Search Results (98)

Background/Objectives: Rett syndrome (RTT) is a rare neurodevelopmental disorder that affects movement and communication skills primarily in females. This study aimed to synthesize the research from the last two decades regarding the verbal and nonverbal communication abilities, assessment procedures, and intervention approaches for individuals with RTT. Methods: A structured literature search was conducted using the Embase, Scopus, and PubMed databases. Fifty-seven studies were selected and analyzed based on inclusion criteria. The data were categorized into four domains (verbal communication skills, nonverbal communication skills, assessment procedures, and intervention approaches). Results: The findings indicated a wide variety of communicative behaviors across the RTT population, including prelinguistic signals, regression in verbal output, and preserved nonverbal communicative intent. Moreover, the results highlighted the importance of tailored assessments (Inventory of Potential Communicative Acts, eye tracking tools, and Augmentative and Alternative Communication) to facilitate functional communication. The individualized intervention approaches were found to be the most effective in improving communicative participation. Conclusions: The current review provides an overview of the current evidence with an emphasis on the need for personalized and evidence-based clinical practices. Additionally, it provided guidance for professionals, clinicians, and researchers seeking to improve the quality of life for individuals with RTT. Full article

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder marked by neurological regression, autonomic dysfunction, seizures, and significant sleep and breathing abnormalities. About 80% of affected individuals, especially young children, experience sleep disturbances such as insomnia, sleep-disordered breathing, nocturnal vocalizations, bruxism, and seizures. Breathing irregularities during sleep—like apnea, alternating hyperventilation, and hypoventilation—are common, with both obstructive and central sleep apnea identified through polysomnography. This review focuses on the prevalent sleep disorders in children with Rett syndrome and highlights current recommendations for the management of sleep disorders. Full article

Background/Objectives: Rett Syndrome (RTT) is a rare neurodevelopmental disorder that affects girls and is characterized by severe motor and cognitive impairments, the loss of purposeful hand use, and communication difficulties. Children with RTT, especially those aged 5 to 9 years, often struggle to develop the foundational skills necessary for adaptive functioning, such as eye contact, object tracking, functional gestures, turn-taking, and basic communication. These abilities are essential for cognitive, social, and motor development and contribute to greater autonomy in daily life. This study aimed to explore the feasibility of a structured telerehabilitation program and to provide preliminary observations of its potential utility for young girls with RTT, addressing the presumed challenge of engaging this population in video-based interactive training. Methods: The intervention consisted of 30 remotely delivered sessions (each lasting 90 min), with assessments at baseline (A), after 5 weeks (B1), and after 10 weeks (B2). Quantitative outcome measures focused on changes in eye contact, object tracking, functional gestures, social engagement, and responsiveness to visual stimulus. Results: The findings indicate that the program was feasible and well-tolerated. Improvements were observed across all measured domains, and participants showed high levels of engagement and participation throughout the intervention. While these results are preliminary, they suggest that interactive digital formats may be promising for supporting foundational learning processes in children with RTT. Conclusions: This study provides initial evidence that telerehabilitation is a feasible approach for engaging young girls with RTT and supporting adaptive skill development. These findings may inform future research and the design of controlled studies to evaluate the efficacy of technology-assisted interventions in this population. Full article

Rett syndrome (RTT) is a multisystem neurological disorder. Pathogenic changes in the MECP2 gene that codes for methyl-CpG-binding protein 2 (MeCP2) in RTT lead to a loss of previously established motor and cognitive skills. Unravelling the mechanisms of neurological regression in RTT is complex, due to multiple components of the neural epigenome being affected. Most evidence has primarily focused on deciphering the complexity of transcriptional machinery at the molecular level. Little attention has been paid to how epigenetic changes across the neural epigenome in RTT lead to neurological regression. In this narrative review, we examine how pathogenic changes in MECP2 can disrupt the balance of the RTT neural epigenome and lead to neurological regression. Environmental and genetic factors can disturb the balance of the neural epigenome in RTT, modifying the onset of neurological regression. Methylation changes across the RTT neural epigenome and the consequent genotoxic stress cause neurons to regress into a senescent state. These changes influence the brain as it matures and lead to the emergence of specific symptoms at different developmental periods. Future work could focus on epidrugs or epi-editing approaches that may theoretically help to restore the epigenetic imbalance and thereby minimise the impact of genotoxic stress on the RTT neural epigenome. Full article

Classical Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene, resulting in a devastating phenotype associated with a lack of gene expression control. Mouse models lacking Mecp2 expression with an RTT-like phenotype have been developed to advance therapeutic alternatives. Environmental enrichment (EE) attenuates RTT symptoms in patients and mouse models. However, the mechanisms underlying the effects of EE on RTT have not been fully elucidated. We housed male hemizygous Mecp2-null (Mecp2^-/y) and wild-type mice in specially conditioned cages to enhance sensory, cognitive, social, and motor stimulation. EE attenuated the progression of the RTT phenotype by preserving neuronal cytoarchitecture and neural plasticity markers. Furthermore, EE ameliorated defects in neuromuscular junction organization and restored the motor deficit of Mecp2^-/y mice. Treatment with plasma from young WT mice was used to assess whether the increased activity could modify plasma components, mimicking the benefits of EE in Mecp2^-/y. Plasma treatment attenuated the RTT phenotype by improving neurological markers, suggesting that peripheral signals of mice with normal motor function have the potential to reactivate dormant neurodevelopment in RTT mice. These findings demonstrate how EE and treatment with young plasma ameliorate RTT-like phenotype in mice, opening new therapeutical approaches for RTT patients. Full article

Rett syndrome (RTT) is a rare X-linked dominant neurodevelopmental disorder caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a methyl-CpG-binding protein (MeCP2) that acts as a repressor of gene expression, crucial in neurons. Dysfunction of MeCP2 due to its pathogenic variants explains the clinical features of RTT. Here, we performed histological and RNA analyses on a post-mortem brain sample from an RTT patient carrying the p.Arg106Trp missense mutation. This patient is part of a cohort of 56 genetically and clinically characterized RTT patients, for whom we provide an overview of the mutation landscape. In the RTT brain specimen, RT-PCR analysis detected preferential transcription of the mutated mRNA. X-inactivation studies revealed a skewed X-chromosome inactivation ratio (95:5), supporting the transcriptional findings. We also mapped the MECP2 transcript in control human brain regions (temporal cortex and cerebellum) using the RNAscope assay, confirming its high expression. This study reports the MECP2 transcript representation in a post-mortem RTT brain and, for the first time, the in situ MECP2 transcript localization in a human control brain, offering insights into how specific MECP2 mutations may differentially impact neuronal functions. We suggest these findings are crucial for developing RNA-based therapies for Rett syndrome. Full article

Background/Objectives: Rett Syndrome (RTT) is a rare neurodevelopmental disorder that causes the loss of motor, communicative, and cognitive skills. While no cure exists, rehabilitation plays a crucial role in improving quality of life. Virtual Reality (VR) has shown promise in enhancing motor function and reducing stereotypic behaviors in RTT. This study aims to assess the impact of VR training on upper limb motor skills in RTT patients, focusing on reaching and hand-opening tasks, as well as examining its role in motivation and engagement during rehabilitation. Methods: Twenty RTT patients (aged 5–33) were randomly assigned to an experimental group (VR training) and a control group (standard rehabilitation). Pre- and post-tests evaluated motor skills and motivation in both VR and real-world contexts. The VR training involved 40 sessions over 8 weeks, focusing on fine motor tasks. Non-parametric statistical methods were used to analyze the data. Results: Results indicated significant improvements in the experimental group for motor parameters, including reduced stereotypy intensity and frequency, faster response times, and increased correct performance. These improvements were consistent across VR and ecological conditions. Moreover, attention time increased, while the number of aids required decreased, highlighting enhanced engagement and independence. However, motivation levels remained stable throughout the sessions. Conclusions: This study demonstrates the potential of VR as a tool for RTT rehabilitation, addressing both motor and engagement challenges. Future research should explore the customization of VR environments to maximize the generalization of skills and sustain motivation over extended training periods. Full article

Background/Objectives: Scoliosis is a prevalent comorbidity in Rett syndrome (RTT), often necessitating surgical intervention. This study investigated the impact of a 10-month individualized home exercise program (HEP) on scoliosis progression and gross motor function in girls aged six to 16 years with RTT. Methods: A multiple-baseline single-case design (AABA) was employed with 20 participants. A remotely supervised HEP, based on established principles focused on posture and physical activity, was implemented daily for at least one hour. The primary outcome was the rate of scoliosis progression assessed through the Cobb angle change measured via spinal radiographs at baseline, pre-intervention, and post-intervention. The secondary outcome was the gross motor function. Results: The HEP did not significantly reduce the rate of scoliosis progression. However, individual responses varied, with three participants showing scoliosis reduction. Significant improvements were observed in gross motor function, particularly in standing, walking, and stair-climbing abilities. Conclusions: The HEP did not significantly impact overall scoliosis progression, but a significant improvement was found in gross motor function. Further research into larger sample sizes is needed to confirm the effectiveness of exercise interventions in people with RTT. Full article

Rett syndrome (RTT), which predominantly affects females, arises in most cases from mutations in the Methyl-CpG-binding Protein-2 (MECP2) gene. When MeCP2 is impaired, it disrupts the regulation of numerous genes, causing the production of dysfunctional proteins associated with various multi-systemic issues in RTT. In this review, we explore the current insights into molecular signaling related to monoamines, immune response, and mitochondrial function, and their implications for the pathophysiology of RTT. Research has shown that monoamines—such as dopamine, norepinephrine, epinephrine, serotonin, and histamine—exhibit alterations in RTT, contributing to a range of neurological symptoms. Furthermore, the immune system in RTT individuals demonstrates dysfunction through the abnormal activity of microglia, macrophages, lymphocytes, and non-immune cells, leading to the atypical release of inflammatory mediators and disruptions in the NF-κB signaling pathway. Moreover, mitochondria, essential for energy production and calcium storage, also show dysfunction in this condition. The delicate balance of producing and scavenging reactive oxygen species—termed redox balance—is disrupted in RTT. Targeting these molecular pathways presents a promising avenue for developing effective therapies. Full article

Genomic sequencing has the potential to revolutionise newborn screening (NBS) programmes. In 2024, Genomics England began to recruit for the Generation Study (GS), which uses whole genome sequencing (WGS) to detect genetic changes in 500 genes in more than 200 rare conditions. Ultimately, its purpose is to facilitate the earlier identification of rare conditions and thereby improve health-related outcomes for individuals. The adoption of rare conditions into the GS was guided by four criteria: (1) the gene causing the condition can be reliably detected; (2) if undiagnosed, the rare condition would have a serious impact; (3) early or presymptomatic testing would substantially improve outcomes; and (4) interventions for conditions screened are accessible to all. Rett syndrome (RTT, OMIM 312750), a paediatric neurodevelopment disorder, was not included in the list of rare conditions in the GS. In this opinion article, we revisit the GS and discuss RTT from the perspective of these four criteria. We begin with an introduction to the GS and then summarise key points about the four principles, presenting challenges and opportunities for individuals with RTT. We provide insight into how data could be collected during the presymptomatic phase, which could facilitate early diagnosis and improve our understanding of the prodromal stage of RTT. Although many features of RTT present a departure from criteria adopted by the GS, advances in RTT research, combined with advocacy from parent-based organisations, could facilitate its entry into future newborn screening programmes. Full article

Background: Rett syndrome (RTT) is an early-onset neurological disorder primarily affecting females, leading to severe cognitive and physical disabilities. Recent studies indicate that an imbalance of redox homeostasis and exacerbated inflammatory responses are key players in the clinical manifestations of the disease. Emerging evidence highlights that the p75 neurotrophin receptor (p75NTR) is implicated in the regulation of oxidative stress (OS) and inflammation. Thus, this study is aimed at investigating the effects of p75NTR modulation by LM11A-31 on fibroblasts derived from RTT donors. Methods: RTT cells were treated with 0.1 µM of LM11A-31 for 24 h, and results were obtained using qPCR, immunofluorescence, ELISA, and Western blot techniques. Results: Our findings demonstrate that LM11A-31 reduces OS markers in RTT fibroblasts. Specifically, p75NTR modulation by LM11A-31 restores protein glutathionylation and reduces the expression of the pro-oxidant enzyme NOX4. Additionally, LM11A-31 significantly decreases the expression of the pro-inflammatory mediators interleukin-6 and interleukin-8. Additionally, LM11A-31 normalizes the expression levels of transcription factors involved in the regulation of the antioxidant response and inflammation. Conclusions: Collectively, these data suggest that p75NTR modulation may represent an effective therapeutic target to improve redox balance and reduce inflammation in RTT. Full article

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Despite advancements in research, no cure exists due to an incomplete understanding of the molecular effects of MeCP2 deficiency. Previous studies have identified impaired tropomyosin receptor kinase (Trk) neurotrophin (NTP) signaling and mitochondrial redox imbalances as key drivers of the pathology. Moreover, altered glycosphingolipid metabolism has been reported in RTT. GM1 ganglioside is a known regulator of the nervous system, and growing evidence indicates its importance in maintaining neuronal homeostasis via its oligosaccharide chain, coded as GM1-OS. GM1-OS directly interacts with the Trk receptors on the cell surface, triggering neurotrophic and neuroprotective pathways in neurons. In this study, we demonstrate that GM1-OS ameliorates RTT deficits in the Mecp2-null model. GM1-OS restored synaptogenesis and reduced mitochondrial oxidative stress of Mecp2-knock-out (ko) cortical neurons. When administered in vivo, GM1-OS mitigated RTT-like symptoms. Our findings indicate that GM1-OS effects were mediated by Trk receptor activation on the neuron’s plasma membrane. Overall, our results highlight GM1-OS as a promising candidate for RTT treatment. Full article

Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology. Full article

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in MECP2 associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old). Contrary to expectation, enrichment of a severe MECP2 variant (R106W) was observed in the older cohort. Overall severity was not different between the cohorts, but specific clinical features varied between the cohorts. Overall severity from first to last visit increased in the younger cohort but not in the older cohort. While some specific clinical features in the older cohort were stable from the first to the last visit, others showed improvement or worsening. These data do not support the hypothesis that mild MECP2 variants or less overall severity leads to increased longevity in RTT but demonstrate that clinical features change with increasing age in adults with RTT. Additional work is needed to understand disease progression in adults with RTT. Full article

Rett syndrome (RTT) is a paediatric neurodevelopmental disorder spanning four developmental stages. This multi-system disorder offers a unique window to explore genotype–phenotype relationships in a disease model. However, genetic prognosticators of RTT have limited clinical value due to the disorder’s heterogeneity on multiple levels. This case report used a precision medicine approach to better understand the clinical phenotype of RTT twins with an identical pathogenic MECP2 mutation and discordant neurodevelopmental profiles. Targeted genotyping, objective physiological monitoring of heart rate variability (HRV) parameters, and clinical severity were assessed in a RTT twin pair (5 years 7 months old) with an identical pathogenic MECP2 mutation. Longitudinal assessment of autonomic HRV parameters was conducted using the Empatica E4 wristband device, and clinical severity was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI) and the Multi-System Profile of Symptoms Scale (MPSS). Genotype data revealed impaired BDNF function for twin A when compared to twin B. Twin A also had poorer autonomic health than twin B, as indicated by lower autonomic metrics (autonomic inflexibility). Hospitalisation, RTT-CGI-S, and MPSS subscale scores were used as measures of clinical severity, and these were worse in twin A. Treatment using buspirone shifted twin A from an inflexible to a flexible autonomic profile. This was mirrored in the MPSS scores, which showed a reduction in autonomic and cardiac symptoms following buspirone treatment. Our findings showed that a combination of a co-occurring rs6265 BDNF polymorphism, and worse autonomic and clinical profiles led to a poorer prognosis for twin A compared to twin B. Buspirone was able to shift a rigid autonomic profile to a more flexible one for twin A and thereby prevent cardiac and autonomic symptoms from worsening. The clinical profile for twin A represents a departure from the disorder trajectory typically observed in RTT and underscores the importance of wider genotype profiling and longitudinal objective physiological monitoring alongside measures of clinical symptoms and severity when assessing genotype–phenotype relationships in RTT patients with identical pathogenic mutations. A precision medicine approach that assesses genetic and physiological risk factors can be extended to other neurodevelopmental disorders to monitor risk when genotype–phenotype relationships are not so obvious. Full article