Rett Syndrome Patients Research Articles

Effects of the Rho GTPase-activating toxin CNF1 on fibroblasts derived from Rett syndrome patients: A pilot study.

The bacterial product CNF1, through its action on the Rho GTPases, is emerging as a modulator of crucial signalling pathways involved in selected neurological diseases characterized by mitochondrial dysfunctions. Mitochondrial impairment has been hypothesized to have a key role in paramount mechanisms underlying Rett syndrome (RTT), a severe neurologic rare disorder. CNF1 has been already reported to have beneficial effects in mouse models of RTT. Using human RTT fibroblasts from four patients carrying different mutations, as a reliable disease-in-a-dish model, we explored the cellular and molecular mechanisms, which can underlie the CNF1-induced amelioration of RTT deficits. We found that CNF1 treatment modulates the Rho GTPases activity of RTT fibroblasts and induces a considerable re-organization of the actin cytoskeleton, mainly in stress fibres. Mitochondria of RTT fibroblasts show a hyperfused morphology and CNF1 decreases the mitochondrial mass leaving substantially unaltered the mitochondrial dynamic. From a functional perspective, CNF1 induces mitochondrial membrane potential depolarization and activation of AKT in RTT fibroblasts. Given that mitochondrial quality control is altered in RTT, our results are suggestive of a reactivation of the damaged mitochondria removal via mitophagy restoration. These effects can be at the basis of the beneficial effects of CNF1 in RTT.

Rett syndrome severity estimation with the BioStamp nPoint using interactions between heart rate variability and body movement.

Rett syndrome, a rare genetic neurodevelopmental disorder in humans, does not have an effective cure. However, multiple therapies and medications exist to treat symptoms and improve patients' quality of life. As research continues to discover and evaluate new medications for Rett syndrome patients, there remains a lack of objective physiological and motor activity-based (physio-motor) biomarkers that enable the measurement of the effect of these medications on the change in patients' Rett syndrome severity. In our work, using a commercially available wearable chest patch, we recorded simultaneous electrocardiogram and three-axis acceleration from 20 patients suffering from Rett syndrome along with the corresponding Clinical Global Impression-Severity score, which measures the overall disease severity on a 7-point Likert scale. We derived physio-motor features from these recordings that captured heart rate variability, activity metrics, and the interactions between heart rate and activity. Further, we developed machine learning (ML) models to classify high-severity Rett patients from low-severity Rett patients using the derived physio-motor features. For the best-trained model, we obtained a pooled area under the receiver operating curve equal to 0.92 via a leave-one-out-patient cross-validation approach. Finally, we computed the feature popularity scores for all the trained ML models and identified physio-motor biomarkers for Rett syndrome.

Deregulated NLRP3 inflammasome response due to a constitutive activation of NF-κB p65 pro-inflammatory pathway in lymphomonocytes of Rett syndrome patients

Deregulated NLRP3 inflammasome response due to a constitutive activation of NF-κB p65 pro-inflammatory pathway in lymphomonocytes of Rett syndrome patients

Telerehabilitation with Computer Vision-Assisted Markerless Measures: A Pilot Study with Rett Syndrome Patients

The use of telerehabilitation systems has shown a significant growth in the past years, demonstrating their crucial relevance in the time of the COVID-19 pandemic. Many devices and sensors have been proposed to analytically measure parameters for patient assessment, with limitations due to costs or feasibility. In this paper, we present a motor telerehabilitation system with computer vision-assisted markerless measures for patients with Rett syndrome. Twenty-one RTT (Rett syndrome) patients, with ages ranging from age 4 to 31 (Median: 12.50; IQR (interquartile range): 9.50–17.25) were recruited. The study follows a pre-test–post-test design, where the patients were submitted to a pre-test, treatment, post-test 1, treatment, post-test 2 procedure. Progress in patient outcomes was assessed by measuring joint passive range of movement (PRoM). Results show the reliability of our system, and the feasibility of a telerehabilitation treatment for RTT patients, with significant improvements in shoulder mobility and in elbow flexion and extension. Limited results in lower limbs suggest that home treatment should be fostered to reduce sedentary time.

Global Impairment of Immediate-Early Genes Expression in Rett Syndrome Models and Patients Linked to Myelination Defects.

Rett syndrome (RTT) is a severe neurodevelopmental disease caused almost exclusively by mutations to the MeCP2 gene. This disease may be regarded as a synaptopathy, with impairments affecting synaptic plasticity, inhibitory and excitatory transmission and network excitability. The complete understanding of the mechanisms behind how the transcription factor MeCP2 so profoundly affects the mammalian brain are yet to be determined. What is known, is that MeCP2 involvement in activity-dependent expression programs is a critical link between this protein and proper neuronal activity, which allows the correct maturation of connections in the brain. By using RNA-sequencing analysis, we found several immediate-early genes (IEGs, key mediators of activity-dependent responses) directly bound by MeCP2 at the chromatin level and upregulated in the hippocampus and prefrontal cortex of the Mecp2-KO mouse. Quantification of the IEGs response to stimulus both in vivo and in vitro detected an aberrant expression pattern in MeCP2-deficient neurons. Furthermore, altered IEGs levels were found in RTT patient's peripheral blood and brain regions of post-mortem samples, correlating with impaired expression of downstream myelination-related genes. Altogether, these data indicate that proper IEGs expression is crucial for correct synaptic development and that MeCP2 has a key role in the regulation of IEGs.

Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome.

Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2-/y) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2-/y mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing. In 7-week-old Mecp2-/y mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR. Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2-/y mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2-/y mice. VPA treatment significantly increased TH mRNA expression in Mecp2-/y mice. Alteration of monoaminergic systems in the caudal medulla of Mecp2-/y mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2-/y mice.

Label-free three-photon imaging of intact human cerebral organoids for tracking early events in brain development and deficits in Rett syndrome.

Human cerebral organoids are unique in their development of progenitor-rich zones akin to ventricular zones from which neuronal progenitors differentiate and migrate radially. Analyses of cerebral organoids thus far have been performed in sectioned tissue or in superficial layers due to their high scattering properties. Here, we demonstrate label-free three-photon imaging of whole, uncleared intact organoids (~2 mm depth) to assess early events of early human brain development. Optimizing a custom-made three-photon microscope to image intact cerebral organoids generated from Rett Syndrome patients, we show defects in the ventricular zone volumetric structure of mutant organoids compared to isogenic control organoids. Long-term imaging live organoids reveals that shorter migration distances and slower migration speeds of mutant radially migrating neurons are associated with more tortuous trajectories. Our label-free imaging system constitutes a particularly useful platform for tracking normal and abnormal development in individual organoids, as well as for screening therapeutic molecules via intact organoid imaging.

0519 Sleep Dysfunction in Rett Syndrome

Abstract Introduction Rett syndrome (RTT) is an X-linked neurodevelopmental disorder affecting females and is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Typical comorbidities in RTT include poor growth, feeding difficulties, hyperventilation and breath-holding, seizures, scoliosis, and disrupted sleep. A few studies indicate sleep disruption in patients with RTT yet there is minimal data on polysomnographic findings in this population. We reviewed our cohort of Rett syndrome patients who underwent polysomnography. Methods This retrospective case control of 10 RTT subjects (mean age, 11.19 years; ranged from 1 to 33 years) underwent standard polysomnography (PSG) recording. Subjects were compared to 10 age and gender matched controls with an AHI <5 and no chronic medical problems using a student paired t test. All studies were scored using the AASM criteria. Results We found our cohort to have increased N3% sleep, decreased N2%, and shorter sleep onset latency (p< 0.05). Trends of lower BMI, lower oxygen saturation, and shorter REM latency (p < 0.10 but > 0.05). Review of PSGs shows the slow wave have morphological of typical slow waves and not that of the slowing seen on wake EEG nor the epileptiform activity. 4 of the 10 PSGs are notable for frequent interictal epileptiform discharges. 2 of the 10 subjects had a central apnea index >5, 2 had an AHI >5 and 1 demonstrated hypoventilation. There were central apneas associated with hyperventilation during awake and sleep-awake transition. Conclusion Our cohort of RTT patients demonstrates differences in sleep architecture, manifested most notably by a high percentage of SWS. This population has high amplitude rhythmic slow (theta) activity on wake EEG, primarily in the frontal-central regions. This slowing was distinct from the epileptiform activity seen in 40% of our cohort. Central apnea also appeared in older patients and the very young. Larger population studies are needed for future research. Support (If Any)

Dysregulated cortical synaptic plasticity under methyl-CpG binding protein 2 deficiency and its implication in motor impairments.

Caused by the mutation of methyl-CpG binding protein 2 (MeCP2), Rett syndrome leads to a battery of severe neural dysfunctions including the regression of motor coordination and motor learning. Current understanding has revealed the motor cortex as the critical region mediating voluntary movement. In this review article, we will summarize major findings from human patients and animal models regarding the cortical synaptic plasticity under the regulation of MeCP2. We will also discuss how mutation of MeCP2 leads to the disruption of cortical circuitry homeostasis to cause motor deficits. Lastly, potential values of physical exercise and neuromodulation approaches to recover neural plasticity and motor function will be evaluated. All of this evidence may help to accelerate timely diagnosis and effective interventions for Rett syndrome patients.

The constitutive activation of TLR4-IRAK1- NFκB axis is involved in the early NLRP3 inflammasome response in peripheral blood mononuclear cells of Rett syndrome patients

Rett syndrome (RTT), a devastating neurodevelopmental disorder, is caused in 95% of the cases by mutations in the X-chromosome-localized MECP2 gene. To date, RTT is considered a broad-spectrum disease, due to multisystem disturbances affecting patients, associated with mitochondrial dysfunctions, subclinical inflammation and an overall OxInflammatory status.Inflammasomes are multi-protein complexes crucially involved in innate immune responses against pathogens and oxidative stress mediators. The assembly of NLRP3:ASC inflammasome lead to pro-caspase 1 activation, maturation of interleukins (IL)-1β and 18 and proteolytic cleavage of Gasdermin D leading eventually to pyroptosis and systemic inflammation.The possible de-regulation of this system, in parallel with upstream nuclear factor (NF)-κB p65 pathway, were analyzed in peripheral blood mononuclear cells (PBMCs) and plasma isolated from RTT patients and matching controls.RTT PBMCs showed a constitutive activation of the axis TLR4 (Toll-like receptor 4)-IRAK1 (interleukin-1 receptor associated kinase 1)-NF-κB p65, together with augmented ROS generation and enhanced IL-18 mRNA levels and NLRP3:ASC co-localization. The deregulation of inflammasome components was even found in THP-1 cells silenced for MECP2 and importantly, in plasma compartment of RTT subjects, from the earliest stages of the pathology or in correlation with the severity of MeCP2 mutations.Taken together, these data provide new insights into the mechanisms involved in RTT sub-clinical inflammatory status present in RTT patients, thus helping to reveal new targets for future therapeutic approaches.

MECP2 Mutations in the Rett Syndrome Patients from South India.

Rett syndrome (RTT) is a rare neurological disorder that primarily affects the females. Most cases of RTT are caused by a de novo mutation in the MECP2 gene located on the X chromosome. About 1000 MECP2 mutations have been found to be associated with RTT. The present study is aimed at the mutation screening of MECP2 gene in the RTT patients belonging to the south Indian state of Kerala. In total 22 girls with a clinical suspicion of RTT were recruited for the study. Exons 2, 3, and 4 of MECP2 were amplified and sequenced. MECP2 mutations were observed in 12 patients. While 7 mutations were pathogenic, 4 were benign. All of the mutations were located in exons 3 and 4 of MECP2, spanning the methyl-CpG DNA binding domain (MBD), transcription repression domain (TRD), and C-terminal domain (CTD) domains of the MECP2 protein. Four novel mutations were identified. There were no mutations in the MECP2 gene of 10 patients with a clinical suspicion of RTT. A recommended screening strategy for RTT is to first look for mutations in exons 3 and 4 of MECP2, followed by exons 1 and 2, testing for large deletions in MECP2, and screening for mutations in genes, such as CDKL5 and FOXG1 that are reported to cause a Rett-like phenotype.

Mecp2 protects kidney from ischemia-reperfusion injury through transcriptional repressing IL-6/STAT3 signaling.

Rationale: Ischemia-reperfusion (IR) induced acute kidney injury (AKI) causes serious clinical problems associated with high morbidity and mortality. Mecp2 is a methyl-CpG binding protein, its mutation or deletion causes a neurodevelopment disease called Rett syndrome. Notably, some Rett syndrome patients present urological dysfunctions. It remains unclear whether and how Mecp2 affects AKI.Methods: Renal tubular cell specific Mecp2 deletion mice challenged with IR injury were used to investigate the effects of Mecp2 on renal tubular damage, function, cell death, fibrosis and inflammation. Cultured renal epithelial cell lines were transfected with wildtype or different domain-deletion mutants of Mecp2 to study the effects of Mecp2 on Il-6/STAT3 signaling.Results: Our results indicated rapidly upregulated Mecp2 upon acute in vivo and in vitro renal injury. Notably, increased tubular MeCP2 staining was also found in the renal sections of AKI patients. Furthermore, ablation of Mecp2 aggravated renal injury, and promoted renal cell death, inflammation, and fibrosis. Mechanistically, through its transcriptional repression domain, Mecp2 bound to the promoter of proinflammatory cytokine Il-6 to negatively regulate its expression, thus inhibiting STAT3 activation.Conclusions: A novel protective role of Mecp2 against AKI via repressing the Il-6/STAT3 axis was suggested.

Surgical Outcomes in Rett Syndrome Patients are Comparable to Cerebral-Palsy Patients

Surgical Outcomes in Rett Syndrome Patients are Comparable to Cerebral-Palsy Patients

Oral Manifestations of Rett Syndrome-A Systematic Review.

Rett Syndrome is an x linked developmental disorder which becomes apparent in females after 6 to 18 months of age. It leads to severe impairments including loss of speech, loss of hand movements/manual dexterity, characteristic hand movements such as hang wringing and intellectual disability/learning problems. This systematic review was carried out to identify the dental manifestation of Rett syndrome and to shed light on treatment options available for oral health problems associated with Rett syndrome. A systematic literature search was conducted on the PubMed, Scopus, Biomed, Web of Science, Embase, Google Scholars, Cochrane and CINAHL using the following entries: Rett syndrome (n = 3790), Oral health and Rett syndrome (n = 17), dental health of Rett syndrome patients (n = 13), and the MeSH terms listed below: Rett syndrome and Oral Health (n = 17), Rett syndrome and dentistry (n = 29). The final review included 22 search articles. The most common oral findings was bruxism. Masseteric hypertrophy was also reported. Anterior open bite and non-physiological tooth wear was observed. Other oral manifestations of Rett syndrome included mouth breathing, tongue thrusting, digit/thumb sucking, high arch palate. Increased awareness and dental education amongst dentists and assistants regarding the dental manifestations of Rett syndrome and similar neurodevelopmental disorders is required to improve the level of care and empathy they can provide to these differently able patients. Research on dental aspects of Rett is scarce and this remains a neglected topic.

Abstract 17250: Quantitative T Wave Morphology Analysis in Rett Syndrome Patients

Introduction: Rett syndrome (RTT) is a genetic neurologic disorder associated with a high incidence of sudden death. Abnormal cardiac repolarization is a potential risk factor for sudden death in this population. RTT patients may have prolonged corrected QT (QTc) on electrocardiogram (ECG) that is a sensitive marker of torsades des pointes. However, other repolarization markers such as T wave morphology, the time it takes the T wave to return to baseline from peak amplitude (Tpeak - Tend), and heart rate corrected JTpeak have not been studied. Hypothesis: Rett syndrome patients have abnormal cardiac repolarization. Methods: Retrospective T wave analysis was performed using QT Guard software. T wave morphology and heterogeneity parameters of RTT patients were compared to ECGs of age and sex matched healthy controls. A composite T wave morphology score was calculated from individual feature of flatness, notching, and asymmetry; a higher score means more abnormal morphology. Heterogeneity of repolarization was represented by the principal component analysis ratio 2 (PCA-2). Results: 57 Rett patients (260 ECG) and 121 controls (134 ECG) were studied. The RTT group had longer QTc (p = 0.001) along with more abnormal T-wave morphology scores and heterogeneity parameters when compared to controls (Tables 1, 2). RTT patients without long QTc also had more abnormal morphology scores than controls (p = 0.001). Conclusion: Cardiac repolarization is diffusely abnormal in RTT even in the absence of long QTc. T wave morphology analysis may be used to detect and monitor abnormal cardiac repolarization in RTT in clinical practice.

46. Surgical outcomes in Rett syndrome patients are comparable to cerebral palsy patients

BACKGROUND CONTEXT Rett syndrome (RS) patients often present with scoliosis, which requires surgical correction. However, literature is limited and reports major surgical complications including respiratory failure, prolonged intubation, infections, significant blood loss, and prolonged hospital stay. Cerebral palsy (CP) patients undergoing scoliosis surgery may be comparable to RS patients. They are often nonverbal, nonambulatory with frequent respiratory and surgical complications. Most surgeons have comparatively more experience treating CP patients than RS. PURPOSE The objective of this study is to compare perioperative outcomes of RS and CP patients. STUDY DESIGN/SETTING Retrospective review. PATIENT SAMPLE A total of 27 RS and 78 CP patients undergoing PSF from 2005-2018. OUTCOME MEASURES Cobb, kyphosis, pelvic obliquity, coronal decompensation, extubation rate, complication rate, EBL, surgical time, anesthesia time, levels fused, fixation points, METHODS Patient demographics, perioperative parameters, and X-ray measurements were collected at pre, post, and follow-up. Furthermore, a subanalysis was performed comparing the nonambulatory patients. Wilcoxon rank sums test and chi-square tests were utilized. RESULTS No significant difference for preop Cobb angle (p=0.16), kyphosis (p=0.20), and pelvic obliquity (p=0.09). No significant difference for fixation points (p=0.42), levels fused (p=0.79), time to extubation (p=0.53), complication rate (p=0.66), length of ICU (p=0.07) or hospital stay (p=0.71). EBL was significantly higher in CP patients (p=0.006) as was duration of anesthesia (p=0.04), and transfusion volume (p=0.01). However, surgical time (p=0.07) was similar. Postop Cobb (p=0.008) was significantly higher for CP, but kyphosis (p=0.18) and pelvic obliquity (p=0.09) were similar. Significant difference was found between both preop (p=0.02) and postop (p=0.03) coronal decompensation. Subanalysis of nonambulatory Rett and CP patients showed no significant difference in outcomes. CONCLUSIONS RS patients are comparable to CP patients in terms of surgical, periop, and radiographic outcomes. CP patients had significantly more EBL, intraop transfusions, and longer anesthesia time. The subjects did not differ in their ICU or hospital stays, nor their complication rate. Outcomes and periop expectations of RS patients are similar to CP. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

Differential brain region-specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey-white matter variation.

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by Methyl CpG Binding Protein 2 (MECP2) gene mutations. Previous studies of MeCP2 in the human brain showed variable and inconsistent mosaic-pattern immunolabelling, which has been interpreted as a reflection of activation-state variability. We aimed to study post mortem MeCP2 and BDNF (MeCP2 target) degradation and brain region-specific detection in relation to RTT pathophysiology. We investigated MeCP2 and BDNF stabilities in non-RTT human brains by immunohistochemical labelling and compared them in three brain regions of RTT and controls. In surgically excised samples of human hippocampus and cerebellum, MeCP2 was universally detected. There was no significantly obvious difference between males and females. However, post mortem delay in autopsy samples had substantial influence on MeCP2 detection. Immunohistochemistry studies in RTT patients showed lower MeCP2 detection in glial cells of the white matter. Glial fibrillary acidic protein (GFAP) expression was also reduced in RTT brain samples without obvious change in myelin basic protein (MBP). Neurons did not show any noticeable decrease in MeCP2 detection. BDNF immunohistochemical detection showed an astroglial/endothelial pattern without noticeable difference between RTT and controls. Our findings indicate that MeCP2 protein is widely expressed in mature human brain cells at all ages. However, our data points towards a possible white matter abnormality in RTT and highlights the importance of studying human RTT brain tissues in parallel with research on animal and cell models of RTT.

Implementation For Augmentative And Alternative Communication (AAC) Tools For Rett Syndrome Individual In Activities Of Daily Living (ADL)

Rett Syndrome occurs between one in 10000 to 15000 girls in Indonesia. In Hasan Sadikin Hospital, Bandung, Indonesia, there is a girl suffering from Rett Syndrome. Doctors in Hasan Sadikin Hospital find a lot of difficulties in communicating with the patient, since Rett Syndrome patients has little-to-no speech capabilities, and their hands often move involuntarily, especially with regards to Activities of Daily Living (ADL). Hence, a method to communicate with Rett Syndrome patient is being proposed using Augmentative and Alternative Communication (AAC) to support communication between the caregiver and the patient. Two of those methods are using gaze-tracking and head-pose. The methods tested consists of head-pose algorithm, gaze-tracking with Dlib, gaze-tracking with Haar Cascades, and EyeTribe. Each method is tested first with normal people before being tested with the patient. EyeTribe, head-pose, and gaze-tracking algorithm using Dlib achieve good results, with the best results being at 50cm distance and with high light intensity, however the Rett Syndrome patient achieves poor results when using the application, although head-pose achieves the best results in terms of determining needed ADL at around 45% accuracy. Hence, the Rett Syndrome patient needs training to use the application properly.

KCC2 expression levels are reduced in post mortem brain tissue of Rett syndrome patients

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the Methyl CpG binding protein 2 (MECP2) gene. Deficient K+-Cl—co-transporter 2 (KCC2) expression is suggested to play a key role in the neurodevelopmental delay in RTT patients’ neuronal networks. KCC2 is a major player in neuronal maturation by supporting the GABAergic switch, through the regulation of neuronal chlorine homeostasis. Previous studies suggest that MeCP2 mutations lead to changed KCC2 expression levels, thereby causing a disturbance in excitation/inhibition (E/I) balance. To investigate this, we performed protein and RNA expression analysis on post mortem brain tissue from RTT patients and healthy controls. We showed that KCC2 expression, in particular the KCC2a isoform, is relatively decreased in RTT patients. The expression of Na+-K+-Cl− co-transporter 1 (NKCC1), responsible for the inward transport of chlorine, is not affected, leading to a reduced KCC2/NKCC1 ratio in RTT brains. Our report confirms KCC2 expression alterations in RTT patients in human brain tissue, which is in line with other studies, suggesting affected E/I balance could underlie neurodevelopmental defects in RTT patients.

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations). MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards. ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients. ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms. SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.