Insights into Rett Syndrome girls' receptive vocabulary through eye movements and parental perception.

OBJECTIVE: This study evaluated the receptive vocabulary of girls diagnosed with Rett Syndrome (RS) by employing eye-tracking technology and examined how these objective measures compared with parents' perceptions of their daughters' language abilities. METHOD: Fourteen girls with RS and eleven typically developing peers participated. Instruments included the Kerr Scale, a parental questionnaire on communication skills, the Peabody Picture Vocabulary Test - PPVT-4, and eye-tracking equipment. The PPVT-4's initial 12 cards, each displaying four images, were presented on screen for 5 s for the child's initial inspection. Subsequently, the same card was shown for 5 s with instructions to identify the picture matching the word, repeated three times in a randomized order. RESULTS: Eye-tracking assessments revealed that girls with RS with less severe symptoms, performed below typically developing peers with aged 3-4 years. The number of eye fixations emerged as a reliable metric for assessing their performance. A positive correlation was found between parental reports of their daughters' vocabulary knowledge and their ability to identify the correct stimulus, suggesting comprehension and active engagement in the testing process. CONCLUSION: This study presents a pioneering approach by combining parental perceptions with eye-tracking measures to assess receptive vocabulary in girls diagnosed with Rett Syndrome. Despite showing lower performance levels compared to significantly younger peers, the findings suggest that these individuals use less effectively eye contact as a mode of communication.

Psychological aspects of being a parent of an individual with Rett syndrome: A scoping review.

BACKGROUND: Rett syndrome (RTT) causes multiple disabilities with a lifelong need for substantial care, placing a tremendous lifelong responsibility on the parents. Parenting an individual with RTT can therefore be challenging. Research on the psychological aspects of parenting individuals with RTT is limited and unclear. We aimed to identify and map the existing literature on this subject. METHOD: A scoping review was conducted with systematic searches in PubMed, PsycINFO and CINAHL. RESULTS: Eighteen studies were included. Negative and positive psychological aspects were described with the majority focusing on the negative. Three factors seemed to especially affect the parents: severity of the diagnosis, time (increasing age of parents or individual with RTT; years of caretaking), work-status of the mother. CONCLUSIONS: Seemingly, parents are highly affected; however, the literature is scarce and has several gaps. Future research should include older parents, fathers, parents of individuals living in group homes, and positive aspects.

HDAC inhibitor ameliorates behavioral deficits in Mecp2308/y mouse model of Rett syndrome.

Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder. More than 95% of classic RETT syndrome cases result from pathogenic variants in the methyl-CpG binding protein 2 (MECP2) gene. Nevertheless, it has been established that a spectrum of neuropsychiatric phenotypes is associated with MECP2 variants in both females and males. We previously reported that microtubule growth velocity and vesicle transport directionality are altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared to that of their wild-type littermates suggesting deficit in microtubule dynamics. In this study, we report that administration of tubastatin A, a selective HDAC6 inhibitor, restored microtubule dynamics in Mecp2-deficient astrocytes. We furthermore report that daily doses of tubastatin A reversed early impaired exploratory behavior in male Mecp2308/y mice. These findings are a first step toward the validation of a novel treatment for RTT.

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway.

Patients with Rett syndrome (RTT) show severe difficulties with communication, social withdrawl, and learning. Music-based interventions improve social interaction, communication skills, eye contact, and physical skills and reduce seizure frequency in patients with RTT. This study aimed to investigate the mechanism by which music-based interventions compromise sociability impairments in mecp2 null/y mice as an experimental RTT model. Male mecp2 null/y mice and wild-type mice (24 days old) were randomly divided into control, noise, and music-based intervention groups. Mice were exposed to music or noise for 6 h/day for 3 consecutive weeks. Behavioral patterns, including anxiety, spontaneous exploration, and sociability, were characterized using open-field and three-chamber tests. BDNF, TrkB receptor motif, and FNDC5 expression in the prefrontal cortex (PFC), hippocampus, basal ganglia, and amygdala were probed using RT-PCR or immunoblotting. mecp2 null/y mice showed less locomotion in an open field than wild-type mice. The social novelty rather than the sociability of these animals increased following a music-based intervention, suggesting that music influenced the mecp2-deletion-induced social interaction repression rather than motor deficit. Mechanically, the loss of BDNF signaling in the prefrontal cortex and hippocampal regions, but not in the basal ganglia and amygdala, was compromised following the music-based intervention in mecp2 null/y mice, whereas TrkB signaling was not significantly changed in either region. FNDC5 expression in the prefrontal cortex region in mecp2 null/y mice also increased following the music-based intervention. Collective evidence reveals that music-based interventions improve mecp2-loss-induced social dysfunction. BDNF and FNDC5 signaling in the prefrontal cortex region mediates the music-based-intervention promotion of social interactions. This study gives new insight into the mechanisms underlying the improvement of social behaviors in mice suffering from experimental Rett syndrome following a music-based intervention.

The DNA repair protein ATM as a target in autism spectrum disorder.

Impairment of the GABAergic system has been reported in epilepsy, autism, attention deficit hyperactivity disorder, and schizophrenia. We recently demonstrated that ataxia telangiectasia mutated (ATM) directly shapes the development of the GABAergic system. Here, we show for the first time to our knowledge how the abnormal expression of ATM affects the pathological condition of autism. We exploited 2 different animal models of autism, the methyl CpG binding protein 2-null (Mecp2y/-) mouse model of Rett syndrome and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, treatment with the specific ATM kinase inhibitor KU55933 (KU) normalized molecular, functional, and behavioral defects in these mouse models, such as (a) delayed GABAergic development, (b) hippocampal hyperexcitability, (c) low cognitive performances, and (d) social impairments. Mechanistically, we demonstrate that KU administration to WT hippocampal neurons leads to (a) higher early growth response 4 activity on Kcc2b promoter, (b) increased expression of Mecp2, and (c) potentiated GABA transmission. These results provide evidence and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders.

Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome.

PURPOSE: To investigate walking ability in Japanese patients with Rett syndrome (RTT). METHODS: Walking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database. RESULTS: Univariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X. CONCLUSIONS: Meaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.

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.

Special Education Supports and Services for Rett Syndrome: Parent Perceptions and Satisfaction.

There are no published studies describing educational experiences for girls with Rett syndrome. Given the extensive educational needs associated with Rett syndrome, it is important to understand how families perceive their daughters' educational experiences to inform education service provision. The purpose of this study was to survey parents of school-aged children with Rett syndrome to describe the educational services that they receive and understand parents' perceptions of and satisfaction with the special educational and related services. The majority of parents were satisfied with their daughters' educational services. Communication was the most frequently endorsed priority skill area, and many parents expressed frustration with limited access to augmentative and alternative communication (AAC) devices and staff training in their use. These results suggest there is a need for high-quality speech therapy and an emphasis on AAC support.

Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients.

Neurodevelopmental spectrum disorders like autism (ASD) are diagnosed, on average, beyond age 4 y, after multiple critical periods of brain development close and behavioral intervention becomes less effective. This raises the urgent need for quantitative, noninvasive, and translational biomarkers for their early detection and tracking. We found that both idiopathic (BTBR) and genetic (CDKL5- and MeCP2-deficient) mouse models of ASD display an early, impaired cholinergic neuromodulation as reflected in altered spontaneous pupil fluctuations. Abnormalities were already present before the onset of symptoms and were rescued by the selective expression of MeCP2 in cholinergic circuits. Hence, we trained a neural network (ConvNetACh) to recognize, with 97% accuracy, patterns of these arousal fluctuations in mice with enhanced cholinergic sensitivity (LYNX1-deficient). ConvNetACh then successfully detected impairments in all ASD mouse models tested except in MeCP2-rescued mice. By retraining only the last layers of ConvNetACh with heart rate variation data (a similar proxy of arousal) directly from Rett syndrome patients, we generated ConvNetPatients, a neural network capable of distinguishing them from typically developing subjects. Even with small cohorts of rare patients, our approach exhibited significant accuracy before (80% in the first and second year of life) and into regression (88% in stage III patients). Thus, transfer learning across species and modalities establishes spontaneous arousal fluctuations combined with deep learning as a robust noninvasive, quantitative, and sensitive translational biomarker for the rapid and early detection of neurodevelopmental disorders before major symptom onset.

Rett syndrome: Teenagers' and young adults' activities, usage of time and responses during an ordinary week - a diary study.

Background: Little is known about the everyday life of individuals with Rett syndrome.Aim/Objective: To describe ten participants' (teenagers/young adults) activities during a period of seven days, the time-use, where and with whom the activities were performed and the participants' responses in the form of visible/audible reactions during activities.Material and method: A time-geographic self-administered diary was filled in by 63 informants (parents/support staff) and analysed using the software, DAILY LIFE 2011.Results/Findings: The most frequently reported activities were hygiene/toilet, moving around indoors, eating and getting dressed. Most time was spent in sleeping, daily care, medical health care and travel/transportation. Little time remained for receptive activities, daytime rest, physical, social/creative, communication, school/daily work and domestic chore activities, especially for the young adults. Most time was spent with staff, thereafter with families and the least time was spent with friends. The most reported response was "interested", and "opposed" was the least reported.Conclusions: Daily and medical health care activities were time consuming. Improved communication between all parties may increase participation and well-being and provide solutions for handling unpleasant activities and sedentary time.Significance: A more varied range of activities may improve the everyday life for individuals with Rett syndrome.

Caregiver- and Clinician-Reported Adaptive Functioning in Rett Syndrome: a Systematic Review and Evaluation of Measurement Strategies.

Rett syndrome is the second most common cause of intellectual disability in females worldwide. The severity of many individuals' impairment limits the effectiveness of traditional assessment. However, clinician and parent reports of adaptive functioning may provide insight into these patients' abilities. This review aims to synthesize the current literature assessing adaptive functioning in Rett syndrome and evaluate existing measurement tools in this population. A search was conducted on PubMed using the search term "Rett syndrome." Studies that quantitatively assessed adaptive functioning outcomes in Rett syndrome with published and normed questionnaire measures were included. Twenty-three studies met inclusion criteria. Overall results indicate that the population of people with Rett syndrome is highly impaired, both in overall adaptive functioning as well as in specific subdomains (e.g., mobility, activities of daily living). Atypical Rett syndrome groups performed better on measures of adaptive functioning relative to patients with classic Rett syndrome. Our findings identified measurement weaknesses, as many of the studies found floor effects and therefore were unable to capture meaningful variability in outcomes. Individuals with Rett syndrome are highly reliant on caregivers due to disrupted adaptive functioning abilities. Optimizing measurement of adaptive skills in Rett syndrome will facilitate the quantification of meaningful change in skills and the identification of efficacious interventions aimed at improving outcomes and quality of life.

The psychopharmacology of autism spectrum disorder and Rett syndrome.

Autism spectrum disorder (ASD) appears in early childhood and is characterized by persistent deficits in communication and social interaction, as well as restricted interests, repetitive behaviors, and unusual sensory issues. ASD can be idiopathic or syndromic, in the latter case representing one of the many manifestations of a genetic disorder, such as Rett syndrome. Psychopharmacology cannot directly ameliorate core autistic symptoms, but rather aims at treating comorbid disorders, such as ADHD, sleep disturbances, psychomotor agitation and aggressiveness, seizures, and anxiety. Until the 1990s, it was mainly based on typical neuroleptics and tricyclic antidepressants, whereas second-generation antipsychotics later became first-line drugs for these same indications. In general, selective serotonin reuptake inhibitors have not proven effective in ASD patients. Psychostimulants are frequently prescribed, but display modest efficacy and enhanced potential for side effects and noncompliance. Targeted patients benefit from mood stabilizers and antiepileptic drugs. Experimental drug treatments for ASD include oxytocin and vasopressin, bumetanide, sulforaphane, nutritional supplements, memantine, and d-cycloserine. Work performed on syndromic forms, represents an important source of information for experimental therapies of ASD and knowledge of the unique mechanisms underlying autism in each individual patient may in the future pave the path to personalized drug treatments.

The effectiveness of music therapy for individuals with Rett syndrome and their families.

BACKGROUND: Patients with Rett syndrome (RTT) present characteristic regression in communication and hand skills, which eventually leads to intellectual and physical disability. Moreover, caregivers of patients with RTT face stressors related to patients' medical and developmental concerns. Given the indications from case reports, this pilot study investigated the effectiveness of music therapy on RTT patients, as well as on parental stress for families of children with RTT. METHODS: Families in the study group were enrolled in a twice-weekly 120-minute music therapy program for 24 weeks (n = 11), whereas families in the control group did not receive music therapy (n = 12). Participants were administered the Vineland Adaptive Behavior Scales, Rett Syndrome Clinical Severity Scale, Rett Syndrome Motor Behavioral Assessment, and Parenting Stress Index for caregivers of RTT children before and after the music therapy program. RESULTS: Music therapy improved receptive language, verbal and non-verbal communication skills, and social interaction for RTT patients. In addition, purposeful hand function, breathing patterns, and eye contact were significantly improved. Of note, music therapy also decreased the frequency of epileptic seizures. Lastly, caregivers in the study group exhibited significantly lower stress following the program. CONCLUSION: The 24-week music therapy program was effective in improving social interaction, communication skills, eye contact, hand function, and reducing seizure frequency among RTT patients. Additionally, music therapy was effective in relieving parenting stress, which may help healthcare providers initiate early intervention strategies that can prevent parenting stress and reduce the risk of depression.

Attentional shifting and disengagement in Rett syndrome.

OBJECTIVE: The purpose of the present study was to deepen our understanding of attention (a core cognitive ability) in Rett syndrome (RTT), an x-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. We focused on 2 key aspects of visual orienting-shifting and disengaging attention-both of which are critical for exploring the visual world. We used gaze-based measures and eye-tracking technology to minimize demands on the limited verbal and motor abilities associated with RTT. METHOD: Shifting and disengaging attention were examined in 31 children (2-12 years) with Rett Syndrome (RTT) and 31 age-matched typically developing (TD) controls. Using the gap-overlap paradigm, the frequency and speed of shifting attention from a central to peripheral target were compared on Baseline trials, where the central stimulus disappears as the peripheral target appears, and Overlap trials, where the central stimulus remains, thus requiring disengagement. RESULTS: Our findings revealed that children with RTT had more "sticky fixations" (p < .001). That is, they had fewer saccades to the peripheral target than TD children, and this was true on both baseline (77% vs. 95%), and overlap trials (63% vs. 90%). The younger children in the RTT group also had slower saccadic RTs (SRTs) than their TD counterparts (p = .04). Within the RTT group, SRTs correlated with symptom severity. Surprisingly, disengagement cost (the relative difference between gap and overlap SRTs) did not differ across groups. CONCLUSION: Our results suggest that children with Rett have difficulty shifting attention and, to a lesser extent, disengaging attention, whereas with other disorders, problems with disengagement are paramount. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Patterns of sedentary time and ambulatory physical activity in a Danish population of girls and women with Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a rare neurodevelopmental disorder leading to multiple disabilities and high dependency on caregivers. This study aimed to: (1) describe the patterns of sedentary time and daily steps and (2) identify the association of individual and environmental characteristics with sedentary time. METHODS: All Danish females with RTT older than 5 years of age and with a MECP2 mutation were invited to participate. The activPAL and StepWatch Activity Monitor (SAM) were worn by participants for at least four days. Sedentary time and step counts were plotted by time to examine daily activity patterns. Associations between sedentary time and individual and environmental covariates were assessed with linear regression models. RESULTS: The median (interquartile range) age of participants was 22.0 (14.3-36.5) years. On average 83.3% (standard deviation 13.9%) of waking hours were spent in sedentary behaviours (n = 48) and the median (interquartile range) daily step count was 5128 (2829-7704) (n = 28). Females older than 33.5 years, and those unable to walk independently were more sedentary. CONCLUSIONS: This study demonstrated high levels of sedentary time and low daily step counts in a Danish population of females with RTT. Advancing age and lower walking skills were associated with higher levels of sedentary time. Implications for Rehabilitation Sedentary lifestyles in individuals with disabilities have a negative impact on health and quality of life. High levels of sedentary time and low daily step counts were demonstrated in a Danish population of females with Rett syndrome. Advancing age and inability to walk independently were strongly associated with higher levels of sedentary time in females with Rett syndrome. Understanding patterns of sedentary behaviour and physical activity can aid health care professionals in developing health-promoting physical activity interventions.

Behavioral profiles in Rett syndrome: Data from the natural history study.

INTRODUCTION: Rett syndrome (RTT) is a complex neurodevelopmental disorder with known behavioral abnormalities, both internalizing (e.g., anxiety, social withdrawal) and externalizing (e.g., aggression, self-abuse). However, a broad evaluation of behavioral abnormalities in a large cohort is lacking. OBJECTIVE: In this report, we describe profiles of internalizing and externalizing behaviors in individuals evaluated in the multi-center U.S. Rett Natural History Study. METHODS: Cross-sectional and longitudinal data were collected from 861 females with RTT and from 48 females who have MECP2 mutations without meeting criteria for RTT. Standard statistical methods including linear regression evaluated internalizing behavioral components from the Child Health Questionnaire (CHQ-PF50) and externalizing components from the Motor Behavioral Assessment (MBA). RESULTS: We found mildly to moderately severe internalizing behaviors in nearly all individuals with RTT, while externalizing behaviors were mild and uncommon. Internalizing behavior in RTT was comparable to groups with psychiatric disorders. Participants with mixed (internalizing and externalizing) behaviors were younger and less affected overall, but showed prominent self-injury and worsening internalizing behaviors over time. CONCLUSIONS: This study revealed that internalizing behaviors are common at a clinically significant level in RTT. Understanding clinical features associated with behavioral profiles could guide treatment strategies.

Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome.

Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.

Facilitators and Barriers of Participation in "Uptime" Activities in Girls and Women With Rett Syndrome: Perspectives From Parents and Professionals.

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually affecting females. It is associated with intellectual and multiple disabilities leading to a high level of dependency in all aspects of daily living including participation in physical activities. This study explored facilitators and barriers to "uptime" (non-sedentary) activities in Danish girls and women with RTT as perceived by parents and professionals using focus groups. Through thematic analysis, one central theme emerged: a constant balance to do the best thing for the girl or woman. Within the central theme, five subthemes of facilitators and barriers were identified relating to the individual and the physical, organizational, social, and attitudinal environments. Environmental barriers can be reduced through policy and management-level changes in health promotion and strong advocacy of physical activity by health professionals. Targeting both facilitators and barriers of "uptime" activities enables the planning and implementing of health-promoting interventions in individuals with RTT.

Longitudinal effects of caregiving on parental well-being: the example of Rett syndrome, a severe neurological disorder.

Little longitudinal research has examined parental well-being in those with a child with specific genetic developmental disorder although the associated severe neurological impairments and multiple physical comorbidities likely place substantial burden of caregiving on the parent. We aimed to examine longitudinally the well-being of parents of individuals included in the Australian Rett Syndrome Database over the period from 2002 to 2011 using the Short Form 12 Health Survey. Residential remoteness, the child being a teenager at baseline, having frequent sleep disturbances or behavioural problems, and the type of MECP2 gene mutation were each associated with later poorer parental physical well-being scores. Being a single parent or on a low income was also associated with later poorer physical well-being, while the child having enteral feeding was associated with later poorer emotional well-being. Both the physical and emotional well-being of the parent improved if the child was living in out-of-home care. Our findings suggest that some opportunities do exist for clinicians to help optimise parental well-being. Being alert to the possibility and need for management of a child's sleep or emotional disturbance is important as is awareness of the additional likely parental burden as the child moves through adolescence into early adulthood and their need for additional support at that time. However, the findings also highlight the complex nature of parental well-being over time in parents of children with a severe neurological disorder and how they may be affected by a range of inter-related family and child factors.