Clinical Features and Disease Progression in Older Individuals with Rett Syndrome.

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old).

A clinical-translational review of sleep problems in neurodevelopmental disabilities.

Sleep disorders are very common across neurodevelopmental disorders and place a large burden on affected children, adolescents, and their families. Sleep disturbances seem to involve a complex interplay of genetic, neurobiological, and medical/environmental factors in neurodevelopmental disorders. In this review, we discuss animal models of sleep problems and characterize their presence in two single gene disorders, Rett Syndrome, and Angelman Syndrome and two more commonly occurring neurodevelopmental disorders, Down Syndrome, and autism spectrum disorders.

Developmental milestones and daily living skills in individuals with Angelman syndrome.

Background: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz.

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).

Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study.

Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.

Adaptive Skills of Individuals with Angelman Syndrome Assessed Using the Vineland Adaptive Behavior Scales, 2nd Edition.

In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes.

Feasibility of wearable devices and machine learning for sleep classification in children with Rett syndrome: A pilot study.

Sleep is vital to many processes involved in the well-being and health of children; however, it is estimated that 80% of children with Rett syndrome suffer from sleep disorders. Caregiver reports and questionnaires, which are the current method of studying sleep, are prone to observer bias and missed information. Polysomnography is considered the gold standard for sleep analysis but is labor and cost-intensive and limits the frequency of data collection for sleep disorder studies.

Top Caregiver Concerns in Rett syndrome and related disorders: data from the US Natural History Study.

Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) has enabled development of novel therapeutic approaches that are currently undergoing clinical evaluation or are proposed to move into clinical development. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top clinical concerns in order to gain information to guide the development and selection of outcome measures for future clinical trials.

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.

Anxiety in Angelman Syndrome.

Angelman Syndrome (AS) is a neurodevelopmental disorder most commonly caused by the impaired expression of the maternal UBE3A gene on chromosome 15. Though anxiety has been identified as a frequently present characteristic in AS, there are limited studies examining anxiety in this population. Studies of anxiety in other neurodevelopmental disorders have found disorder specific symptoms of anxiety and age specific displays of anxiety symptoms.

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.

Developmental Skills of Individuals with Angelman Syndrome Assessed Using the Bayley-III.

We describe the development of 236 children with Angelman syndrome (AS) using the Bayley Scales of Infant and Toddler Development, Third Edition. Multilevel linear mixed modeling approaches were used to explore differences between molecular subtypes and over time. Individuals with AS continue to make slow gains in development through at least age 12 years of age at about 1-2 months/year based on age equivalent score and 1-16 growth score points/year depending on molecular subtype and domain.

Multisite Study of Evoked Potentials in Rett Syndrome.

Objective: The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments.

Method: Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study.

Phenotypic features in MECP2 duplication syndrome: Effects of age.

Background: MECP2 Duplication syndrome (MDS) is a rare X-linked genomic disorder that is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Although phenotypic features in MDS have been described, there is a limited understanding of the range of severity of these features, and how they evolve with age.

Methods: The cross-sectional results of N = 69 participants (ages 6 months-33 years) enrolled in a natural history study of MDS are presented.

Cortisol profiles and clinical severity in MECP2 duplication syndrome.

Background: MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity.

Evoked Potentials and EEG Analysis in Rett Syndrome and Related Developmental Encephalopathies: Towards a Biomarker for Translational Research.

Rett syndrome is a debilitating neurodevelopmental disorder for which no disease-modifying treatment is available. Fortunately, advances in our understanding of the genetics and pathophysiology of Rett syndrome has led to the development of promising new therapeutics for the condition. Several of these therapeutics are currently being tested in clinical trials with others likely to progress to clinical trials in the coming years.

Comparison of Core Features in Four Developmental Encephalopathies in the Rett Natural History Study.

Objective: Rett syndrome, CDKL5-deficiency disorder, FOXG1 disorder, and MECP2 duplication disorder are developmental encephalopathies with shared and distinct features. Although they are historically linked, no direct comparison has been performed. The first head-to-head comparison of clinical features in these conditions is presented.

A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome.

Background: Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele.

Maladaptive behaviors in individuals with Angelman syndrome.

Maladaptive behaviors are challenging and a source of stress for caregivers of individuals with Angelman Syndrome (AS). There is limited information on how these maladaptive behaviors vary over time among individuals with AS due to different genetic etiologies. In this study, caregivers of 301 individuals with AS were asked questions about their child's behavior and completed the Aberrant Behavior Checklist-Community version (ABC-C).

Characterizing the phenotypic effect of Xq28 duplication size in MECP2 duplication syndrome.

Individuals with methyl CpG binding protein 2 (MECP2) duplication syndrome (MDS) have varying degrees of severity in their mobility, hand use, developmental skills, and susceptibility to infections. In the present study, we examine the relationship between duplication size, gene content, and overall phenotype in MDS using a clinical severity scale. Other genes typically duplicated within Xq28 (eg, GDI1, RAB39B, FLNA) are associated with distinct clinical features independent of MECP2.