Electroencephalographic assessment in patients with Rett syndrome during cognitive stimulation by means of eye tracking technology and alternative and augmentative communication systems.

Rett syndrome (RTT) is considered a rare disease despite being the leading genetic disorder to cause severe intellectual disability in women. There is no cure for RTT, so the treatment is symptomatic and supporting, requiring a multidisciplinary approach. Occupational therapy can help girls and their families to improve communication, being one of the main concerns when verbal language and intentional hand movement are impaired or lost. This paper presents a pilot study of cognitive training through the combined use of eye-tracking technology (ETT) and augmentative and alternative communication (AAC) using the Peabody Picture Vocabulary Test (PPVT-IV). The objective was to evaluate brain activation by means of electroencephalography (EEG) during the stimulation of non-verbal communication. EEG data were recorded during an eyes-open resting state (EO-RS) period and during cognitive stimulation via AAC activity. To assess their effect, both signals were compared at the spectral level, focusing on frequency, brain symmetry and connectivity. During the task, a redistribution of power towards fast frequency bands was observed, as well as an improvement in the brain symmetry index (BSI) and functional synchronicity through increased coherence. Therefore, the results of the spectral analysis showed a possible deviation from the pathological pattern, manifesting a positive effect in the use of non-verbal cognitive stimulation activities. In conclusion, it was observed that it is possible to establish a cognitive training system that produces brain activation and favors communication and learning despite intentional language loss.Clinical Relevance- This manifests a method of cognitive training that would induce brain activation in RTT patients with absence of intentional communication. The evaluation system through spectral analysis could complement the standardized protocols to asses communication that are based on verbal and motor production.

Preliminary assessment of the reliability and validity of infrared skin temperature measurements in Rett syndrome.

BACKGROUND: As clinical trials for Rett syndrome are underway, there is a need to validate potential supplemental outcome measures that reflect important signs and symptoms. Autonomic dysfunction, particularly vasomotor dysfunction, is one potential area for which biomarkers could be developed. METHODS: In the current study, infrared thermal images of hands and feet from 26 females with Rett syndrome (aged 62 months to 39 years), and 17 females without known intellectual, genetic or neurological disorders (aged 55 months to 39 years) were collected. Between-group differences in skin temperature, and temporal stability of skin temperature measures in the Rett syndrome group, and relationships between skin temperature measures and parent-reported and researcher-evaluated indicators of autonomic dysfunction were evaluated. RESULTS: Between-group differences showed lower hand and foot temperatures in the Rett syndrome group. Hand temperature measurements were stable over time and were moderately correlated with parent-reported autonomic symptoms. Foot temperature measurements were more variable than hand temperatures but showed stronger correlations with parent-reported autonomic symptoms. CONCLUSIONS: The results provide preliminary support for the reliability and validity of hand and foot skin temperature measures in Rett syndrome. Additional research is needed to replicate these results and evaluate the temporal stability of these measures over shorter time scales.

A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials.

Rett syndrome (RTT) is a neurodevelopmental disorder that primarily affects females. Recent work indicates the potential for disease modifying therapies. However, there remains a need to develop outcome measures for use in clinical trials. Using data from a natural history study (n = 1,075), we examined the factor structure, internal consistency, and validity of the clinician-reported Motor Behavior Assessment scale (MBA). The analysis resulted in a five-factor model: (1) motor dysfunction, (2) functional skills, (3) social skills, (4) aberrant behavior, and (5) respiratory behaviors. Item Response Theory (IRT) analyses demonstrated that all items had acceptable discrimination. The revised MBA subscales showed a positive relationship with parent reported items, age, and a commonly used measure of clinical severity in RTT, and mutation type. Further work is needed to evaluate this measure longitudinally and to add items related to the RTT phenotype.

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

BACKGROUND: Rett syndrome is a neurodevelopmental disorder with potential for improvement through novel targeted therapeutics. Reliable outcome measures are critical to the development of treatments. We examined the merits and flaws of the Rett Syndrome Behavioural Questionnaire, an outcome measure for clinical trials. METHODS: The Rett Syndrome Behavioural Questionnaire was administered alongside other clinical scales in three cohorts, an online survey, a clinic-based study, and the screening period for a clinical trial. Data were collected from individuals with Rett syndrome and related disorders at three time points, separated by a minimum of one week and a maximum of two months. We hypothesized that for clinical trial use, little change should occur among visits. Distribution statistics, internal consistency, intraclass correlation coefficient, percent agreement, and Cohen's kappa were examined. RESULTS: Among 149 with classic Rett syndrome, the Rett Syndrome Behavioural Questionnaire was completed 377 times. Median total score was 33, ranging from 3 to 73. Of the 51 items tested in the original Rett Syndrome Behavioural Questionnaire study, 24 exhibited either floor or ceiling effects. Friedman's analysis of variance revealed significant difference among visits (P = 0.024), and graphical analysis using Bland-Altman plots demonstrated systematic positive bias with a 95% confidence interval including up to 12.9 points higher to 15.7 points lower at retest. Median agreement measured by kappa was 0.53 for retest at visit 2 and 0.49 for retest at visit 3. CONCLUSIONS: The Rett Syndrome Behavioural Questionnaire did not achieve acceptable standards as an outcome assessment for clinical trials in Rett syndrome.

Prevalence, clinical investigation, and management of gallbladder disease in Rett syndrome.

AIM: This study determined the prevalence of cholelithiasis and/or cholecystectomy in Rett syndrome, described gallbladder function in a clinical cohort, and identified recommendations for assessment and management of gallbladder disease. METHOD: The incidence of cholelithiasis/cholecystectomy was estimated from data describing 270 and 681 individuals with a pathogenic MECP2 mutation in the Australian Rett Syndrome Database and the International Rett Syndrome Phenotype Database respectively. Gallbladder function in 25 females (mean age 16y 5mo, SD 20y 7mo, range 3y 5mo-47y 10mo) with Rett syndrome (RTT) was evaluated with clinical assessment and ultrasound of the gallbladder. The Delphi technique was used to develop assessment and treatment recommendations. RESULTS: The incidence rate for cholelithiasis and/or cholecystectomy was 2.3 (95% confidence interval [CI] 1.1-4.2) and 1.8 (95% CI 1.0-3.0) per 1000 person-years in the Australian and International Databases respectively. The mean contractility index of the gallbladder for the clinical sample was 46.5% (SD 38.3%), smaller than for healthy individuals but similar to children with Down syndrome, despite no clinical symptoms. After excluding gastroesophageal reflux, gallbladder disease should be considered as a cause of abdominal pain in RTT and cholecystectomy recommended if symptomatic. INTERPRETATION: Gallbladder disease is relatively common in RTT and should be considered in the differential diagnosis of abdominal pain in RTT.

Aging in Rett syndrome: a longitudinal study.

Little is known about the aging process of people with specific syndromes, like Rett syndrome (RTT). Recognition of the clinical and behavioral characteristics of the adult RTT is needed in order to improve future management of the RTT girl and counseling of parents. In association with the Dutch RTT parent association, a 5-year longitudinal study was carried out. The study population consisted of 53 adult women with a clinical diagnosis of RTT. Postal questionnaires were sent, including demographic features, skills, physical and psychiatric morbidity. At the time of the second measurement seven women had died. In 2012, 80% of the questionnaires (37/46) were returned. Mean age of the women was 31.4 years. Molecular confirmation was possible for 83% of the women for whom analyses were carried out. The adult RTT woman has a more or less stable condition. The general disorder profile is that of a slow on-going deterioration of gross motor functioning in contrast to a better preserved cognitive functioning, less autonomic and epileptic features and good general health. This is the first longitudinal cohort study about aging in RTT. Continuing longitudinal studies are needed to gain more insight into the aging process in RTT.

Rapid detection of deletions in hotspot C-terminal segment region of MECP2 by routine PCR method: report of two classical Rett syndrome patients of Indian origin.

Rett syndrome (RS) is an X-linked dominant neurodevelopment disorder with normal prenatal and postnatal development till 6-18 months, followed by stagnation and regression of acquired skills. RS primarily manifests in females, and there are a few reports with males having RS. Sporadic or de novo mutations of the methyl CpG binding protein 2 (MECP2) gene have been reported in 70-90% of affected girls. Conventional methods such as fluorescence in situ hybridization, real-time PCR, southern blotting, multiplex ligation-dependent probe amplification, and DNA sequencing have been previously reported for the detection of insertions or deletions in the MECP2 gene. Here, we report detection of two deletions of 44 bp (c.1157_1200del44 or p.L386fs) and 38 bp (c.1151_1188del38 or p.P384fs) in exon 4 or C-terminal segment (CTS) region of MECP2 using a simple PCR technique that is rapid, accurate, and cost effective as compared to other techniques. The deletions were detected by routine PCR amplification followed by 2% agarose gel electrophoresis. We suggest that a simple PCR can easily detect deletions in the hotspot CTS region of the MECP2 gene and can be used for routine molecular diagnostics of RS.

Rare childhood diseases: how should we respond?

Paradoxically, rare diseases are common, collectively affecting 6-10% of the population and have a huge impact on patients and families, health services, clinicians and the wider community. Accurate data are required to inform clinical practice, government policy and health service planning. We recommend a national approach, similar to that adopted in the USA and Europe, to support research and promote advocacy and equitable access to services for children with rare diseases.

Brief report: pilot investigation of service receipt by young children with autistic spectrum disorders.

Whether children with autistic spectrum disorders (ASD) and their families are receiving recommended assessments and services is poorly known. This pilot study examined service receipt as reported by parents of young children with ASD (n = 64) from four specialty centers in Canada. While almost all children had a speech and language assessment (94%), less than half had psychological (42%), or genetic (31%) testing. Speech and language (88%) and occupational (78%) therapies were the most frequently received treatments. Overall, certain findings did not correspond to recent recommended practice guidelines. Future studies should obtain more detailed information on assessments and treatments received from larger and more representative samples to better determine the quality of care received by families with children with ASD.

Characteristics of children with autism spectrum disorders who received services through community mental health centers.

Despite the presence of significant psychiatric comorbidity among children with autism spectrum disorders (ASDs), little research exists on those who receive community-based mental health services. This project examined one year (2004) of data from the database maintained by 26 community mental health centers (CMHCs) in the Midwestern US state of Kansas. Children with autism were compared to children with other ASDs - Asperger's disorder, Rett's disorder, and PDD-NOS. Children with autism predictably received more special education services than children with other ASDs, while the latter were more likely to have experienced prior psychiatric hospitalization. Children with ASDs other than autism were also significantly more likely to be diagnosed with attention deficit hyperactivity disorder, oppositional defiant disorder, depressive disorders, and bipolar disorder. In 2004, Kansas CMHCs served less than 15 percent of the children estimated to have an ASD. Implications of these findings are discussed.

Community introduction of practice parameters for autistic spectrum disorders: Advancing early recognition.

OBJECTIVES: Within a strong interdisciplinary framework, improvement in the quality of care for children with autistic spectrum disorders through a 2 year implementation program of Practice Parameters, aimed principally at improving early detection and intervention. METHOD: We developed Practice Parameters (PPs) for Pervasive Developmental Disorders and circulated the PPs to all child and adolescent psychiatrists practicing in the region. RESULTS: PP development and parallel information strategies resulted in a significant decrease of 1.5 years in the mean-age-at-diagnosis. However, further analysis indicated that improvement was only transient. CONCLUSION: Despite the encouraging improvement in mean-age-at-diagnosis 2 years after PP implementation, other indicators showed a failure to maintain the improvements. A systematic screening program would be the most reliable method to reinforce the PPs.

[Rett syndrome: individual differences in developmental and behavioral markers and psychosocial stress]. / Rett-Syndrom: Individuelle Variabilität in Entwicklungs- und Verhaltensmerkmalen und psychosoziale Belastung.

OBJECTIVES: Rett Syndrome is a severe neurological developmental disorder caused by a genetic mutation on the long arm of the X chromosome (Xq28). This disorder is characterized by a loss of purposeful hand use, verbal language, and specific behaviors. METHODS: Data were obtained from a survey of the parents of 83 girls on pre-verbal skills (Pre-verbal Communication Schedule), behavioral characteristics and emotional expression (Rett Syndrome Behaviour Questionnaire) and on maternal psychosocial stress (Handicap-related Problems for Parents Inventory). RESULTS: There is considerable individual variability in the developmental and behavioral characteristics which is not explained as a function of age. Maternal stress correlates with the daughters' mood, anxious reactions and night-time behaviors. CONCLUSIONS: Some implications for diagnosis and family counseling are discussed.