Utility of the Rett syndrome behavior questionnaire (RSBQ) for Japanese patients with Rett syndrome: A pilot study

Rett syndrome (RTT) is a complex neurodevelopmental X-linked disorder associated with severe functional impairments and multiple comorbidities. There is wide variation in the clinical presentation, and because of its unique characteristics, several evaluation tools of clinical severity, behavior, and functional motor abilities have been proposed specifically for it. This opinion paper aims to present up-to date evaluation tools which have specifically been adapted for individuals with RTT often used by the authors in their clinical and research practice and to provide the reader with essential considerations and suggestions regarding their use. Due to the rarity of Rett syndrome, we found it important to present these scales in order to improve and professionalize their clinical work. The current article will review the following evaluation tools: (a) the Rett Assessment Rating Scale; (b) the Rett Syndrome Gross Motor Scale; (c) the Rett Syndrome Functional Scale; (d) the Functional Mobility Scale-Rett Syndrome; (e) the Two-Minute Walking Test modified for Rett syndrome; (f) the Rett Syndrome Hand Function Scale; (g) the StepWatch Activity Monitor; (h) the activPALTM; (i) the Modified Bouchard Activity Record; (j) the Rett Syndrome Behavioral Questionnaire; and (k) the Rett Syndrome Fear of Movement Scale. The authors recommend that service providers consider evaluation tools validated for RTT for evaluation and monitoring to guide their clinical recommendations and management. In this article, the authors suggest factors that should be considered when using these evaluation tools to assist in interpreting scores.

Although physical features, including loss of hand skills, deceleration of head growth, spasticity and scoliosis, are cardinal features of Rett syndrome (RS), a number of behavioural features are also associated with the disorder, including hand stereotypies, hyperventilation and breath holding. No study has tested the specificity of these behavioural features to individuals with RS, compared to individuals with severe to profound mental retardation (SMR). A novel checklist of characteristic RS behavioural and emotional features, the Rett Syndrome Behaviour Questionnaire (RSBQ), was developed to test the type and specificity of behavioural features of RS against those found in girls with SMR. After controlling for the effects of RS-related physical disabilities, the RSBQ discriminated between the groups. Some aspects of the behaviours found to be specific to RS are included in the necessary or supportive RS diagnostic criteria, notably hand behaviours and breathing problems. Additional behavioural features were also more frequently reported in the RS than the SMR group, including mood fluctuations and signs of fear/anxiety, inconsolable crying and screaming at night, and repetitive mouth and tongue movements and grimacing. Full validation of the scale requires confirmation of its discriminatory power and reliability with independent samples of individuals with RS and SMR. Further delineation of the specific profile of behaviours seen in RS may help in identification of the function of the MECP2 gene and in improved differential diagnosis and management of individuals with RS.

BackgroundAlzheimer's disease (AD) and Rett syndrome (Rett) share overlapping genetic and molecular features. NA‐831, a small‐molecule drug, promotes neuroprotection and neurogenesis for AD treatment. NA‐921, an analog of NA‐831, modulates MeCP2 expression and function for Rett treatment.MethodNA‐831: A randomized clinical trial was conducted in 112 participants with mild to moderate AD. Subjects were randomized to receive either NA‐831 or placebo. Patients with mild cognitive impairment (MCI) received 10 mg/day of NA‐831 or placebo orally, while patients with mild to moderate AD received 30 mg/day. Subjects with MCI to meet the NIA‐AA core clinical criteria, CDR score of 0.5 and a Memory Box score of 0.5 or greater at Screening and Baseline and an MMSE ≥22. Subjects with mild to moderate AD had MMSE scores between 17–21. (ClinicalTrials.gov ID: NCT03538522)NA‐921: A randomized, double‐blind, placebo‐controlled Phase 2/3 study evaluated NA‐921 (Bionetide) in girls and women with Rett syndrome. (ClinicalTrials.gov ID: NCT06849973)ResultNA‐831: After 24 weeks of treatment, patients with mild to moderate AD receiving NA‐831 showed a significant improvement in ADAS‐Cog‐13 scores, with an average change of 4.1 compared to placebo (p = 0.001; ITT). CIBIC‐Plus results showed improvement in 78% of patients (p = 0.01; ITT). NA‐831 was well tolerated at 30 mg/day, with no serious adverse events observed, suggesting a safer oral alternative to current AD treatments.NA‐921: NA‐921 significantly improved outcomes in Rett syndrome. On the Rett Syndrome Behavior Questionnaire (RSBQ), the least squares mean change at week 12 was ‐5.5 for NA‐921 vs. ‐1.6 for placebo (p = 0.001; n = 86 vs. 87). For Clinical Global Impression–Improvement (CGI‐I), scores at week 12 were 3.60 (NA‐921) vs. 3.83 (placebo), with a significant effect size of 0.42 (p = 0.0020). NA‐921 is a potential treatment for Rett Syndrome with fewer side effects and improved patient retention rates.ConclusionThese findings support a potential mechanistic link between Alzheimer’s disease and Rett syndrome. Both NA‐831 and NA‐921 show promise as novel, well‐tolerated therapeutic agents. Further studies are warranted to validate these results and deepen our understanding of the shared molecular pathways between this neurodegenerative and neurodevelopmental disorder.

Rett syndrome is a rare neurodevelopmental disorder primarily affecting females. This syndrome is associated with many comorbidities and impairments related to motor function, breathing, sleep, expressive language, and repetitive hand movements. The Rett Syndrome Behaviour Questionnaire (RSBQ) is one measure used to assess changes in Rett syndrome-related manifestations or core symptoms. Little is known about how caregivers think about meaningful changes in the items that make up the RSBQ scale. This qualitative study explored how caregivers of individuals with Rett syndrome viewed changes in the symptoms covered in the RSBQ. We conducted semistructured interviews with 40 caregivers and employed thematic analysis, identifying themes using an iterative process. Two factors characterized caregivers' thoughts about meaningful changes in Rett syndrome manifestations. First, general features of these symptoms rendered them bothersome: the extent of bother compared to other symptoms, if or how they prevented desirable behaviors and their temporal qualities. Second, caregivers evaluated the meaning of improvements by considering the decrease in bother and the potential benefits of change. Improvements had social and psychological consequences for individuals with Rett syndrome and caregivers. In addition, implications for health, fine and gross motor skills, and communication were also substantial.

Rett syndrome is a neurodevelopmental disorder observed almost exclusively in girls, and is characterized by autistic tendency, severe mental retardation, stereotyped hand movements, seizures, and acquired microcephaly. Recently, the MECP2 (methyl-CpG-binding protein 2) gene, mapped on chromosome Xq28, was reported to be responsible for Rett syndrome. We performed mutational analysis of the MECP2 gene in 26 Japanese patients with Rett syndrome (who were sporadic cases), and identified disease alleles in 19 patients. The mutations consisted of 12 different types including 3 missense, 3 nonsense, and 6 frameshift mutations. Of these, 8 mutations are novel. Most of these mutations affect the functional domains, methyl-CpG binding domain (MBD), and transcriptional repression domain (TRD), and therefore may critically affect the function of MeCP2. The disease phenotype of patients with mutations in the MBD tended to be more severe than the phenotype of those with mutations in the TRD. We also identified 2 types of silent mutations and 4 types of missense mutations as benign variants, and these are all novel ones. Most of the nucleotide substitutions involve C-->T transitions at CpG hotspots. The novel disease alleles and benign variants of the MECP2 gene found in this study should contribute to the establishment of a reliable diagnosis of Rett syndrome.

R133C and R168X mutations in Japanese Rett syndrome patients: a caution for misdiagnosis

What is this summary about? This is a summary of an article about the LAVENDER study, which was published in Nature Medicine in June 2023. The study involved girls and young women with a rare genetic condition called Rett syndrome, which affects the way the brain develops. Researchers wanted to find out if a drug called trofinetide could improve the symptoms of Rett syndrome. What happened during the LAVENDER study? A total of 187 girls and young women took trofinetide (brand name DAYBUE™) liquid or a placebo (something that looks the same as the trofinetide liquid but does not contain medicine) 2 times a day either by drinking it or through a tube into the stomach called a gastrostomy tube (g-tube). Changes in Rett syndrome symptoms were looked for by study doctors for 12 weeks by using a rating scale called the Clinical Global Impression–Improvement (CGI–I) and by caregivers (usually a parent) who completed a questionnaire called the Rett Syndrome Behaviour Questionnaire (RSBQ). Caregivers were also asked to rate communication and social interaction skills, which resulted in the ‘Social Composite’ score on a questionnaire called the Communication and Symbolic Behavior Scales Developmental Profile™ Infant–Toddler (CSBS-DP-IT) checklist. What were the results? After 12 weeks of treatment, girls and young women who received trofinetide had greater improvements in their symptoms than those who took the placebo, as rated by the RSBQ and CGI–I. Participants who took trofinetide could communicate better than participants who took the placebo as rated on the CSBS–DP–IT Social Composite scale. The differences between trofinetide and the placebo were statistically significant, which means that it was unlikely that the benefit seen with trofinetide was caused by chance. The most common side effects in the trofinetide group were diarrhea (frequent watery bowel movements) and vomiting, and in almost all cases these were mild or moderate. What do the results of the study mean? In the LAVENDER study, trofinetide helped girls and young women with Rett syndrome by improving several important symptoms. This is the first study to show that a medicine, trofinetide, improves the symptoms of Rett syndrome. Clinical Trial Registration: NCT04181723 (LAVENDER) ( ClinicalTrials.gov )

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

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

IntroductionRett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and stereotypic hand movements. Given the limited treatment options for Rett syndrome, there is a dire need for effective interventions.ObjectiveTo evaluate the safety and efficacy of trofinetide in Randomized Controlled Trials (RCTs) that report on Rett syndrome patients.MethodsWe identified 109 articles from four databases (Scopus, PubMed, Web of Science, and Cochrane CENTRAL). After removing the duplicates, we narrowed them down to 59 articles for further assessment. We included RCTs that evaluated the efficacy and safety of trofinetide in patients with Rett syndrome. Three studies were eligible for inclusion. Two independent reviewers evaluated the identified studies’ titles, abstracts, and full texts, extracting pertinent data. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) 2.0 tool. We then conducted a meta-analysis using the fixed effects model in the case of insignificant heterogeneity; otherwise, we used the random effects model. Based on the nature of the outcome, we analyzed the mean difference or the odds ratio. Analysis was conducted using RevMan version 5.3.ResultsAmong the analyzed outcomes in 181 patients in the trofinetide group and 134 patients in the placebo group, significant improvement in Rett Syndrome Behavior Questionnaire (RSBQ) scores was observed at 200 mg dosage (overall mean difference: -3.53, p = 0.001). Clinical Global Impression-Improvement (CGI-I) scores improved considerably at 200 mg dosage (overall mean difference: -0.34, p < 0.0001). No substantial changes were observed in Motor Behavioral Assessment (MBA) or Top 3 Caregiver Concerns. We evaluated Treatment Emergent Adverse Events (TEAEs) across the various dosages and noted significant associations with diarrhea (200 mg), vomiting (200 mg), and irritability (200 mg). However, we did not find a significant association between any of the dosages and the incidence of decreased appetite.ConclusionTrofinetide demonstrated potential in improving RSBQ and CGI-I scores at 200 mg dosage. Although no substantial changes were found in MBA and top 3 caregiver concerns. Adverse events were linked to specific dosages.

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study (https://clinicaltrials.gov identifier NCT04181723), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was −4.9 versus −1.7 (P = 0.0175; Cohen’s d effect size, 0.37), and LSM Clinical Global Impression–Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist Social Composite score was −0.1 versus −1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

Generation of human induced pluripotent stem cell lines derived from four Rett syndrome patients with MECP2 mutations

IntroductionTrofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based dosing regimen. Exposure–response (E–R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration–time curve for the dosing interval of 0–12 h [AUC0–12]) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen.MethodsEfficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E–R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression–Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant–Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC).ResultsHigher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC0–12 values of 800–1200 μg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55–4.94) versus placebo (0.76). Significant E–R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores.ConclusionE–R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide.Trial RegistrationNCT01703533, NCT02715115, NCT04181723.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-024-02796-y.

This study compared the behavior profile of cases in the Australian Rett Syndrome Database (ARSD) with those in a British study using the Rett Syndrome Behavior Questionnaire (RSBQ) and then examined behavioral patterns as measured by the RSBQ by genetic status. There were 145 Australian cases meeting the criteria for the first arm of the study and 135 for the second arm. Comparison of the scores obtained from the British and Australian cohorts indicated that the RSBQ was a satisfactory measure for describing behaviors in Rett Syndrome (RS). Overall, there were some differences among the behavior patterns of cases with the well-known common mutations. Fear/anxiety was more commonly reported in those with R133C and R306C. Those with the R294X mutation were more likely to have mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. In contrast, hand behaviors were more commonly reported in those with R270X or R255X. We found the RSBQ is an appropriate instrument for measuring behavior in girls with RS. Some behaviors differ according to genetic mutation but there is both inter and intra mutation variation in behavior and there is a need for larger studies involving international collaboration to improve statistical power.

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.