Electroencephalographic Correlates of Clinical Severity in the Natural history study of RTT and Related Disorders.

OBJECTIVE: This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT). METHODS: EEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow-up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year. RESULTS: Compared to neurotypical participants, participants with RTT had greater amplitude variability and greater low-frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within-subject consistency in these measures. INTERPRETATION: Overall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024;96:175-186.

Rett syndrome diagnostic odyssey: Limitations of NextGen sequencing.

Typical (or classic) Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by a period of regression, partial or complete loss of purposeful hand movements, and acquired speech, impaired gait, and stereotyped hand movements. In over 95% of typical RTT, a pathogenic variant is found in the methyl-CPG binding protein 2 gene (MECP2). Here, we describe a young woman with clinically diagnosed typical RTT syndrome who lacked a genetic diagnosis despite 20 years of investigation and multiple rounds of sequencing the MECP2 gene. Recently, additional genetic testing using next-generation sequencing was completed, which revealed a partial insertion of the BCL11A gene within exon 4 of MECP2, resulting in a small deletion in MECP2, causing likely disruption of MeCP2 function due to a frameshift. This case demonstrates the ever-changing limitations of genetic testing, as well as the importance of continual pursuit of a diagnosis as technologies improve and are more widely utilized.

Communication of individuals with CDKL5 deficiency disorder as observed by caregivers: A descriptive qualitative study.

CDKL5 deficiency disorder (CDD) is a genetically caused developmental epileptic encephalopathy that causes severe communication impairments. Communication of individuals with CDD is not well understood in the literature and currently available measures are not well validated in this population. Accurate and sensitive measurement of the communication of individuals with CDD is important for understanding this condition, clinical practice, and upcoming interventional trials. The aim of this descriptive qualitative study was to understand how individuals with CDD communicate, as observed by caregivers. Participants were identified through the International CDKL5 Disorder Database and invited to take part if their child had a pathogenic variant of the CDKL5 gene and they had previously completed the Communication and Symbolic Behavior Checklist (CSBS-DP ITC). The sample comprised caregivers of 23 individuals with CDD, whose ages ranged from 2 to 30 years (median 13 years), 15 were female, and most did not use words. Semistructured interviews were conducted via videoconference and analyzed using a conventional content analysis. Three overarching categories were identified: mode, purpose and meaning, and reciprocal exchanges. These categories described the purposes and mechanism of how some individuals with CDD communicate, including underpinning influential factors. Novel categories included expressing a range of emotions, and reciprocal exchanges (two-way interactions that varied in complexity). Caregivers observed many communication modes for multiple purposes. Understanding how individuals with CDD communicate improves understanding of the condition and will guide research to develop accurate measurement for clinical practice and upcoming medication trials.

Parent-reported outcome measures evaluating communication in individuals with rare neurodevelopmental disorders: A systematic review.

BACKGROUND: Communication impairments are a leading concern for parent caregivers of individuals with rare neurodevelopmental disorders (RNDDs). Clinical trials of disease modifying therapies require valid and responsive outcome measures that are relevant to individuals with RNDDs. Identifying and evaluating current psychometric properties for communication measures is a critical step towards the selection and use of appropriate instruments. AIMS: This systematic review offers (1) a description of parent-reported communication measures and (2) evidence for their psychometric properties, in RNDDs. METHODS: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022334649). MEDLINE (Ovid), Embase, PsychINFO, Web of Science, CINAHL Plus, Cochrane Library, ClinicalTrials.gov, the Australian New Zealand Clinical Trials Registry were searched from inception to August 2023. Methodological assessment of quality was completed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. Parent-reported measures used in observational studies and clinical trials were identified. Data on utility, reliability and validity for RNDDs were extracted. MAIN CONTRIBUTION: Sixteen parent-reported communication measures were used in RNDD research, the Vineland Adaptive Behavior Scales being most commonly used. Validation data in RNDDs were identified for six of these measures. Limitations related to sample size or the scope of psychometric testing. CONCLUSIONS: Many communication measures have been used for RNDDs but there are few data validating their use. Valid and reliable methods of measuring communication in persons with RNDDs is a priority for future high-quality clinical trials. WHAT THIS PAPER ADDS: What is already known on the subject Communication is a critical domain for families with a child with a rare neurodevelopmental disorder (RNDD). Validated outcome measures are essential for accurate evaluation and interpretation of responses to treatments in clinical trials. What this paper adds to existing knowledge We identified 16 parent-reported communication measures that have been used with RNDDs, but only six measures had validation data for at least one RNDD. High quality evidence is accumulating, with all validation studies in this review published between 2020 to 2023. Modifications of existing measures may be required to assess communication for RNDDs. What are the clinical implications of this work? This systematic review catalogues the available psychometric data for communication measures and indicates an ongoing need for new validation studies to ensure they are fit-for-purpose for upcoming clinical trials in RNDDs. This review will inform the selection of communication measures for clinical trials and research studies.

Loss of Postnatal Arx Transcriptional Activity in Parvalbumin Interneurons Reveals Non-cell Autonomous Disturbances in CA1 Pyramidal Cells.

Maintenance of proper electrophysiological and connectivity profiles in the adult brain may be a perturbation point in neurodevelopmental disorders (NDDs). How these profiles are maintained within mature circuits is unclear. We recently demonstrated that postnatal ablation of the Aristaless (Arx) homeobox gene in parvalbumin interneurons (PVIs) alone led to dysregulation of their transcriptome and alterations in their functional as well as network properties in the hippocampal cornu Ammoni first region (CA1). Here, we characterized CA1 pyramidal cells (PCs) responses in this conditional knockout (CKO) mouse to further understand the circuit mechanisms by which postnatal Arx expression regulates mature CA1 circuits. Field recordings of network excitability showed that CA1 PC ensembles were less excitable in response to unpaired stimulations but exhibited enhanced excitability in response to paired-pulse stimulations. Whole-cell voltage clamp recordings revealed a significant increase in the frequency of spontaneous inhibitory postsynaptic currents onto PCs. In contrast, excitatory drive from evoked synaptic transmission was reduced while that of inhibitory synaptic transmission was increased. Current clamp recordings showed increase excitability in several sub- and threshold membrane properties that correlated with an increase in the conductance of Na+ current. Our data suggest that, in addition to cell-autonomous disruption in PVIs, loss of Arx postnatal transcriptional activity in PVIs led to complex dysfunctions in PCs in CA1 microcircuits. These non-cell autonomous effects are likely the product of breakdown in feedback and/or feedforward processes and should be considered as fundamental contributors to the circuit mechanisms of NDDs such as Arx-linked early-onset epileptic encephalopathies.

Trofinetide Treatment Demonstrates a Benefit Over Placebo for the Ability to Communicate in Rett Syndrome.

BACKGROUND: Trofinetide was approved by the US Food and Drug Administration for the treatment of Rett syndrome (RTT) in March 2023. Benefiting the ability to communicate in RTT is often identified as the most important caregiver goal for new therapies. This analysis reports the communication-related end points from the phase 3 LAVENDER study of trofinetide in RTT. METHODS: Females with RTT, aged five to 20 years, were randomized 1:1 to trofinetide or placebo for 12 weeks. Secondary efficacy end points related to communication were based on change from baseline to week 12 and included the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite score (key secondary end point; scores ranged from 0 to 26 [higher scores indicated better communication]) and novel clinician rating scales (0 [normal] to 7 [severe impairment]) measuring the ability to communicate choices nonverbally (RTT-COMC) and verbally (RTT-VCOM). RESULTS: Trofinetide demonstrated a statistically significant difference versus placebo for the CSBS-DP-IT Social Composite score (least squares mean [LSM] difference = 1.0; 95% confidence interval [CI], 0.3 to 1.7; P = 0.0064; Cohen's d effect size = 0.43) and a nominally significant difference for the RTT-COMC (LSM difference: -0.3; 95% CI, -0.6 to -0.0; P = 0.0257; Cohen's d effect size = 0.36). As expected, there was no difference for the RTT-VCOM. CONCLUSIONS: Significant treatment benefit for trofinetide versus placebo was observed in scales measuring the ability to communicate. These scales may be appropriate for future clinical studies in RTT and other neurodevelopmental disorders.

Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.

STUDY OBJECTIVES: Sleep difficulties are common in CDKL5 deficiency disorder (CDD), a developmental and epileptic encephalopathy (DEE). This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Daytime Somnolence (DOES) and Sleep Breathing Disorders (SBD) domains of the Sleep Disturbance Scale for Children (SDSC) for CDD. METHODS: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a US Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. RESULTS: The median age was 10.3 years (range 3.2 - 40.7 years) and 105 (84%) were female. Two of the three SBD items related were not observed by most respondents and analysis was restricted to the DIMS and DOES domains. Using all items in the initial confirmatory factor analysis, two items in the DIMS domain and one item in the DOES domain loaded poorly. After deleting these items and repeating the analysis, item loading (0.524-0.814) and internal consistency (DIMS: 0.78, DOES: 0.76) statistics were good. The square of the inter-domain correlation coefficient was 0.17, less than Average Variance Extracted values for both domains and indicating good discriminant validity. The Tucker-Lewis and Comparative Fit indices were slightly lower than the threshold of >0.9 for establishing goodness of fit. CONCLUSIONS: The modified DIMS and DOES domains from the SDSC could be suitable clinical outcome assessments of insomnia and related impairments in CDD and potentially other DEE conditions.

Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study.

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER. METHODS: Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40. FINDINGS: Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively. CONCLUSIONS: Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER. FUNDING: The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).

Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS).

Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS). Using data from the Rett Natural History Study (n = 649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS. The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and convergent validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire. These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed.

Trofinetide for the treatment of Rett syndrome: Long-term safety and efficacy results of the 32-month, open-label LILAC-2 study.

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome (RTT) in patients aged ≥2 years based on the results of the 12-week, randomized, phase 3 LAVENDER study. In LILAC, a 40-week, open-label extension study of LAVENDER, trofinetide continued to improve the symptoms of RTT, with a similar safety profile as LAVENDER. Here, we report long-term safety and efficacy results of LILAC-2, a 32-month, open-label extension study. METHODS: Females aged 5-22 years who completed LILAC were eligible to enter LILAC-2. Safety and tolerability were assessed with the incidence of adverse events (AEs). Efficacy was assessed with Rett Syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression-Improvement (CGI-I) scores. Caregiver interviews explored the patient's experience with RTT and the efficacy of trofinetide during study participation. FINDINGS: In total, 77 participants were enrolled in LILAC-2. The most common AEs were diarrhea (53.2%), COVID-19 (27.3%), and vomiting (19.5%). The mean (standard error [SE]) change in RSBQ score from LAVENDER baseline to week 104 of LILAC-2 was -11.8 (2.45). The mean (SE) CGI-I score from LILAC baseline to week 12 of LILAC-2 was 3.1 (0.10). Most caregivers (96%; n = 24/25) were satisfied or very satisfied with the benefits of trofinetide. CONCLUSIONS: Long-term treatment with trofinetide continued to improve RTT symptoms, without new safety concerns. Caregivers reported satisfaction with trofinetide related to improvements that were meaningful for their child and themselves. FUNDING: The study was supported by Acadia Pharmaceuticals (San Diego, CA, USA). This study was registered at ClinicalTrials.gov: NCT04776746.

Distribution of hand function by age in individuals with Rett syndrome.

Objective: To determine the longitudinal distribution of hand function skills in individuals with classic Rett Syndrome (RTT), an X-linked dominant neurodevelopmental disorder, and correlate with MECP2 variants. Method: We conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus in this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups. Results: Following the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C-terminal truncations) compared to groups composed of individuals with more severe variants. Conclusions: These temporal variations in hand use represent specific considerations which could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.