Treatment guidelines for rare, early-onset conditions associated with epileptic seizures: a literature review on Rett syndrome and tuberous sclerosis complex.

BACKGROUND: Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a range of different epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-specific and international treatment guidelines available for pharmacological management of seizures in RTT and TSC. METHODS: A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and guideline databases, and websites of national heath technology assessment bodies were conducted for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as defined by pre-specified eligibility criteria. Search terms were developed for each condition and translated into local languages where appropriate. Eligible publications were defined as guidelines/guidance reporting pharmacological management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus, author information and treatment recommendations were extracted from guidelines. An author map was generated using R version 3.5.1 to visualise extent of collaboration between authors. RESULTS: 24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC, respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83% [20/24]) were country-specific, with guideline authors predominantly publishing in contained national groups; four guidelines were classified as 'International,' linking author groups in the US, UK, Italy and France. High levels of heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67 recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr 23(6):633-9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236-41) recommendations; vigabatrin received the highest number of positive recommendations (Kaur, Christodoulou (2019)). CONCLUSIONS: This review highlights the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC. TRIAL REGISTRATION: Not applicable.

Electroencephalographic assessment in patients with Rett syndrome during cognitive stimulation by means of eye tracking technology and alternative and augmentative communication systems.

Rett syndrome (RTT) is considered a rare disease despite being the leading genetic disorder to cause severe intellectual disability in women. There is no cure for RTT, so the treatment is symptomatic and supporting, requiring a multidisciplinary approach. Occupational therapy can help girls and their families to improve communication, being one of the main concerns when verbal language and intentional hand movement are impaired or lost. This paper presents a pilot study of cognitive training through the combined use of eye-tracking technology (ETT) and augmentative and alternative communication (AAC) using the Peabody Picture Vocabulary Test (PPVT-IV). The objective was to evaluate brain activation by means of electroencephalography (EEG) during the stimulation of non-verbal communication. EEG data were recorded during an eyes-open resting state (EO-RS) period and during cognitive stimulation via AAC activity. To assess their effect, both signals were compared at the spectral level, focusing on frequency, brain symmetry and connectivity. During the task, a redistribution of power towards fast frequency bands was observed, as well as an improvement in the brain symmetry index (BSI) and functional synchronicity through increased coherence. Therefore, the results of the spectral analysis showed a possible deviation from the pathological pattern, manifesting a positive effect in the use of non-verbal cognitive stimulation activities. In conclusion, it was observed that it is possible to establish a cognitive training system that produces brain activation and favors communication and learning despite intentional language loss.Clinical Relevance- This manifests a method of cognitive training that would induce brain activation in RTT patients with absence of intentional communication. The evaluation system through spectral analysis could complement the standardized protocols to asses communication that are based on verbal and motor production.

Epidemiology and patient journey of Rett syndrome in the United States: a real-world evidence study.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females and is associated with high clinical burden. However, literature characterizing the real-world journey of patients with RTT is limited. This study provided an overview of the epidemiology, patient characteristics, clinical manifestations, healthcare resource utilization (HRU), costs, and treatment patterns of patients with RTT in the US. METHODS: IQVIA™ Medical Claims Data and Longitudinal Prescription Data (11/01/2016-10/31/2019) were used to identify female patients with RTT, with the first observed diagnosis defined as the index date. Annual incidence and prevalence of RTT were assessed over the entire study period; clinical manifestations, all-cause and RTT-related HRU and costs, and treatment patterns were evaluated during the observation period-from the index date to end of clinical activity or end of data availability, whichever occurred first. Results were further stratified into pediatric (< 18 years) and adult (≥ 18 years) subgroups. RESULTS: In 2019, prevalence and incidence of RTT was 0.32 and 0.23 per 10,000 enrollees, respectively. Among 5,940 female patients (pediatric: 3,078; adult: 2,862) with mean observation period of 2.04 years, the most prevalent clinical manifestations were neurological disorders (72.8%), gastrointestinal/nutritional disorders (41.9%), and orthopedic disorders (34.6%). The incidence rate of all-cause HRU was 44.43 visits per-patient-per-year and RTT-related HRU comprised 47% of all-cause HRU. Mean all-cause healthcare costs were $40,326 per-patient-per-year, with medical costs driven by home/hospice care visits, therapeutic services, outpatient visits, and inpatient visits. RTT-related healthcare costs comprised 45% of all-cause healthcare costs. The most prevalent supportive therapy and pharmacologic agent were feeding assistance (37.9%) and antiepileptic drugs (54.8%), respectively. Trends were similar by subgroup; although, rates of HRU were generally higher among pediatric patients relative to adult patients (all-cause: 52.43 and 35.86, respectively), which translated into higher mean healthcare costs (all-cause: $45,718 and $34,548, respectively). CONCLUSIONS: Patients with RTT have substantial disease burden, including prevalent clinical manifestations, high rates of HRU and annual healthcare costs, and reliance on pharmacologic and supportive therapies. These findings underscore the unmet need for effective therapies to target the multifactorial manifestations of RTT.

Preliminary assessment of the reliability and validity of infrared skin temperature measurements in Rett syndrome.

BACKGROUND: As clinical trials for Rett syndrome are underway, there is a need to validate potential supplemental outcome measures that reflect important signs and symptoms. Autonomic dysfunction, particularly vasomotor dysfunction, is one potential area for which biomarkers could be developed. METHODS: In the current study, infrared thermal images of hands and feet from 26 females with Rett syndrome (aged 62 months to 39 years), and 17 females without known intellectual, genetic or neurological disorders (aged 55 months to 39 years) were collected. Between-group differences in skin temperature, and temporal stability of skin temperature measures in the Rett syndrome group, and relationships between skin temperature measures and parent-reported and researcher-evaluated indicators of autonomic dysfunction were evaluated. RESULTS: Between-group differences showed lower hand and foot temperatures in the Rett syndrome group. Hand temperature measurements were stable over time and were moderately correlated with parent-reported autonomic symptoms. Foot temperature measurements were more variable than hand temperatures but showed stronger correlations with parent-reported autonomic symptoms. CONCLUSIONS: The results provide preliminary support for the reliability and validity of hand and foot skin temperature measures in Rett syndrome. Additional research is needed to replicate these results and evaluate the temporal stability of these measures over shorter time scales.

Pain in Rett syndrome: a pilot study and a single case study on the assessment of pain and the construction of a suitable measuring scale.

BACKGROUND: Rett Syndrome (RTT) is a severe, neurodevelopmental disorder mainly caused by mutations in the MECP2 gene, affecting around 1 in 10,000 female births. Severe physical, language, and social impairments impose a wide range of limitations in the quality of life of the patients with RTT. Comorbidities of patients with RTT are varied and cause a lot of pain, but communicating this suffering is difficult for these patients due to their problems, such as apraxia that does not allow them to express pain in a timely manner, and their difficulties with expressive language that also do not permit them to communicate. Two studies, a pilot study and a single case study, investigate the manifestation of pain of patients with RTT and propose a suitable scale to measure it. AIMS OF THIS STUDY: The first aim was to describe pain situations of RTT by collecting information by parents; the second aim was to test and compare existing questionnaires for non-communicating disorders on pain such as Pain assessment in advanced demenzia (PAINAD), the Critical care pain observation tool (CPOT) and the Non-communicating Children's Pain Checklist-Revised (NCCPC-R) to assess which of them is best related to the pain behavior of patients with RTT. The third aim was to identify the specific verbal and non-verbal behaviors that characterize pain in girls with Rett syndrome, discriminating them from non-pain behaviors. METHOD: Nineteen participants, eighteen girls with RTT and one girl with RTT with 27 manifestations of pain were video-recorded both in pain and base-line conditions. Two independent observers codified the 90 video-recording (36 and 54) to describe their behavioral characteristics. RESULTS: The two studies showed that the most significant pain behaviors expressed by girls with respect to the baseline condition, at the facial level were a wrinkled forehead, wide eyes, grinding, banging teeth, complaining, making sounds, crying and screaming, and the most common manifestations of the body were tremors, forward and backward movement of the torso, tension in the upper limbs, increased movement of the lower limbs and a sprawling movement affecting the whole body. CONCLUSION: The results of the two studies helped to create an easy-to-apply scale that healthcare professionals can use to assess pain in patients with Rett's syndrome. This scale used PAINAD as its basic structure, with some changes in the items related to the behavior of patients with RTT.

Nordic treatment guidelines for rare epileptic conditions: A literature review.

INTRODUCTION: The onset of severe, drug-resistant seizures in early childhood is characteristic of the rare epileptic disorders Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and CDKL5 deficiency disorder (CDD) and is frequently observed in the rare genetic conditions tuberous sclerosis complex (TSC) and Rett syndrome (RTT). High-quality treatment guidelines are needed for optimal management of these conditions. This review aimed to assess content, availability, and development of treatment guidelines for these disorders in the Nordics region (Denmark, Finland, Iceland, Norway, and Sweden). METHODS: A targeted literature review (TLR) was therefore conducted in November/December 2020 by manually searching online rare disease and guideline databases in addition to relevant health technology assessment and regulatory agency websites to identify pharmacological treatment guidelines for DS, LGS, TSC, RTT, and CDD. Search terms for each disorder were translated to identify country-specific guidelines. Treatment recommendations, geographical focus, and guideline development methodology was extracted into a predetermined extraction grid. RESULTS: Most of the 24 eligible guidelines identified (16/24; 66%) were specific to particular countries; Sweden was the most represented (7/24 [29%] guidelines), while no guidelines were identified for Iceland. Guideline development methodologies were heterogeneous, including systematic literature reviews/TLRs and expert consultation; several methodologies did not report details on the evidence sources used (7/24 [29%] guidelines). Treatment recommendation availability was variable across disorders, ranging from 126 treatment recommendations (LGS) to none (RTT, CDD). CONCLUSION: Comprehensive, consensus-based treatment guidance developed via international collaboration within the Nordics region is necessary to optimize patient care in these five rare epileptic conditions.

The GAIRS Checklist: a useful global assessment tool in patients with Rett syndrome.

BACKGROUND: Rett Syndrome is a severe, neurodevelopmental disorder mainly caused by mutations in the MECP2 gene, affecting around 1 in 10,000 female births. Severe physical, language, and social impairments impose a wide range of limitations in the assessment of the abilities of Rett patients. This study proposes an analysis and first validation of a Global Assessment and Intervention in Rett syndrome (GAIRS) Checklist for assessing behavioral, intellectual, academic, neuropsychological and psychosocial manifestations in patients with Rett Syndrome. We administered the GAIRS Checklist to 113 Italian patients with Rett Syndrome aged 4-42. AIMS OF THIS STUDY: To examine the psychometric characteristics of the GAIRS Checklist. Moreover, the aim is also to examine the validity of GAIRS with test-retest correlation, convergent validity with similar functional measurements, such as the Vineland scales, and divergent validity with severity of disease scale, such as the RARS scale and severity of neuropsychiatric evaluations. RESULTS: All 10 subscales of GAIRS were positively and significantly related to each other and to the total GAIRS score, and the subscales showed high levels of Cronbach's alpha values (from .77 to .95). Principal axis factoring suggested two factors that explain 60% of the variance. Test-retest reliability is 0.82. This means that psychometric properties are reliable. Correlation for Concurrent validity with Vineland score was high and Divergent Validity with RARS was also high. CONCLUSION: The GAIRS Checklist used for Rett syndrome is acceptable and feasible to complete assessment in a clinical setting. Moreover, it can detect the complexity of this disease and may suggest the next step in terms of specific training in Rett syndrome.

Assessment of the gut bacterial microbiome and metabolome of girls and women with Rett Syndrome.

BACKGROUND: Gastrointestinal problems affect the health and quality of life of individuals with Rett syndrome (RTT) and pose a medical hardship for their caregivers. We hypothesized that the variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome and metabolome in RTT, predisposing these individuals to gastrointestinal dysfunction. OBJECTIVES: We characterized the gut bacterial microbiome and metabolome in girls and young women with RTT (n = 44) and unaffected controls (n = 21), and examined the relation between the composition of the microbiome and variations in the RTT phenotype. METHODS: Demographics and clinical information, including growth and anthropometric measurements, pubertal status, symptoms, clinical severity score, bowel movement, medication use, and dietary intakes were collected from the participants. Fecal samples were collected for analysis of the gut microbiome using Illumina MiSeq-based next-generation sequencing of the 16S rRNA gene followed by bioinformatics analysis of microbial composition, diversity, and community structure. Selected end-products of microbial protein metabolism were characterized by liquid chromatography-mass spectrometry. RESULTS: The gut bacterial microbiome differed within the RTT cohort based on pubertal status (p<0.02) and clinical severity scores (p<0.02) of the individuals and the type of diet (p<0.01) consumed. Although the composition of the gut microbiome did not differ between RTT and unaffected individuals, concentrations of protein end-products of the gut bacterial metabolome, including γ-aminobutyric acid (GABA) (p<0.001), tyrosine (p<0.02), and glutamate (p<0.06), were lower in the RTT cohort. Differences in the microbiome within RTT groups, based on symptomatic anxiety, hyperventilation, abdominal distention, or changes in stool frequency and consistency, were not detected. CONCLUSIONS: Although variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome, we presently cannot infer causality between gut bacterial dysbiosis and gastrointestinal dysfunction. Nevertheless, alterations in the gut metabolome may provide clues to the pathophysiology of gastrointestinal problems in RTT.

A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials.

Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females. Recent work indicates the potential for disease modifying therapies. However, there remains a need to develop outcome measures for use in clinical trials. Using data from a natural history study (n = 1,075), we examined the factor structure, internal consistency, and validity of the clinician-reported Motor Behavior Assessment scale (MBA). The analysis resulted in a five-factor model: (1) motor dysfunction, (2) functional skills, (3) social skills, (4) aberrant behavior, and (5) respiratory behaviors. Item Response Theory (IRT) analyses demonstrated that all items had acceptable discrimination. The revised MBA subscales showed a positive relationship with parent reported items, age, and a commonly used measure of clinical severity in RTT, and mutation type. Further work is needed to evaluate this measure longitudinally and to add items related to the RTT phenotype.

Increasing item engagement and decreasing automatically reinforced problem behavior within a modified competing stimulus assessment.

A competing stimulus assessment (CSA) is commonly used to identify leisure items for use in treatments designed to decrease automatically reinforced problem behavior. However, this type of assessment may not yield useful information if participants do not readily engage with leisure items. The purpose of this study was to evaluate a modified CSA that included additional treatment components (i.e., prompting, prompting plus differential reinforcement of alternative behavior). The modified CSA identified the treatment components and leisure items that were most effective for increasing leisure-item engagement and decreasing problem behavior for each participant. Modified CSA outcomes maintained during an extended treatment analysis in a natural setting and when intervention components were faded.

Assessment of a Clinical Trial Metric for Rett Syndrome: Critical Analysis of the Rett Syndrome Behavioural Questionnaire.

BACKGROUND: Rett syndrome is a neurodevelopmental disorder with potential for improvement through novel targeted therapeutics. Reliable outcome measures are critical to the development of treatments. We examined the merits and flaws of the Rett Syndrome Behavioural Questionnaire, an outcome measure for clinical trials. METHODS: The Rett Syndrome Behavioural Questionnaire was administered alongside other clinical scales in three cohorts, an online survey, a clinic-based study, and the screening period for a clinical trial. Data were collected from individuals with Rett syndrome and related disorders at three time points, separated by a minimum of one week and a maximum of two months. We hypothesized that for clinical trial use, little change should occur among visits. Distribution statistics, internal consistency, intraclass correlation coefficient, percent agreement, and Cohen's kappa were examined. RESULTS: Among 149 with classic Rett syndrome, the Rett Syndrome Behavioural Questionnaire was completed 377 times. Median total score was 33, ranging from 3 to 73. Of the 51 items tested in the original Rett Syndrome Behavioural Questionnaire study, 24 exhibited either floor or ceiling effects. Friedman's analysis of variance revealed significant difference among visits (P = 0.024), and graphical analysis using Bland-Altman plots demonstrated systematic positive bias with a 95% confidence interval including up to 12.9 points higher to 15.7 points lower at retest. Median agreement measured by kappa was 0.53 for retest at visit 2 and 0.49 for retest at visit 3. CONCLUSIONS: The Rett Syndrome Behavioural Questionnaire did not achieve acceptable standards as an outcome assessment for clinical trials in Rett syndrome.

In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment.

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order-disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT.

Developing a database for Rett syndrome research performed in the European Union: A resource for researchers and stakeholders.

BACKGROUND: For most rare diseases, which are often significantly under-resourced, sufficient information on funding landscape is missing, which may prevent effective use of research resources and be an obstacle to making effective decisions on research. The objective of this research was to create a database of Rett syndrome research projects carried out in the European Union (EU) and to provide a research landscape analysis. METHOD: Websites of organizations funding research projects were identified and systematically checked. Projects were analysed by date, place, funder types, and research topics. RESULTS: The analysis revealed that the total expenditure on Rett syndrome research was almost €70 million, allocated among 247 projects mostly performed in Italy and the United Kingdom. The main research sponsor was the European Commission. Highlighting research trends and gaps, this work facilitates changes in rare disease research data management. CONCLUSION: This work demonstrates the feasibility of creating an EU-based research database on Rett syndrome projects. It provides a source of information on research development which is useful for individuals, organizations and key players in the private and public sector to make progressive decisions on Rett syndrome research.

Disparities in Familiarity With Developmental Disabilities Among Low-Income Parents.

OBJECTIVE: Parent knowledge about developmental disabilities (DDs) may facilitate access to DD care; however, parents may vary in their knowledge and familiarity with common DDs. This study aimed to assess racial/ethnic and language differences in low-income families' familiarity, knowledge, and personal experience with DDs. METHODS: We conducted a child development survey among 539 low-income parents of young children attending visits at the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in 6 Oregon counties in 2015. Survey items assessed parent familiarity with early signs of DDs, self-reported knowledge about DDs, and personal experience with a friend or family member with a DD. Bivariable and multivariable analyses assessed differences in outcomes among non-Latino white (white), Latino English-proficient (Latino-EP), Latino limited-English-proficient (Latino-LEP), and non-Latino other race English-proficient (other race) parents. RESULTS: Overall, parent participants correctly identified 64.7% of early signs of DDs. White parents correctly identified the most early signs, even after adjustment for sociodemographic factors. Compared with white parents, Latino-LEP, Latino-EP, and other race parents were less likely to have heard of prevalent DDs, such as attention-deficit/hyperactivity disorder and autism, and less likely to have a friend or family member with a DD. CONCLUSIONS: Low-income Latino-LEP and other race parents have less familiarity or personal experience with DDs and are less aware of early signs of DDs compared to low-income white parents. Study findings suggest that interventions to reduce disparities in DD diagnosis and treatment should include increasing information transfer to parents in racial/ethnic and language minority communities.

Development of the Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database and the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire.

INTRODUCTION: Rett syndrome (RTT) is a pervasive neurodevelopmental disorder that presents with deficits in brain functioning leading to language and learning regression, characteristic hand stereotypies and developmental delay. Different mutations in the gene implicated in RTT-methyl-CpG-binding protein 2 (MECP2) establishes RTT as a disorder with divergent symptomatology ranging from individuals with severe to milder phenotypes. A reliable and single multidimensional questionnaire is needed that can embrace all symptoms, and the relationships between them, and can map clinically meaningful data to symptomatology across the lifespan in patients with RTT. As part of the HealthTracker-based Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database, the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire will be able to marry with the physiological aspects of the disease obtained using wearable sensor technology, along with genetic and psychosocial data to stratify patients. Taken together, the web-based TRIAL database will empower clinicians and researchers with the confidence to delineate between different aspects of disorder symptomatology to streamline care pathways for individuals or for those patients entering clinical trials. This protocol describes the anticipated development of the REST questionnaire and the TRIAL database which links with the outcomes of the wearable sensor technology, and will serve as a barometer for longitudinal patient monitoring in patients with RTT. METHODS AND ANALYSIS: The US Food and Drug Administration Guidance for Patient-Reported Outcome Measures will be used as a template to inform the methodology of the study. It will follow an iterative framework that will include item/concept identification, item/concept elicitation in parent/carer-mediated focus groups, expert clinician feedback, web-based presentation of questionnaires, initial scale development, instrument refinement and instrument validation. ETHICS AND DISSEMINATION: The study has received favourable opinion from the National Health Service (NHS) Research Ethics Committee (REC): NHS Research Ethics Committee (REC)-London, Bromley Research Ethics Committee (reference: 15/LO/1772).

Functional assessment of MeCP2 in Rett syndrome and cancers of breast, colon, and prostate.

Ever since the first report that mutations in methyl-CpG-binding protein 2 (MeCP2) causes Rett syndrome (RTT), a severe neurological disorder in females world-wide, there has been a keen interest to gain a comprehensive understanding of this protein. While the classical model associated with MeCP2 function suggests its role in gene suppression via recruitment of co-repressor complexes and histone deacetylases to methylated CpG-sites, recent discoveries have brought to light its role in transcription activation, modulation of RNA splicing, and chromatin compaction. Various post-translational modifications (PTMs) of MeCP2 further increase its functional versatility. Involvement of MeCP2 in pathologies other than RTT, such as tumorigenesis however, remains poorly explored and understood. This review provides a survey of the literature implicating MeCP2 in breast, colon and prostate cancer.

Assessment of Caregiver Inventory for Rett Syndrome.

Rett syndrome (RTT) requires total caregiver attention and leads to potential difficulties throughout life. The Caregiver Burden Inventory, designed for Alzheimer disease, was modified to a RTT Caregiver Inventory Assessment (RTT CIA). Reliability and face, construct, and concurrent validity were assessed in caregivers of individuals with RTT. Chi square or Fisher's exact test for categorical variables and t tests or Wilcoxon two-sample tests for continuous variables were utilized. Survey completed by 198 caregivers; 70 caregivers completed follow-up assessment. Exploratory factor analysis revealed good agreement for physical burden, emotional burden, and social burden. Internal reliability was high (Cronbach's alpha 0.898). RTT CIA represents a reliable and valid measure, providing a needed metric of caregiver burden in this disorder.