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Journal of Psychiatric Research Jun 2021Rett syndrome (RTT) is a severe genetic neurodevelopmental disorder. Emotional, Behavioural and Autonomic Dysregulation (EBAD), is frequent in RTT and is associated with...
BACKGROUND
Rett syndrome (RTT) is a severe genetic neurodevelopmental disorder. Emotional, Behavioural and Autonomic Dysregulation (EBAD), is frequent in RTT and is associated with multiple impairments. There are major challenges in the clinical assessment of emotions, behaviours, and autonomic function in RTT patients that limit the management of symptoms.
METHODS
Web-based technology (HealthTracker™) to measure the phenotype, and non-invasive, wearable sensor technology to evaluate autonomic function through Electrodermal Activity (EDA) and Heart Rate Variability (HRV) in 10 RTT patients was used, and treatment response of EBAD symptoms was monitored after different pharmacological treatments.
RESULTS
and discussion: 4 patients received buspirone, 2 sertraline, 1 gabapentin and 3 were not started on medications. Buspirone normalized the EDA in 3 patients with associated improvement in EBAD, whilst another patient only improved marginally. Both patients treated with sertraline (including one with normal EDA) significantly improved symptomatically. The patients on unchanged regimens showed no change in symptoms and autonomic function. Within 24 h of our assessment, one patient required intensive inpatient care due to septicaemia - this patient had been on gabapentin and showed a sharp and sustained EDA increase without obvious worsening of emotional and behavioural symptoms. Unlike the EDA, the analyses of HRV metrics did not reveal patterns that were associated with clinical outcomes. Our findings suggest a reasonable association of EDA normalization and symptomatic improvement in RTT subjects with EBAD treated with buspirone and point out its potential application as a measure of dysautonomia in RTT. Very high and sustained EDA levels may be a biomarker for concurrent serious physical illness in RTT.
Topics: Emotions; Heart Rate; Humans; Primary Dysautonomias; Rett Syndrome; Technology; Wearable Electronic Devices
PubMed: 33862302
DOI: 10.1016/j.jpsychires.2021.03.052 -
Cell Oct 2016This year marks the 50 anniversary of the publication of Andreas Rett's report on 22 girls who developed a peculiar and devastating neurological disorder that later came...
This year marks the 50 anniversary of the publication of Andreas Rett's report on 22 girls who developed a peculiar and devastating neurological disorder that later came to bear his name. On this occasion, we reflect on the progress that has occurred in understanding Rett Syndrome, development of potential treatments, and the ramifications that Rett research has had on the fields of neurobiology and genetics.
Topics: Child; Female; History, 20th Century; Humans; Methyl-CpG-Binding Protein 2; Mutation; Neurobiology; Phenotype; Rett Syndrome
PubMed: 27716498
DOI: 10.1016/j.cell.2016.09.039 -
Brain Research Feb 2020There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive neurodevelopmental disorder caused by mutations in the transcriptional... (Review)
Review
There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. Because MECP2 is subjected to X-inactivation, most affected individuals are female heterozygotes who display cellular mosaicism for normal and mutant MECP2. Males who are hemizygous for mutant MECP2 are more severely affected than heterozygous females and rarely survive. Mecp2 loss-of-function is less severe in mice, however, and male hemizygous null mice not only survive until adulthood, they have been the most commonly studied model system. Although heterozygous female mice better recapitulate human RTT, they have not been as thoroughly characterized. This is likely because of the added experimental challenges that they present, including delayed and more variable phenotypic progression and cellular mosaicism due to X-inactivation. In this review, we compare phenotypes of Mecp2 heterozygous female mice and male hemizygous null mouse models. Further, we discuss the complexities that arise from the many cell-type and tissue-type specific roles of MeCP2, as well as the combination of cell-autonomous and non-cell-autonomous disruptions that result from Mecp2 loss-of-function. This is of particular importance in the context of the female heterozygous brain, composed of a mixture of MeCP2+ and MeCP2- cells, the ratio of which can alter RTT phenotypes in the case of skewed X-inactivation. The goal of this review is to provide a clearer understanding of the pathophysiological differences between the mouse models, which is an essential consideration in the design of future pre-clinical studies.
Topics: Animals; Disease Models, Animal; Female; Male; Methyl-CpG-Binding Protein 2; Mice; Mosaicism; Mutation; Phenotype; Rett Syndrome; Sex Characteristics
PubMed: 31904347
DOI: 10.1016/j.brainres.2019.146644 -
Seizure Oct 2011To investigate the association between genotype (methyl-CpG-binding protein 2 (MECP2 gene mutation)) and epileptic seizure phenotype in Rett syndrome. (Comparative Study)
Comparative Study
PURPOSE
To investigate the association between genotype (methyl-CpG-binding protein 2 (MECP2 gene mutation)) and epileptic seizure phenotype in Rett syndrome.
METHODS
We used the British Isles Rett syndrome survey to identify 137 subjects with one of the nine most frequent MECP2 gene mutations and invited their parents or carers to participate in a postal questionnaire and telephone interview. The questionnaire recorded information about epileptic seizure types, non-epileptic vacant spells and treatments. Two investigators conducted telephone interviews and three epileptologists classified their epileptic seizures.
RESULTS
89 subjects (65%) responded. The epilepsy prevalence was 67%, and 74% had non-epileptic vacant spells. The epilepsy prevalence within specific genotypes ranged from 47% (mutation C-terminal deletion, downstream of the Transcription Repression Domain) to 100% (mutation p.R270X, c.808C>T). The prevalence of non-epileptic vacant spells within genotypes ranged from 50% (mutation p.R306C, c.916C>T) to 100% (mutation p.R106W, c.316C>T). The epileptologists differed considerably in their classification of events, particularly of non-epileptic vacant spells.
CONCLUSIONS
The large majority of people with Rett syndrome have epilepsy. Most have multiple epileptic seizure types, although generalised tonic-clonic seizures are the most common. There were no significant clinical differences between genotypes. The clinical differentiation of non-epileptic vacant spells is difficult. Discordance in epileptic seizure classification between clinicians suggests that caution is needed, since the clinical history alone cannot adequately classify the epileptic seizure type in Rett syndrome.
Topics: Adolescent; Adult; Child; Child, Preschool; Epilepsy; Female; Genotype; Humans; Phenotype; Prevalence; Rett Syndrome; Young Adult
PubMed: 21764336
DOI: 10.1016/j.seizure.2011.06.010 -
Journal of Intellectual Disability... Apr 2023As clinical trials for Rett syndrome are underway, there is a need to validate potential supplemental outcome measures that reflect important signs and symptoms....
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.
Topics: Female; Humans; Rett Syndrome; Skin Temperature; Reproducibility of Results; Foot; Hand
PubMed: 36744445
DOI: 10.1111/jir.13010 -
Neurobiology of Learning and Memory Nov 2019Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental... (Review)
Review
Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and breathing abnormality. Despite being a monogenic disorder, the pathogenic mechanisms by which mutations in MeCP2 impair neuronal function and underlie the RTT symptoms have been challenging to elucidate. The seemingly simple genetic root and the availability of genetic data from RTT patients have led to the generation and characterization of a series of mouse models recapitulating RTT-associated genetic mutations. This review focuses on the studies of RTT mouse models and describe newly obtained pathogenic insights from these studies. We also highlight the potential of studying pathophysiology using genetics-based modeling approaches in rodents and suggest a future direction to tackle the pathophysiology of intellectual disability with known or complex genetic causes.
Topics: Animals; Disease Models, Animal; Humans; Intellectual Disability; Mice; Rett Syndrome
PubMed: 30447288
DOI: 10.1016/j.nlm.2018.11.006 -
Pediatric Neurology May 2016Rett syndrome is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of Rett syndrome are known to impact...
OBJECTIVE
Rett syndrome is a severe neurodevelopmental disorder affecting approximately one in 10,000 female births. The clinical features of Rett syndrome are known to impact both patients' and caretakers' quality of life in Rett syndrome. We hypothesized that more severe clinical features would negatively impact caretaker physical quality of life but would positively impact caretaker mental quality of life.
METHODS
Participants were individuals enrolled in the Rett Natural History Study with a diagnosis of classic Rett syndrome. Demographic data, clinical disease features, caretaker quality of life, and measures of family function were assessed during clinic visits. The Optum SF-36v2 Health Survey was used to assess caretaker physical and mental quality of life (higher scores indicate better quality of life). Descriptive, univariate, and multivariate analyses were used to characterize relationships between child and caretaker characteristics and caretaker quality of life.
RESULTS
Caretaker physical component scores (PCS) were higher than mental component scores (MCS): 52.8 (9.7) vs 44.5 (12.1). No differences were demonstrated between the baseline and 5-year follow-up. In univariate analyses, disease severity was associated with poorer PCS (P = 0.006) and improved MCS (P = 0.003). Feeding problems were associated with poorer PCS (P = 0.007) and poorer MCS (P = 0.018). In multivariate analyses, limitations in caretaker personal time and home conflict adversely affected PCS. Feeding problems adversely impacted MCS.
CONCLUSIONS
Caretaker quality of life in Rett syndrome is similar to that for caretakers in other chronic diseases. Disease characteristics significantly impact quality of life, and feeding difficulties may represent an important clinical target for improving both child and caretaker quality of life. The stability of quality-of-life scores between baseline and five years adds important value.
Topics: Adolescent; Adult; Caregivers; Child; Child, Preschool; Chronic Disease; Family; Female; Follow-Up Studies; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Quality of Life; Rett Syndrome; Severity of Illness Index
PubMed: 26995066
DOI: 10.1016/j.pediatrneurol.2015.12.021 -
American Journal of Medical Genetics.... Jun 2017Rett syndrome (RTT) is caused by MECP2 mutations, resulting in various neurological symptoms. Prolonged corrected QT interval (QTc) is also reported and is a speculated...
Rett syndrome (RTT) is caused by MECP2 mutations, resulting in various neurological symptoms. Prolonged corrected QT interval (QTc) is also reported and is a speculated cause of sudden death in RTT. The purpose of this study was to correlate QTc in RTT patients with age, clinical severity, and genotype. 100 RTT patients (98 females, 2 males) with MECP2 mutations underwent baseline neurological evaluation (KKI-RTT Severity Scale) and QTc measurement (standard 12 lead electrocardiogram) as part of our prospective natural history study. Mean QTc of the cohort was 422.6 msec, which did not exceed the normal values for age. 7/100 patients (7%) had QTc prolongation (>450 msec). There was a trend for increasing QTc with age and clinical severity (P = 0.09). No patients with R106C, R106W, R133C, R168*, R270*, R294*, R306C, R306H, and R306P mutations demonstrated QTc prolongation. There was a relatively high proportion of QTc prolongation in patients with R255* mutations (2/8, 25%) and large deletions (1/4, 25%). The overall presence of QTc prolongation did not correlate with mutation category (P = 0.52). Our findings demonstrate that in RTT, the prevalence of QTc prolongation is lower than previously reported. Hence, all RTT patients warrant baseline ECG; if QTc is prolonged, then cardiac followup is warranted. If initial QTc is normal, then annual ECGs, particularly in younger patients, may not be necessary. However, larger sample sizes are needed to solidify the association between QTc and age and clinical severity. The biological and clinical significance of mild QTc prolongation above the normative data remains undetermined.
Topics: Adolescent; Age Factors; Child; Child, Preschool; Death, Sudden, Cardiac; Electrocardiography; Female; Genotype; Heart Conduction System; Humans; Infant; Male; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome
PubMed: 28394409
DOI: 10.1002/ajmg.a.38191 -
Developmental Medicine and Child... Aug 2020To summarize existing interventions and their outcomes in Rett syndrome (RTT) rehabilitation and identify gaps in the literature. (Review)
Review
AIM
To summarize existing interventions and their outcomes in Rett syndrome (RTT) rehabilitation and identify gaps in the literature.
METHOD
Five databases (Ovid MEDLINE, Ovid Embase Classic, Ovid PsycINFO, EBSCO CINAHL Plus, and ProQuest ERIC) were systematically searched up to 23rd July 2018 for studies describing rehabilitation interventions. Data on study participants, design, and outcomes were extracted.
RESULTS
Sixty-two articles were included in the final review. Evidence consistently demonstrated that females with RTT can improve their gross motor, fine motor, and communicative skills with rehabilitation. All 11 interventions targeting gross motor function, namely ambulation, achieved functional improvements. Twenty of 24 articles describing fine motor rehabilitation studies succeeded in decreasing stereotypies, improving functional hand use, and/or reducing self-injurious behaviors. Twenty-one of 22 studies describing communication interventions succeeded in training choice-making, communicative language, or socialization behavior. Other key findings include the positive interplay between physical and communicative rehabilitation outcomes, and the ability of females with RTT to improve their cognitive abilities during intervention.
INTERPRETATION
Rehabilitation can impact the daily lives of females with RTT and their caregivers in clinically meaningful ways.
Topics: Humans; Quality of Life; Recovery of Function; Rett Syndrome; Treatment Outcome
PubMed: 32472972
DOI: 10.1111/dmcn.14565 -
Revista Brasileira de Psiquiatria (Sao... Jun 2003This article is focus on the currently knowledge about Rett syndrome, based on the more recent information in the international literature on genetic and epidemiological... (Review)
Review
This article is focus on the currently knowledge about Rett syndrome, based on the more recent information in the international literature on genetic and epidemiological aspects of this condition, as well as on its clinical and laboratory diagnosis, neuropathology, electrophysiology. and clinical outcome (epilepsy, respiratory disorders, autonomic disturbances and nutritional aspects). Although it has been known as a female condition, nowadays it is described the possibility of affected males with a different phenotype.
Topics: Female; Humans; Male; Rett Syndrome
PubMed: 12975709
DOI: 10.1590/s1516-44462003000200012