates to the core clinical features of RTT. Here, we describe the characteristics of the RSBQ, review the literature on its validity and reliability as well as its performance in a phase 2 study and the recent phase 3 LAVENDER study. The RSBQ was first shown to discriminate RTT from other intellectual disorders with good inter-rater and test-retest reliability scores. It was subsequently validated as an appropriate instrument for measuring behavior in females with RTT and adopted as a clinical trial outcome. In LAVENDER, the FDA-approved drug trofinetide significantly improved the RSBQ total score over placebo in girls and women with RTT and change from baseline for all RSBQ subscores were directionally in favor of trofinetide. The change in RSBQ was aligned with the Clinical Global Impression-Improvement scale, suggesting that improvement in behavioral components may be related to overall clinical status. Given its validity and ubiquity in RTT clinical studies, it is important that the interplay of the domains and the psychometric profile of the RSBQ are understood.
PubMed: 37635789
DOI: 10.3389/fped.2023.1229553 -
Pediatric Neurology Mar 2024This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye...
BACKGROUND
This study investigates the distinctive social behaviors observed in individuals with Rett syndrome (RTT), characterized by the loss of spoken language, impaired eye gaze communication, gait abnormalities, and sleep issues. The research aims to identify social profiles in RTT and explore their correlation with sleep, sleep-disordered breathing (SDB), and daytime sleepiness.
METHODS
Standard overnight sleep macrostructure and respiratory parameters were assessed. Extracting 25 social-related items and one for daytime sleepiness from the Rett Syndrome Behavioral Questionnaire, factor analysis was applied to establish latent social profiles. These profiles were then correlated with sleep parameters. The nonparametric Mann-Whitney U test compared social profiles based on the presence of SDB (defined by an apnea-hypopnea index greater than one per hour) and daytime sleepiness.
RESULTS
The study involved 12 female subjects with confirmed RTT diagnoses and MECP2 mutations, aged 8.54 ± 5.30 years. The Rett Syndrome Behavioral Questionnaire revealed a total average score of 25.83 ± 12.34, indicating varying degrees of social impairments. Comprising 25 social-related items, factor analysis yielded four social profiles: "interactive motricity," "mood change," "anxiety/agitation," and "gazing." Longer sleep onset latency correlated with increased socio-behavioral impairments, particularly in interactive motricity reduction. Conversely, higher rapid eye movement sleep was associated with fewer interactive socio-motor behaviors. No significant differences in social profiles were found concerning the presence of SDB or daytime sleepiness.
CONCLUSIONS
The findings suggest four distinct social profiles in RTT individuals, hinting at shared disrupted circuits between sensorimotor functioning and sleep-related neuronal pathways. Despite the absence of differences in SDB or daytime sleepiness, the study highlights the relationship between sleep parameters, such as sleep onset latency and rapid eye movement sleep, and socio-behavioral outcomes in RTT with MECP2 mutations.
Topics: Humans; Female; Rett Syndrome; Polysomnography; Sleep; Sleep Apnea Syndromes; Disorders of Excessive Somnolence
PubMed: 38290182
DOI: 10.1016/j.pediatrneurol.2024.01.004 -
Intractable & Rare Diseases Research Nov 2023Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 () gene,...
Rett syndrome (RTT) is a rare genetic neurological disorder that primarily affects girls and is caused by mainly mutations in the methyl-CpG-binding protein 2 () gene, leading to critical issues in normal brain function. The condition has a global prevalence of 5 to 10 cases per 100,000 females, and there is currently no cure for RTT. However, therapy is available to manage the symptoms and improve quality of life. Trofinetide, an insulin-like growth factor 1, was originally developed as a stroke medication and progressed to Phase II clinical trials, where it exhibited favorable safety and efficacy profiles by improving several core RTT symptoms. Recently, Trofinetide received the US Food and Drug Administration (FDA) approval and orphan drug designation for the treatment of RTT, making it the first approved drug for this rare genetic disorder. It has also shown to be safe, well-tolerated and with no known drug interactions. These findings suggest that Trofinetide is a promising treatment option for individuals with RTT.
PubMed: 38024580
DOI: 10.5582/irdr.2023.01060 -
BMC Pediatrics Mar 2024Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and stereotypic hand movements. Given the limited treatment options for Rett syndrome, there is a dire need for effective interventions.
OBJECTIVE
To evaluate the safety and efficacy of trofinetide in Randomized Controlled Trials (RCTs) that report on Rett syndrome patients.
METHODS
We identified 109 articles from four databases (Scopus, PubMed, Web of Science, and Cochrane CENTRAL). After removing the duplicates, we narrowed them down to 59 articles for further assessment. We included RCTs that evaluated the efficacy and safety of trofinetide in patients with Rett syndrome. Three studies were eligible for inclusion. Two independent reviewers evaluated the identified studies' titles, abstracts, and full texts, extracting pertinent data. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) 2.0 tool. We then conducted a meta-analysis using the fixed effects model in the case of insignificant heterogeneity; otherwise, we used the random effects model. Based on the nature of the outcome, we analyzed the mean difference or the odds ratio. Analysis was conducted using RevMan version 5.3.
RESULTS
Among the analyzed outcomes in 181 patients in the trofinetide group and 134 patients in the placebo group, significant improvement in Rett Syndrome Behavior Questionnaire (RSBQ) scores was observed at 200 mg dosage (overall mean difference: -3.53, p = 0.001). Clinical Global Impression-Improvement (CGI-I) scores improved considerably at 200 mg dosage (overall mean difference: -0.34, p < 0.0001). No substantial changes were observed in Motor Behavioral Assessment (MBA) or Top 3 Caregiver Concerns. We evaluated Treatment Emergent Adverse Events (TEAEs) across the various dosages and noted significant associations with diarrhea (200 mg), vomiting (200 mg), and irritability (200 mg). However, we did not find a significant association between any of the dosages and the incidence of decreased appetite.
CONCLUSION
Trofinetide demonstrated potential in improving RSBQ and CGI-I scores at 200 mg dosage. Although no substantial changes were found in MBA and top 3 caregiver concerns. Adverse events were linked to specific dosages.
Topics: Female; Humans; Rett Syndrome; Randomized Controlled Trials as Topic; Glutamates; Diarrhea
PubMed: 38521908
DOI: 10.1186/s12887-024-04526-3 -
Human Molecular Genetics Dec 2023MeCP2 (Methyl CpG binding protein 2) is an intrinsically disordered protein that binds to methylated genome regions. The protein is a critical transcriptional regulator... (Review)
Review
MeCP2 (Methyl CpG binding protein 2) is an intrinsically disordered protein that binds to methylated genome regions. The protein is a critical transcriptional regulator of the brain, and its mutations account for 95% of Rett syndrome (RTT) cases. Early studies of this neurodevelopmental disorder revealed a close connection with dysregulations of the ubiquitin system (UbS), notably as related to UBE3A, a ubiquitin ligase involved in the proteasome-mediated degradation of proteins. MeCP2 undergoes numerous post-translational modifications (PTMs), including ubiquitination and sumoylation, which, in addition to the potential functional outcomes of their monomeric forms in gene regulation and synaptic plasticity, in their polymeric organization, these modifications play a critical role in proteasomal degradation. UbS-mediated proteasomal degradation is crucial in maintaining MeCP2 homeostasis for proper function and is involved in decreasing MeCP2 in some RTT-causing mutations. However, regardless of all these connections to UbS, the molecular details involved in the signaling of MeCP2 for its targeting by the ubiquitin-proteasome system (UPS) and the functional roles of monomeric MeCP2 ubiquitination and sumoylation remain largely unexplored and are the focus of this review.
Topics: Humans; Methyl-CpG-Binding Protein 2; Sumoylation; Proteasome Endopeptidase Complex; Rett Syndrome; Ubiquitination; Ubiquitin
PubMed: 37694858
DOI: 10.1093/hmg/ddad150 -
BioRxiv : the Preprint Server For... Jul 2023Mutations in give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology...
UNLABELLED
Mutations in give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain's capacity to respond to changes in neuronal activity and sensory experience. Here we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from that previously reported for null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.
SIGNIFICANCE STATEMENT
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that predominantly affects girls. RTT is caused by loss of function mutations in a single gene MeCP2. Girls with RTT develop normally during their first year of life, but then experience neurological abnormalities including breathing and movement difficulties, loss of speech, and seizures. This study investigates the function of the MeCP2 protein in the brain, and how MeCP2 activity is modulated by sensory experience in early life. Evidence is presented that sensory experience affects MeCP2 function, and that this is required for synaptic pruning in the brain. These findings provide insight into MeCP2 function, and clues as to what goes awry in the brain when the function of MeCP2 is disrupted.
PubMed: 37461668
DOI: 10.1101/2023.07.03.547549 -
Genes Dec 2023Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders...
Inactivating mutations and the duplication of methyl-CpG binding protein 2 (MeCP2), respectively, mediate Rett syndrome (RTT) and duplication syndrome. These disorders underscore the conceptual dose-dependent risk posed by gene therapy for mosaic RTT patients. Recently, a miRNA-Responsive Autoregulatory Element (miRARE) mitigated the dose-dependent toxicity posed by self-complementary adeno-associated viral vector serotype 9 (AAV9) mini gene therapy (scAAV9/mini) in mice. Here, we report an efficacy assessment for the human-ready version of this regulated gene therapy (TSHA-102) in male knockout (KO) mice after intracerebroventricular (ICV) administration at postnatal day 2 (P2) and after intrathecal (IT) administration at P7, P14 (±immunosuppression), and P28 (±immunosuppression). We also report qPCR studies on KO mice treated at P7-P35; protein analyses in KO mice treated at P38; and a survival safety study in female adult mice. In KO mice, TSHA-102 improved respiration, weight, and survival across multiple doses and treatment ages. TSHA-102 significantly improved the front average stance and swing times relative to the front average stride time after P14 administration of the highest dose for that treatment age. Viral genomic DNA and mini mRNA were present in the CNS. MiniMeCP2 protein expression was higher in the KO spinal cord compared to the brain. In female mice, TSHA-102 permitted survivals that were similar to those of vehicle-treated controls. In all, these pivotal data helped to support the regulatory approval to initiate a clinical trial for TSHA-102 in RTT patients (clinical trial identifier number NCT05606614).
Topics: Adult; Humans; Female; Male; Animals; Mice; Rett Syndrome; MicroRNAs; Mental Retardation, X-Linked; Brain; DNA, Viral; Genetic Therapy; Mice, Knockout
PubMed: 38254921
DOI: 10.3390/genes15010031