Development and validation of parent-reported gastrointestinal health scale in MECP2 duplication syndrome.

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials. METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale. RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis (CFA). The final MDS-specific GHS included 38 items and 7 factors that underwent further reliability and validity assessments. The power of the study was at least 0.982. The Cronbach's alphas of the instruments were General Health: 0.799, Eating-Chewing-Swallowing: 0.809, Reflux: 0.794, Motility: 0.762, Mood: 0.906, Medication: 0.595, Parenting: 0.942 and all items together: 0.928. The correlation coefficient between total and individual item scores ranged from 0.215 to 0.730. Because of the ordinal nature of the variables, the diagonal weighted least squares estimation (DWLS) method was used to execute the CFA and Structural Equation Modeling. The GHS had excellent model fit with the acceptable range of fit indices values. CONCLUSIONS: We developed a parent-reported, reliable, and valid MDS-specific GHS. This scale can be utilized in clinical settings or as an outcome measure in translational and clinical research.

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.

Parental age effects and Rett syndrome.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder, and pathogenic Methyl-CpG-binding Protein 2 (MECP2) variants are identified in >95% of individuals with typical RTT. Most of RTT-causing variants in MECP2 are de novo and usually on the paternally inherited X chromosome. While paternal age has been reported to be associated with increased risk of genetic disorders, it is unknown whether parental age contributes to the risk of the development of RTT. Clinical data including parental age, RTT diagnostic status, and clinical severity are collected from 1226 participants with RTT and confirmed MECP2 variants. Statistical analyses are performed using Student t-test, single factor analysis of variance (ANOVA), and multi-factor regression. No significant difference is observed in parental ages of RTT probands compared to that of the general population. A small increase in parental ages is observed in participants with missense variants compared to those with nonsense variants. When we evaluate the association between clinical severity and parental ages by multiple regression analysis, there is no clear association between clinical severity and parental ages. Advanced parental ages do not appear to be a risk factor for RTT, and do not contribute to the clinical severity in individuals with RTT.

A review of the Rett Syndrome Behaviour Questionnaire and its utilization in the assessment of symptoms associated with Rett syndrome.

The Rett Syndrome Behaviour Questionnaire (RSBQ), which is completed by the caregiver, is one of the most widely used efficacy measures in clinical studies of Rett syndrome (RTT) due to its specificity to the core features of RTT. As healthcare providers participate in routine healthcare assessments of individuals with RTT in clinical practice, there is a need for these providers to understand the psychometric properties of the RSBQ and how it relates to the core clinical features of RTT. Here, we describe the characteristics of the RSBQ, review the literature on its validity and reliability as well as its performance in a phase 2 study and the recent phase 3 LAVENDER study. The RSBQ was first shown to discriminate RTT from other intellectual disorders with good inter-rater and test-retest reliability scores. It was subsequently validated as an appropriate instrument for measuring behavior in females with RTT and adopted as a clinical trial outcome. In LAVENDER, the FDA-approved drug trofinetide significantly improved the RSBQ total score over placebo in girls and women with RTT and change from baseline for all RSBQ subscores were directionally in favor of trofinetide. The change in RSBQ was aligned with the Clinical Global Impression-Improvement scale, suggesting that improvement in behavioral components may be related to overall clinical status. Given its validity and ubiquity in RTT clinical studies, it is important that the interplay of the domains and the psychometric profile of the RSBQ are understood.

Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study.

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.

Exploring gastrointestinal health in MECP2 duplication syndrome.

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare neurogenetic syndrome caused by duplications of MECP2 at the Xq28 region. Although constipation and gastrointestinal reflux are reported in MDS, a comprehensive characterization of gastrointestinal health has not been fully explored. METHODS: We conducted a parent survey to explore the characteristics of gastrointestinal health in individuals with MDS using a secure online registry and compared differences in gastrointestinal symptoms between individuals with MDS and those with Rett syndrome (RTT). KEY RESULTS: One hundred six surveys were analyzed. Symptoms commonly associated with constipation occurred in 72% to 89% of MDS individuals. Eleven percent of MDS individuals underwent surgery for complications associated with constipation. We observed a bimodal distribution for gastroesophageal reflux disease (GERD) and gastrostomy feeding, with higher prevalence in 0-3 and >12-year-old MDS individuals. Constipation and GERD were significantly more common, and gas bloating was significantly less common in MDS than in RTT. Biliary tract disease requiring surgery was an unrecognized problem in 5% of MDS individuals. We determined that gastrointestinal problems in MDS individuals contribute to caretaker burden. CONCLUSION AND INFERENCES: Our study is the first in-depth investigation that characterizes gastrointestinal health in MDS and enumerates differences in gastrointestinal symptoms between MDS and RTT. Strategies to reduce gastrointestinal symptoms will alleviate caregiver burden in MDS. Further studies are needed to examine the mechanisms that cause gastrointestinal problems in MDS.

Development of trofinetide for the treatment of Rett syndrome: from bench to bedside.

Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2 years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases.

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.

Assessing the Burden on Caregivers of MECP2 Duplication Syndrome.

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare neurogenetic disorder characterized by severe neurodevelopmental disorder, refractory epilepsy, recurrent infections, and functional gastrointestinal problems. Because of the significant clinical problems and lifelong disability of children with this disorder we hypothesized that the burden on parents/caregivers of these children is significant. However, there are no reports of the impact on caregivers of individuals with MDS. METHODS: We developed and validated a burden scale to investigate the challenges of caregivers of children and adults with MDS and identified factors contributing to the burden on caregivers. We developed a Health Insurance Portability and Accountability Act-compliant patient registry for families with MDS and delivered caregiver burden survey through the registry. RESULTS: Of 237 completed surveys, 101 were eligible for the study. We identified increased levels of self-perceived anxiety, depression, and emotional exhaustion in caregivers that correlated with higher burden scores. Epilepsy was the only clinical feature that caused a higher burden in caregivers of individuals with MDS. In addition, a higher burden was found in Hispanic caregivers. The duration of care negatively correlated with burden score. CONCLUSIONS: This is the first study to investigate the burden on caregivers of individuals with MDS and identify several factors contributing to increased burden. Addressing these concerns has the potential to improve the health of individuals with MDS and contribute to the well-being of their caretakers.

Exploring the characteristics and most bothersome symptoms in MECP2 duplication syndrome to pave the path toward developing parent-oriented outcome measures.

BACKGROUND: MECP2 Duplication Syndrome (MDS), resulting from the duplication of Xq28 region, including MECP2, is a rare disorder with a nascent understanding in clinical features and severity. Studies using antisense oligonucleotides revealed a broad phenotypic rescue in transgenic mice. With human clinical trials on the horizon, there is a need to develop clinical outcome measures for MDS. METHODS: We surveyed caregivers of MDS individuals to explore the frequency and severity of MDS clinical features, and identify the most meaningful symptoms/domains that need to be included in the outcome measure scales. RESULTS: A total of 101 responses were eligible for the survey. The top six most meaningful symptoms to caregivers in descending order included epilepsy, gross motor, fine motor, communication, infection, and constipation problems. Epilepsy was present in 58.4% of the subjects and 75% were drug-resistant, Furthermore, ~12% required intensive care unit (ICU) admission. Infections were present in 55% of the subjects, and one-fourth of them required ICU admission. Constipation was present in ~85% of the subjects and one-third required enemas/suppositories. CONCLUSION: Our study is one of the largest cohorts conducted on MDS individuals characterizing the frequency and severity of MDS symptoms. Additionally, these study results will contribute to establishing a foundation to develop parent-reported outcomes in MDS.

Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281.

Diagnosis and management of sleep disorders in Prader-Willi syndrome.

Clinical experience and a growing body of evidence suggest that sleep disturbances are common in people with Prader-Willi syndrome (PWS). PWS is a rare neuroendocrine disorder characterized by early hypotonia and feeding difficulties; developmental delays; endocrinopathies; and behavioral concerns, especially rigidity, anxiety, and behavioral outbursts. PWS is also characterized by decreased resting energy expenditure and transition to hyperphagia and obesity. We propose that, for many people with PWS, clinical diagnosis and management of sleep disorders is an unmet need. We present current information to suggest disordered sleep is a significant burden for individuals with PWS and often overlooked. While central and obstructive sleep apnea are more widely recognized in PWS, other sleep disorders have increasingly gained recognition, including hypersomnia, narcolepsy-like phenotypes, and insomnia. Sleep disorders can impact behavior, cognition, and quality of life and health for individuals with PWS. Our goal is to bring sleep disorders to the forefront of therapeutic intervention for patients with PWS. This paper presents a review of the literature and recommendations for clinical practice based on published research and our clinical experience as sleep specialists, geneticists, psychiatrists, pediatricians, otolaryngologists, and pulmonologists with extensive experience with this patient population. We recommend that management of sleep be considered an integral part of successful medical management of PWS. Further research concerning sleep problems in PWS is urgently needed to develop best practices and work toward a consensus statement for medical management to meet the needs of people with PWS. CITATION: Duis J, Pullen LC, Picone M, et al. Diagnosis and management of sleep disorders in Prader-Willi syndrome. J Clin Sleep Med. 2022;18(6):1687-1696.

Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome.

INTRODUCTION: Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5-15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT. METHODS: This 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5-20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow. DISCUSSION: This study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT. TRIAL REGISTRATION: Clinicaltrials.govNCT04181723.

Anthropometric Measures Correspond with Functional Motor Outcomes in Females with Rett Syndrome.

OBJECTIVE: To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. STUDY DESIGN: We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. RESULTS: Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. CONCLUSIONS: The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials.

Characteristic behaviors associated with gait of individuals with Rett syndrome.

BACKGROUND: Individuals with Rett syndrome (RTT) exhibit impaired motor performance and gait performance, leading to decreased quality of life. Currently, there is no robust observational instrument to identify gait characteristics in RTT. Current scales are limited as individuals with intellectual disorders may be unable to understand instructions. Our primary purpose was to utilize video analysis to characterize the behaviors associated with walking in individuals with RTT and explore the relationship between behaviors during overground and during treadmill walking. METHODS: Fourteen independently ambulatory females with RTT were video-taped and observed during overground and treadmill walking. Their gait was codified into an observational checklist to reveal prominent features associated with gait in this population. RESULTS: Participants exhibited similar rates of freezing, veering, and hand stereotypies between overground and treadmill walking; however, freeze duration was shortened during treadmill walking. Toe walking was prominently exhibited during overground, but not treadmill walking. During both walking modes, participants required extensive external motivation to maintain their walking patterns. CONCLUSIONS: Results identify several gait characteristics observable during overground and treadmill walking. In general, participants behaved similarly during overground and treadmill walking. We conclude that both overground and treadmill walking are appropriate tools to evaluate gait in this population.Implications for rehabilitationLocomotor rehabilitation may increase the quantity of walking performed by the patients, which can alleviate negative effects of the sedentary lifestyle commonly observed in patients with Rett syndrome (RTT).Video analysis of natural walking can be an effective tool to characterize gait in patients with RTT which does not require particular instructions which may not be fully understood.Both overground and treadmill walking are appropriate means of evaluating gait in individuals with RTT.

Clinical application of home sleep apnea testing in children: a prospective pilot study.

STUDY OBJECTIVES: (1) To determine the sensitivity and specificity of the home sleep apnea test (HSAT) performed in typically developing children who were diagnosed with moderate to severe obstructive sleep apnea during overnight attended laboratory polysomnography (LPSG). (2) To determine the utility of a screening questionnaire to identify children at increased risk for obstructive sleep apnea. METHODS: Participants completed 2 consecutive study nights, the first night with the HSAT followed by LPSG on the second night. The SHOOTS questionnaire, composed of 6 questions (snoring, hyperactivity, obesity, observed apnea, tonsillar hypertrophy, and sleepiness) concerning sleep-disordered breathing, was administered by the clinician before the first study night. RESULTS: Thirty-eight participants completed both studies. The mean age was 13.8 ± 3.0 years. Twenty (53%) were male. Most participants were obese. The mean LPSG total sleep time was 7.34 ± 1.19 hours; the mean HSAT total recording time was 8.86 ± 1.73 hours (P < .001). The median obstructive apnea-hypopnea index for LPSG and HSAT was 6.6 and 0.8 events/h, respectively. For an obstructive apnea-hypopnea index ≥ 3.1 events/h by HSAT, the sensitivity was 71.43% (95% confidence interval, 41.9-91.6) and the specificity was 95.83% (95% confidence interval, 78.9-99.9) for identifying those with an LPSG obstructive apnea-hypopnea index of ≥ 10 events/h. For a SHOOTS score with ≥ 4 "yes" responses, the sensitivity and specificity were 85.7% (95% confidence interval, 57.2-98.2) and 54.2% (95% confidence interval, 32.8-74.4), respectively, for identifying those with an LPSG obstructive apnea-hypopnea index ≥ 10 events/h. CONCLUSIONS: Using HSAT, we clinically applied cutoff values to identify moderate to severe obstructive sleep apnea in typically developing children. The SHOOTS questionnaire may aid in identifying children at risk for obstructive sleep apnea and who are candidates for HSAT. CITATION: Revana A, Vecchio J, Guffey D, Minard CG, Glaze DG. Clinical application of home sleep apnea testing in children: a prospective pilot study. J Clin Sleep Med. 2022;18(2):533-540.

Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome.

STUDY OBJECTIVES: Excessive daytime sleepiness is common in Prader-Willi syndrome (PWS), with prevalence ranging from 52% to 100%. The goal of this study was to establish the content validity (ie, evidence that an instrument measures an intended concept of interest) of the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a measure of daytime sleepiness, in PWS. METHODS: Qualitative, dyadic semistructured video interviews were conducted with 18 caregivers and their children with PWS from April to June 2020. Concept elicitation and cognitive interview techniques were implemented. Thematic analyses allowed for examination of themes and data patterns. RESULTS: All caregivers (mean age 49 years) were mothers of individuals with PWS who experienced troublesome daytime sleepiness (mean age 14 years). The most prevalent observable signs/symptoms of daytime sleepiness were sleepy/sleepiness (n = 17; 94.4%), tired/tiredness (n = 16; 88.9%), exhaustion/exhausted (n = 5; 27.8%), anxious/stressed (n = 5; 27.8%), irritable/frustrated (n = 5; 27.8%), having tantrums/outbursts (n = 5; 27.8%), and lethargy (n = 4; 22.2%). Daytime sleepiness impacted various aspects of health including mental, emotional, physical, and social well-being. When caregivers were asked about the activities associated with daytime sleepiness, all salient concepts elicited mapped to the ESS-CHAD; saturation was met after the first 4 interviews. Only 2 concepts, after physical exertion and while inactive/bored, did not map. Caregiver statements indicated that these concepts, although related to daytime activities, were atypical of daily routines. The ESS-CHAD was well understood and relevant to caregivers. CONCLUSIONS: This study supports the content validity of the ESS-CHAD and its appropriateness for evaluating treatment efficacy of daytime sleepiness in PWS. CITATION: Patel VP, Patroneva A, Glaze DG, Davis K, Merikle E, Revana A. Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome. J Clin Sleep Med. 2022;18(2):485-496.

Evaluating Sleep Disturbances in Children With Rare Genetic Neurodevelopmental Syndromes.

BACKGROUND: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. METHODS: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. RESULTS: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. CONCLUSIONS: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

Neurology of Sleep.

Healthy sleep, including proper amounts in the 24-hour day/night period, is crucial for developing children. Sleep development in infants and children is characterized by increased amounts of sleep, including rapid eye movement and non-rapid eye movement (NREM) slow-wave sleep. Expected changes as well as deviations may contribute to sleep problems, which are common in typically developing children and very common in those with neurodevelopmental disorders and often are chronic. Periodic screening of children for sleep problems is important for timely and effective management of these.