Rett Syndrome Research Articles

Proteomic analysis of serum from a MeCP2 patient reveals an arginine biosynthesis pathway affected by the p.Lys254* variant.

This study reports a Chinese male patient with a novel MeCP2 p.Lys254*variant. Upon birth, the patient presented with typical symptoms, such as abnormal electroencephalogram, immature sleep rhythm, hypotonia, feeding difficulties, pulmonary fluid accumulation, horizontal fissures in the lungs, hypoventilation, and heart defects. MeCP2 is a gene located on the X chromosome and the main pathogenic gene responsible for Rett syndrome, which mainly occurs in females. Herein, we identified a male patient with a novel MeCP2 p.Lys254* variant through whole-exome sequencing, although both parents are wild type. Upon birth, the patient presented with typical symptoms, such as abnormal electroencephalogram, immature sleep rhythm, hypotonia, feeding difficulties, pulmonary fluid accumulation, horizontal fissures in the lungs, hypoventilation, and other symptoms. Period of breathing support, but also found that the boy had a heart defect and horizontal fissure in the lungs. Our discovery of a new spontaneous MeCP2 nonsense mutation enriches the understanding of Rett syndrome and provides a reference for its early diagnosis and treatment.

Cerebral organoid research for pediatric patients with neurological disorders.

Cerebral organoids derived from human induced pluripotent stem cells offer a groundbreaking foundation for the analysis of pediatric neurological diseases. Unlike organoids from other somatic systems, cerebral organoids present unique challenges, such as the high sensitivity of neuronal cells to environmental conditions and the complexity of replicating brain-specific architectures. Cerebral organoids replicate the human brain development and pathology, enabling research on conditions such as microcephaly, Rett syndrome, autism spectrum disorders, and brain tumors. This review explores the utility of cerebral organoids for modeling diseases and testing therapeutic interventions. Despite current limitations such as variability and lack of vascularization, recent technological advancements have improved the reliability and application of such interventions. Cerebral organoids provide valuable insight into the mechanisms underlying complex neural disorders and hold promise as novel treatment strategies for pediatric neurological diseases.

Trofinetide benefits the ability to communicate in Rett syndrome: a plain language summary of the LAVENDER trial

Trofinetide benefits the ability to communicate in Rett syndrome: a plain language summary of the LAVENDER trial

Long Term Ventilation in Pediatric Central Apnea: Etiologies and Therapeutic Approach over a Decade.

This retrospective study aimed to analyze the clinical characteristics, ventilatory strategies, and effectiveness of ventilation in pediatric patients with central apneas treated at the Sleep Medicine and Long-Term Ventilation Unit of the Bambino Gesù Children's Hospital in Rome from 2012 to 2022. Among all ventilated patients at our Center from January 2012 to December 2022, we retrospectively included children with a cAHI ≥ 1 events/h on baseline poly(somno)graphic study. Additional parameters assessed included the underlying disease, type of ventilation (non-invasive vs. invasive), age at ventilation onset, ventilation mode, and transcutaneous capnometry parameters. To assess the effectiveness of ventilation on central apneas, we compared the cAHI at baseline and on ventilation. Sixty-seven patients met the inclusion criteria for central apnea (cAHI > 1 events/h). Diagnoses included hypoxic-ischemic encephalopathy, 15 (22.4%); Ondine syndrome, 14 (20.9%); polymalformative syndrome, 10 (14.9%); Prader-Willi syndrome, 8 (11.9%); brain tumor, 6 (9.0%); Down syndrome, 4 (6.0%); ROHHAD syndrome, 2 (3.0%); other infrequent pathologies were, Arnold-Chiari II, primary central apnea, epilepsy, lisosomal diseases, hydrocephalus, myopathy, obesity, Rett Syndrome. Pressure-supported ventilation (PSV) was the most common mode used (45 out 67 patients, 67.2%), followed by pressure-controlled ventilation (PCV) (15 out 67 patients, 22.4%) and continuous positive airway pressure (CPAP) (7 out 67 patients, 10.4%). Statistically significant improvement (p < 0.05) in cAHI was observed in patients with polymalformative syndrome (3.5 vs. 0.3, p = 0.01), hypoxic-ischemic encephalopathy (3.1 vs. 0.1, p = < 0.01), and Prader-Willi syndrome (3.5 vs. 0.1, p = 0.03), while there was no significant improvementn in children with brain tumor (6.2 vs. 1.5, p = 0.21). Central apneas are present in children with various underlying pathologies. Ventilatory strategies tailored to the specific diagnosis and severity of central apneas yield significant improvements in cAHI. PSV was the preferred ventilation mode in this study and there was notable effectiveness across different diagnostic categories. PCV was employed in most severe cases. CPAP was exclusively used in patients with predominantly obstructive sleep apneas.

The role of prenatal choline and its impact on neurodevelopmental disorders.

Extensive evidence demonstrates that prenatal nutrition is crucial for adequate fetal development. Specifically, maternal choline intake plays a significant role in gene expression, epigenetics, and cell membrane formation. Preclinical models have shown that maternal dietary intake improves the development of the cerebral cortex and hippocampus. This review focuses on the role of prenatal choline intake and discusses its potential role in neurodevelopmental disorders especially since choline has emerged as a promising coadjutant to mitigate cognitive and developmental disorders. However, more evidence regarding timing, dosage, and molecular mechanisms is needed. In this review, we discuss the impact of prenatal choline availability, evidence from current models, and gaps to address in how choline may impact the symptomology and manifestation of Rett syndrome, fragile X syndrome, and Down syndrome. Our ultimate goal is to highlight the importance of choline for maternal health and its potential beneficial impact on neurodevelopmental disorders.

P75NTR Modulation Reduces Oxidative Stress and the Expression of Pro-Inflammatory Mediators in a Cell Model of Rett Syndrome.

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.

Physiologically-Based Pharmacokinetic Modeling of Trofinetide in Moderate Renal Impairment for Phase 1 Clinical Study Dose Selection with Model Validation.

Trofinetide, the first approved treatment for Rett syndrome (RTT), is primarily excreted unchanged in the urine; therefore, it is important to assess the extent to which the exposure is affected in patients with renal impairment. Pharmacokinetic modeling overcomes the challenge of dose finding in phase 1 studies that include special populations where there is the potential for increased exposure to study drug. The objectives of this phase 1 study were to evaluate trofinetide pharmacokinetics, safety, and tolerability in a population with moderate renal impairment and normal renal function. The observed pharmacokinetic profiles were used to validate the dosing adjustments in moderate renal impairment that were previously predicted using a physiologically-based pharmacokinetic (PBPK) model. The PBPK model was first used to predict dose adjustments that are necessary to achieve similar exposure in the four stages of renal impairment (mild, moderate, severe, end stage renal disease) as in healthy controls. The predicted dose adjustment from 12 to 6 g for the moderate renal impairment category was then applied to the phase 1 clinical study. Subsequent validation of the PBPK model was achieved by comparing the model-predicted and clinically observed exposures in subjects with moderate renal impairment. In a phase 1, open-label study, trofinetide exposure was assessed in healthy (n = 10) and moderate renal impairment (n = 10) participants receiving single oral doses of 12 g or 6 g, respectively. Observed exposures [area under the blood concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were compared with predicted exposures from simulations in virtual healthy and moderate renal impairment populations (n = 100) to validate a PBPK model of renal impairment that had previously predicted doses across renal impairment categories. Dose-normalized geometric mean ratios for Cmax were comparable [1.02 (90% CI 0.69-1.50)] while AUCinf was approximately two-fold higher [1.81 (90% CI 1.31-2.50)] in moderate renal impairment participants compared with healthy controls. These observed values closely aligned with predicted distributions. Treatment-emergent adverse events were reported in two (20.0%) participants with moderate renal impairment and four healthy participants (40.0%). PBPK modeling of trofinetide in a virtual population with moderate renal impairment predicted a 50% dose reduction compared to individuals with normal renal function. Comparison of observed pharmacokinetic results from a phase 1 study in subjects with moderate renal impairment and matched healthy participants to the model-predicted exposures validated this dose reduction. No new safety concerns for trofinetide emerged.

Rett syndrome.

Rett syndrome (RTT) is a severe, progressive, neurodevelopmental disorder, which affects predominantly females. In most cases, RTT is associated with pathogenic variants in MECP2. MeCP2, the protein product of MECP2, is known to regulate gene expression and is highly expressed in the brain. RTT is characterized by developmental regression of spoken language and hand use that, with hand stereotypies and impaired ambulation, constitute the four core diagnostic features. Affected individuals may present multiple other neurological impairments and comorbidities, such as seizures, breathing irregularities, anxiety and constipation. Studies employing neuroimaging, neuropathology, neurochemistry and animal models show reductions in brain size and global decreases in neuronal size, as well as alterations in multiple neurotransmitter systems. Management of RTT is mainly focused on preventing the progression of symptoms, currently improved by guidelines based on natural history studies. Animal and cellular models of MeCP2 deficiency have helped in understanding the pathophysiology of RTT and guided the development of trofinetide, an IGF1-related compound, which is an approved drug for RTT, as well as of other drugs and gene therapies currently under investigation.

Rett syndrome.

Rett syndrome.

Perioperative Considerations in Patients with Rett Syndrome as Compared to Those with Cerebral Palsy.

Retrospective cohort study. This study aimed to compare perioperative outcomes of Rett syndrome and Cerebral palsy patients undergoing posterior spinal fusion for neuromuscular scoliosis. Surgical correction in the treatment of scoliosis for patients with Rett syndrome (RS) has been shown to increase survival rate. Cerebral palsy (CP) patients, like RS patients, are often nonverbal, nonambulatory, with frequent surgical complications. Retrospective review of 36 RS and 80 CP patients undergoing PSF from 2005-2023. Data and x-ray measurements were collected pre- and post-operatively. Sub-analysis was performed comparing non-ambulatory patients (GMFCS IV-V). Wilcoxon-Rank Sum, Fisher's Exact, and Chi-square tests were utilized. The primary outcome measure, complication rates, was similar between the groups (P=0.09). Preoperative Cobb angle, levels fused, fixation points, and LOS were similar (P>0.05). EBL was significantly higher in CP patients as was rate of transfusion (P=0.001) and surgical time (P=0.001). Postoperative Cobb angle (P=0.002) was significantly higher for CP patients. There was no significant difference between CP and RS patients in both preoperative (P=0.383) and postoperative (P=0.051) coronal decompensation. Nonambulatory status was associated with increased odds of having a postoperative complication (OR=6.17, 95% C.I. 1.36 - 28.04). Sub-analysis of non-ambulatory RS and CP patients revealed significantly higher postoperative Cobb (P=0.008), EBL (P=0.019) and surgical time (P=0.017) in CP patients compared to RS patients. There were no significant differences in preoperative Cobb, levels fused, fixation points, hospital stay, or complication rate (P>0.05). RS patients are shown to have better outcomes to CP patients in terms of surgical, perioperative, and radiographic variables. Ambulatory status was identified as an independent risk factor for complications.

Rett syndrome: interferon-γ to the rescue?

Rett syndrome: interferon-γ to the rescue?

Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy.

Trofinetide is a first-in-class pharmacological treatment proposed for patients with Rett Syndrome. It is a long half-life derivative of glycine-proline-glutamate, the tripeptide normally excided from Insulin-like Growth Factor 1 upon degradation. Due to containing glutamate and glycine in its structure, trofinetide is thought to act through NMDA receptor modulation, thus providing a normalization of neuronal activity and survival. Trofinetide was tested in a series of short and long-term trials, showing good efficacy at improving scores on the Clinical Global Impression-Improvement scale and Rett Syndrome Behavior Questionnaire, with specific effect only on some subscales, ie General Mood subscale and Repetitive Face Movement subscale. No effects were documented on other subscales or on epilepsy, heart and bone -related symptoms. The main adverse effects of trofinetide, severe enough to determine discontinuation, include diarrhea, vomiting, and consequent weight loss. These may be scarcely avoidable, given the need to assume a very large amount of trofinetide per day. Other inherent limitations of use possibly regard the limited duration of drug supplies, as one bottle may last three days only, depending on weight, and the relatively high cost per bottle. Trofinetide has no direct competitors: single symptoms of the Rett Syndrome, for instance, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the Rett Syndrome. This leads to suboptimal efficacy and increased risk of adverse effects. The place in therapy of trofinetide is yet to be determined, based on the results of clinical trials, on its practical usability, and on the windows of opportunity for intervention. Moreover, trofinetide may be curative if given early enough during brain development, or merely symptomatic if given to young adults, and no data exist on this aspect. The place in therapy of trofinetide will require reassessment after competing treatments enter the market.

LEDGF interacts with the NID domain of MeCP2 and modulates MeCP2 condensates.

Methyl-CpG-binding protein 2 (MeCP2) is a ubiquitously expressed nuclear protein involved in transcriptional regulation and chromatin remodeling. MeCP2 exists in two isoforms, MeCP2 E1 and E2, which share the same functional domains. Loss-of-function mutations in the MeCP2 gene are the main cause of Rett syndrome (RTT). Previous studies identified a complex formation between MeCP2 and lens epithelium derived growth factor (LEDGF), a transcriptional regulator that exists in two isoforms, LEDGF/p75 and LEDGF/p52. Here, we characterized the molecular and functional interaction between MeCP2 and LEDGF. The NCoR interaction domain (NID) domain in MeCP2 is essential for the direct binding to the PWWP-CR1 region of LEDGF. Introduction of R306C, an RTT mutation in the NID of MeCP2, reduced the interaction with LEDGF. Our data reveal mutual inhibition of MeCP2 and LEDGF multimerization due to overlapping binding sites. Aligning with this observation, LEDGF depletion resulted in larger MeCP2 and DNA foci in NIH3T3 cells, suggesting a role for the MeCP2-LEDGF complex in chromatin organization.

Endocrine disorders in Rett syndrome: a systematic review of the literature.

Rett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that involves mainly girls and is the second most frequent cause of genetic intellectual disability. RTT leads to neurological regression between 6 and 18 months of life and could be associated with a variable neurological impairment. However, RTT affects not only neurological function but also wide aspects of non-neurological organs. Recent data showed that the endocrine system is often involved in RTT patients, including disorders of growth, bone health, thyroid, puberty onset, and weight abnormalities However, systematic data on endocrinopathies in RTT are scarce and limited. This review aims to analyze the prevalence and type of endocrine comorbidities in RTT population, to allow a precocious diagnosis and appropriate endocrinological management. Systematic research was carried out from January 2000 to March 2024 through MEDLINE via PubMed, Scopus, and the Cochrane Library. After the selection phase, a total of 22 studies (1090 screened) met the inclusion criteria and were reported in the present review. Five studies were observational-retrospective, four were cross-sectional and case report or series, three were survey, prospective, and case-control, and finally one study for descriptive-transversal and longitudinal population-based study. The sample population consisted of multiethnic groups or single ethnic groups. The main endocrinopathies reported were malnutrition, bone alterations, and alterations of puberty onset. Our analysis shows that endocrinopathies are not rare in RTT patients. Therefore, in the context of a multidisciplinary approach, accurate screening and monitoring for endocrinopathies should be recommended in all RTT patients, to improve clinical practice, healthcare management, and, finally, patients' quality of life.

Alterations of synaptic plasticity in Angelman syndrome model mice are rescued by 5-HT7R stimulation

Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectrum Disorders (ASD). It is known that stimulation of the serotonin receptor 7 (5-HT7R) can rescue some of the behavioral and neuroplasticity dysfunctions in animal models of Fragile X and Rett syndrome, two pathologies associated with ASD. In view of these observations, we hypothesised that alterations of 5-HT7R signalling might also be involved in AS. To test this hypothesis, we stimulated 5-HT7R with the selective agonist LP-211 to investigate its possible beneficial effects on synaptic dysfunctions and altered behavior in the AS mice model. In mutant mice, we observed impairment of the synaptic machinery of protein synthesis, which was reversed by 5-HT7R activation. Moreover, stimulation of 5-HT7R was able to: i) enhance dendritic spine density in hippocampal neurons, which was reduced in AS mice; ii) restore impaired long-term potentiation (LTP) in hippocampal slices of the AS mice; iii) improve cognitive performance of the mutant animals subjected to the fear conditioning paradigm. Altogether, our results, showing beneficial effects of 5-HT7R stimulation in restoring molecular and cognitive deficits associated with AS, suggest that targeting 5-HT7R could be a promising therapeutic approach for the pathology.

GM1 Oligosaccharide Ameliorates Rett Syndrome Phenotypes In Vitro and In Vivo via Trk Receptor Activation.

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.

Gastrointestinal manifestations of Rett syndrome: An updated analysis using the Gastrointestinal Health Questionnaire.

We conducted a nationwide survey using a validated Gastrointestinal Health Questionnaire (GHQ) for Rett syndrome (RTT) to provide an updated and accurate baseline assessment of the prevalence of common gastrointestinal (GI) issues in RTT, based on parental reporting. Parents and caregivers of females with RTT or normally developing, unaffected, age-matched controls completed the GHQ survey. The prevalence of GI symptoms and personality and mood symptoms due to stomach or intestinal problems, as well as GI medication usage and surgical interventions, were assessed in females with RTT and unaffected controls. The relation between GI symptoms and medication usage, surgical status, age, and genetic mutation were analyzed. Parents of 118 females with RTT and 27 unaffected females completed the GHQ. GI symptoms were common in females with RTT, including constipation (81%), gas and bloating (70%), issues with eating, chewing and swallowing (73%), and irritability because of stomach or intestinal problems (53%). Females with RTT commonly used proton pump inhibitors (52%) and laxatives (64%). Medication usage was associated with significantly higher GHQ symptom scores. Parents of individuals with RTT reported a significantly higher prevalence of GI symptoms affecting their daughters in all symptom categories compared with unaffected females. GI problems are common in RTT and pose a significant medical burden to caregivers. The GHQ is a useful tool to assess GI issues in individuals with RTT. Improved recognition of these issues may allow for improved treatment and enhanced quality of life for girls and women affected by RTT.

Associations between genotype, phenotype and behaviours measured by the Rett syndrome behaviour questionnaire in Rett syndrome

IntroductionRett syndrome (RTT) is a rare neurodevelopmental disorder with developmental impairments, comorbidities, and abnormal behaviours such as hand stereotypies and emotional features. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed to describe the behavioural and emotional features of RTT. Little is known how RSBQ scores are associated with genetic and clinical characteristics in RTT. This study investigated relationships between genotype, age, walking, hand function, sleep, and RSBQ total and subscale scores in RTT.MethodsThis is a cross-sectional analysis of data collected in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database. Parent caregivers completed the RSBQ and Sleep Disturbance Scale for Children [subscales for disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence (DOES)], and provided information on age, variant type, functional abilities (mobility, hand function), seizure frequency and gastrointestinal problems. Associations between the RSBQ scores and the independent variables were modelled using linear regression.ResultsData were available for 365 individuals with RTT [median (range) age 17.8 (2.9–51.9) years, 2 males]. Compared to adults, 2- to 12-year-old children had higher mean Total, Night-time Behaviour and Fear/Anxiety scores. Compared to individuals with a C-terminal deletion, individuals with the p.Arg255* variant had higher mean Total and Night-time Behaviours scores, whereas the p.Arg294* variant had higher mean Mood scores. Individuals with intermediate mobility and hand function abilities had a higher mean Total score. Total RSBQ and subscale scores were similar across categories for seizures, constipation, and reflux, but were higher with abnormal DIMS and abnormal DOES scores.ConclusionExcept for associations with sleep, the RSBQ measures the behavioural phenotype rather than clinical severity in RTT, as traditionally conceptualised in terms of functional abilities and comorbidities. When designing clinical trials, the RSBQ needs to be complemented by other outcome measures to assess specific core functions and associated comorbidities in RTT.

RettDb: the Rett syndrome omics database to navigate the Rett syndrome genomic landscape.

Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females and leading to a variety of impairments and disabilities from mild to severe. In >95% cases, RTT is due to mutations in the X-linked gene MECP2, but the molecular mechanisms determining RTT are unknown at present, and the complexity of the system is challenging. To facilitate and provide guidance to the unraveling of those mechanisms, we developed a database resource for the visualization and analysis of the genomic landscape in the context of wild-type or mutated Mecp2 gene in the mouse model. Our resource allows for the exploration of differential dynamics of gene expression and the prediction of new potential MECP2 target genes to decipher the RTT disorder molecular mechanisms. Database URL: https://biomedinfo.di.unipi.it/rett-database/.

MiR126-mediated impaired vascular integrity in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by mutations in melty-CpG binding protein 2 (MeCP2). MeCP2 is a non-cell type-specific DNA binding protein, and its mutation influences not only neural cells but also non-neural cells in the brain, including vasculature associated with endothelial cells. Vascular integrity is crucial for maintaining brain homeostasis, and its alteration may be linked to the pathology of neurodegenerative disease, but a non-neurogenic effect, especially the relationship between vascular alternation and Rett syndrome pathogenesis, has not been shown. Here, we recapitulate a microvascular network using Rett syndrome patient-derived induced pluripotent stem (iPS) cells that carry MeCP2[R306C] mutation to investigate early developmental vascular impact. To expedite endothelial cell differentiation, doxycycline (DOX)-inducible ETV2 expression vectors were inserted into the AAVS1 locus of Rett syndrome patient-derived iPS cells and its isogenic control by CRISPR/Cas9. With these endothelial cells, we established a disease microvascular network (Rett-dMVNs) and observed higher permeability in the Rett-dMVNs compared to isogenic controls, indicating altered barrier function by MeCP2 mutation. Furthermore, we unveiled that hyperpermeability is involved in the upregulation of miR126-3p in Rett syndrome patient-derived endothelial cells by microRNA profiling and RNAseq, and rescue of miR126-3p level can recover their phenotype. We discover miR126-3p-mediated vascular impairment in Rett syndrome patients and suggest the potential application of these findings for translational medicine.