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Proportion of Rett syndrome cases with epilepsy and monthly seizure rates in those with a diagnosis of epilepsy by age group
Source publication
Rett syndrome is a neurodevelopmental disorder mainly affecting females. It is principally caused by mutations in the MECP2 gene. Seizures occur in about 80% of subjects but there has been little research into the factors contributing to their frequency.
To investigate seizure frequency in Rett syndrome and its relationship with other factors, incl...
Context in source publication
Citations
... This finding may be due to a paucity of randomised controlled trials, the high cost of developing rare disease medicines, and the ethical challenges of conducting such studies on the developing brain [60]. The five most frequently recommended ASMs for RTT in this review are consistent with findings from other studies [7,[61][62][63]. However, as only a small number of patients have been included in reports addressing the effectiveness of newer ASMs, such as lamotrigine, levetiracetam, and topiramate (combined with the fact that new ASMs are likely to be developed) the number of available treatment recommendations for these medications may increase as further research is conducted [5]. ...
Background
Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a range of different epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-specific and international treatment guidelines available for pharmacological management of seizures in RTT and TSC.
Methods
A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and guideline databases, and websites of national heath technology assessment bodies were conducted for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as defined by pre-specified eligibility criteria. Search terms were developed for each condition and translated into local languages where appropriate. Eligible publications were defined as guidelines/guidance reporting pharmacological management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus, author information and treatment recommendations were extracted from guidelines. An author map was generated using R version 3.5.1 to visualise extent of collaboration between authors.
Results
24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC, respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83% [20/24]) were country-specific, with guideline authors predominantly publishing in contained national groups; four guidelines were classified as ‘International,’ linking author groups in the US, UK, Italy and France. High levels of heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67 recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr 23(6):633–9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236–41) recommendations; vigabatrin received the highest number of positive recommendations (Kaur, Christodoulou (2019)).
Conclusions
This review highlights the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC.
Trial registration
Not applicable.
... RS has several epileptic symptoms, according to many studies 39,40 . Many studies on epilepsy and age concentrate on teenagers and young adults, separating the few older than 20 41,39,42 . Epilepsy begins in clinical stages II or III at about 4 years of age and peaks between 7 and 12 years. ...
Rett syndrome is a neurodevelopmental disorder primarily affecting females, characterised by slowed growth, developmental regression, loss of fine motor skills, communication difficulties, and stereotypical hand movements. It is strongly associated with mutations in the MECP2 gene, while other variations have been linked to FOXG1 and CDKL5 mutations. This review provides an in-depth understanding of Rett syndrome, including its causes, symptoms, and available treatments. The epidemiology of Rett syndrome indicates a varying prevalence across different regions. Males with Rett syndrome, though rare, have been reported. The aetiology of Rett syndrome involves MECP2 mutations that lead to functional loss, affecting synapse development and maintenance. Mitochondrial dysfunction and oxidative stress have also been implicated in the disorder. Neuropathological findings reveal specific abnormalities in various brain regions. The symptoms of Rett syndrome include slowed head growth, abnormal gait, loss of intentional hand movements, breathing difficulties, and loss of speech. Complications such as metabolic issues, epilepsy, scoliosis, and gastrointestinal dysfunction are common. The diagnosis relies on clinical criteria and genetic testing for MECP2 mutations. Treatment for Rett syndrome is symptomatic and includes individualised rehabilitation therapies such as physical therapy, applied behaviour analysis, environmental enrichment, hydrotherapy, and music therapy. The review emphasises the importance of early intervention and family involvement in rehabilitation programmes.
... In addition, Rett syndrome is associated with epilepsy and scoliosis. Poor growth is also one of the symptoms accompanying this disease [4][5][6][7]. It is caused by a number of factors affecting food intake, including feeding difficulties (despite good appetite), oromotor dysfunctions and other gastrointestinal disorders, as well as factors probably determined by the genotype and being an integral part of the disease [8]. ...
(1) Background: Rett syndrome may be considered a disease strongly associated with nutritional disorders that are likely to require special management strategies, extending beyond what is usually required for children with other developmental disorders. The aim of the study was to assess the nutritional status and diet of Polish girls with Rett syndrome. (2) Methods: Each patient (study group = 49, control group = 22) underwent anthropometric measurements, including body weight and height, waist, hip and arm circumference, and skinfold measurement. The assessment of the diet was based on the analysis of 7-day menus and the Food Frequency Questionnaire (FFQ-6). Data were analyzed using Statistica 13.3. (3) Results: The majority of the girls with Rett syndrome were deficient in weight and height, and consumed fewer calories, less protein, dietary fiber, calcium, and iron than the control group. They also drank less fluid. Soft products that were easy to chew and considered to be high in energy value were significantly more common in the menus. (4) Conclusions: Girls with Rett syndrome are characterized by weight deficiencies, poor growth that deteriorates with age, and are at risk of food shortages. Various nutritional intervention strategies should be explored to reduce and, if possible, prevent malnutrition and cachexia in such patients.
... Another consequence of RTT-linked MECP2 mutations is its impact on excitation/inhibition (E/I). Increased excitation can influence network oscillations and increase susceptibility to seizures [58,64,74]. Several studies also suggest that levels of several brain circuitry components may also be offered. ...
Rett syndrome (RTT) is a neurodevelopmental disorder that is a leading cause of severe cognitive and physical impairment. RTT typically occurs in females, although rare cases of males with the disease exist. Its genetic cause, symptoms, and clinical progression timeline have also become well-documented since its initial discovery. However, a relatively late diagnosis and lack of an available cure signify that our understanding of the disease is incomplete. Innovative research methods and tools are thereby helping to fill gaps in our knowledge of RTT. Specifically, mouse models of RTT, video analysis, and retrospective parental analysis are well-established tools that provide valuable insights into RTT. Moreover, current and anticipated treatment options are improving the quality of life of the RTT patient population. Collectively, these developments are creating optimistic future perspectives for RTT.
... Halbach et al. also showed a deterioration in patients over the age of 30 and confirmed a reduction in sleep-related problems between the ages of 16 and 20 (102). Epilepsy has a high prevalence in RTT syndrome, from 48% as shown by Glaze et al. to 94% reported in other studies (103)(104)(105)(106). Frequent seizures seem to be associated with poor sleep, as well as interfering with sleep architecture (95,107). ...
Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with a ratio of 1:10.000. De novo mutations in the Methyl-CpG Binding protein 2 (MECP2) gene on the long arm of X chromosome are responsible for more than 95% cases of classical Rett. In the remaining cases (atypical Rett), other genes are involved such as the cyclin-dependent kinase-like 5 (CDKL5) and the forkhead box G1 (FOXG1). Duplications of the MECP2 locus cause MECP2 duplication syndrome (MDS) which concerns about 1% of male patients with intellectual disability. Sleep disorders are common in individuals with intellectual disability, while the prevalence in children is between 16 and 42%. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first 7 years of life and some degree of variability in correlation to age and genotype. Abnormalities in circadian rhythm and loss of glutamate homeostasis play a key role in the development of these disorders. Sleep disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). Sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with epilepsy, regression and others. Sleep dysfunction and epilepsy are deeply linked. Sleep deprivation could be an aggravating factor of epilepsy and anti-comitial therapy could interfere in sleep structure. Epilepsy prevalence in atypical Rett syndrome with severe clinical phenotype is higher than in classical Rett syndrome. However, RTT present a significant lifetime risk of epilepsy too. Sleep disturbances impact on child's development and patients' families and the evidence for its management is still limited. The aim of this review is to analyze pathophysiology, clinical features, the impact on other comorbidities and the management of sleep disorders in Rett syndrome and Rett-related syndrome.
... Tarquinio and colleagues reported that another atypical form of RTT with more profound developmental delay exhibited higher prevalence of seizures [43]. In line with this link between RTT severity and epilepsy, patients with a classic RTT phenotype who are more severely affected are more likely to have seizures [43,51,104]. As standardized measures of cognition cannot typically be used to assess cognitive function in individuals with RTT, we highlight the study of Vignolli and colleagues [49] that implicated eye-tracking to objectively evaluate cognitive performance of 18 girls with RTT at clinical stage III and IV on several cognitive tasks. ...
Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.
... For example, approximately 80% develop scoliosis, 3 and seizures occur in 50%-85% of individuals. 4,5 Many females with RTT will survive into adulthood 6 and, therefore, the setting of achievable therapeutic goals for the individual with RTT over the lifespan is vital. 7 Therapies for RTT have had some success when delivered in clinic 8 or school settings. ...
... Over the Program mostly performed as initially suggested. 5 10 50 ...
Background: Rett syndrome (RTT) is a genetically caused neurodevelopmental disorder associated with severe disability. We assessed the feasibility of a telehealth program supporting gross motor skills in RTT.
Methods: Five girls with RTT were assessed and a home-based exercise program developed in response to functional goals. Families then participated in monthly Skype sessions for 6 months, guided by a physiotherapist to monitor progress and adjust the program as necessary. Goal Attainment Scaling was used to evaluate progress and a parental satisfaction questionnaire was administered.
Results: Four goals were established for each participant and progress was greater than would be expected in 16 of 20 goals. Parents evaluated the program as feasible and useful for their daughters.
Discussion: A telehealth model of home-based intervention supported individuals with RTT to achieve gross motor skills and was found to be feasible. This model is important at present times during COVID-19 outbreak and lockdown.
... However, we noted scoliosis, breathing problems, peripheral vasomotor disturbances and sleep problems in 37.5%, 18.7%, 25% and 12.5% of the patients, respectively. The rates of these clinical features in our study were lower than those reported by Bebbington et al., it may be associated with the lower mean age of the participants(25).The prevalence epilepsy was reported as 58 to 80% in RTT patients(25)(26)(27). Seizures started around four years of age in about half of RTT patients(28,29). The results ofstudies investigating the relationship between epilepsy and mutation are conflicting. ...
... Rett syndrome (RTT, MIM:312750) is a rare neurodevelopmental disorder affecting approximately 1 in 9000 live female births. 1 It is characterised by largely normal early development followed by loss of acquired hand and communication skills. There are four main criteria: loss of hand skills, loss of communication skills, hand stereotypies and gait abnormalities. 2 RTT is caused by a mutation in the X-linked MECP2 gene, 3 it is a severe neurodevelopmental disorder 4 impacting multiple body systems [5][6][7] and associated with severe functional impairments. The clinical spectrum is broad and varied and closely linked to the type of genetic mutation. ...
Introduction
Individuals with Rett syndrome (RTT) experience impaired gross motor skills, limiting their capacity to engage in physical activities and participation in activities. There is limited evidence of the effectiveness of supported physical activity interventions. This study aims to evaluate the effects of a telehealth-delivered physical activity programme on physical activity, sedentary behaviour and quality of life in RTT.
Methods and analysis
This is a multicentre study, conducted in Australia, Denmark and Israel. It is a randomised waitlist-controlled trial comparing an intervention to support physical activity with usual care. Participants are children and adults with RTT, recruited from the Australian Rett Syndrome Database, the Danish Center for Rett Syndrome and the Rett Syndrome Association of Israel. The intervention duration is 12 weeks, including fortnightly telephone contact to plan, monitor and develop individual activity programmes. Outcomes are measured at baseline, at 13 weeks and then at 25 weeks. The primary outcomes are sedentary behaviour assessed with an activPAL accelerometer and the number of daily steps measured with a StepWatch Activity Monitor. Secondary outcomes include sleep, behaviour and quality of life. Caregiver experiences will be assessed immediately after the intervention using a satisfaction questionnaire. Group differences for each outcome will be evaluated with analysis of covariance, adjusting for baseline values on an intention-to-treat basis.
Ethics and dissemination
Ethics approval has been obtained in Western Australia from the Child and Adolescent Health Services (RGS3371), in Denmark from the Capital Region Ethics Committee (H-19040514) and in Israel from the Ariel University Institutional Review Board (AU-HEA-ML-20190331). Manuscripts on the development of the intervention from pilot work and the results of the intervention will be submitted to peer-reviewed journals. Results will be presented at conferences and consumer forums. We will develop an online resource documenting the physical activity programme and available supporting evidence.
Trial registration number
NCT04167059 ; Pre-results.
... In this study, we found that individuals with mutations in R106W experience a higher frequency of seizures with at least one generalized seizure and one seizure of any type weekly or more often than weekly. The consistency of these results with investigations of seizure onset [11,12], in conjunction with the higher percent of epilepsy in R106W in previous research [13], highlight the association between R106W and seizure occurrence. Our research expands the investigation of seizures in the R106W population [5,9,14], showing that R168X and R133C follow after R106W in having the highest percentages of generalized seizure occurrence. ...
BACKGROUND: Rett Syndrome (RTT), an incurable neurodevelopmental disorder associated in >96% with the X-linked gene, MECP2 includes seizures, among its most difficult issues, impacting many features and increasing morbidity and mortality. Linking these seizures with clinical severity in RTT is critical for estimating risk and guiding therapy. OBJECTIVE: Our primary purpose was to identify associations between type and frequency of seizures, disease severity, and specific MECP2 mutations to address the hypothesis that seizure frequency correlates with specific mutations and directly impacts clinical severity. METHODS: Mutation, seizure type and frequency, and clinical severity assessed by the Clinical Severity Scale (CSS) were extracted from the 5211 Natural History Study of Rett Syndrome and Related Disorders [1]. This involved observations from 222 Persons with classic or variant RTT and MECP2 mutation positive non-Rett diagnoses. Descriptive analyses were assessed utilizing SPSS software. Mutations include R106W, R133C, R168X, R294X, R306C, other point mutations, and early truncations. RESULTS: Greater frequency of generalized seizures and seizures of any type were associated with R106W mutations; R168X mutations had the highest disease severity, and R133C mutations had the lowest disease severity. CONCLUSION: Important correlations exist across several common MECP2 mutations, including the novel association between generalized seizure frequency and mild CSS.
