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Systematic Reviews Jan 2023Rett syndrome is a rare, severe neurodevelopmental disorder. Almost all cases occur in girls, in association with spontaneous (non-inherited) mutations involving the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rett syndrome is a rare, severe neurodevelopmental disorder. Almost all cases occur in girls, in association with spontaneous (non-inherited) mutations involving the methyl-CpG-binding protein 2 gene located on the X chromosome. Diagnostic criteria for typical Rett syndrome require a period of regression, followed by recovery or stabilization, and fulfillment of all four main criteria (loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements). Our objective was to estimate the prevalence of Rett syndrome in the general population, stratified by sex.
METHODS
We conducted a search of PubMed, Embase, Web of Science, Cochrane Library, LILACS, and LIVIVO to retrieve studies published in English between Jan. 1, 2000, and June 30, 2021. Pooled prevalence with a 95% confidence interval (CI) was estimated using a random-effects meta-analysis based on a generalized linear mixed model with a logit link.
RESULTS
Ten eligible studies were identified (all in females), with a combined sample size of 9.57 million women and 673 Rett syndrome cases. The pooled prevalence estimate (random effects) was 7.1 per 100,000 females (95% CI: 4.8, 10.5, heterogeneity p < 0.001). Despite greatly variable precision of estimation, all estimates were compatible with a prevalence range of approximately 5 to 10 cases per 100,000 females based on their respective 95% CIs.
CONCLUSION
These findings may facilitate planning of therapeutic trials in this indication in terms of target sample size and accrual times.
Topics: Humans; Female; Rett Syndrome; Methyl-CpG-Binding Protein 2; Prevalence; Mutation
PubMed: 36642718
DOI: 10.1186/s13643-023-02169-6 -
Frontiers in Neurology 2021is one of the most common epilepsy genes. About 80% of gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More... (Review)
Review
is one of the most common epilepsy genes. About 80% of gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More than 1,800 mutations have been identified in . Although it is known that is the main cause of DS and genetic epilepsy with febrile seizures plus (GEFS+), there is a dearth of information on the other related diseases caused by mutations of . The aim of this study is to systematically review the literature associated with and other non-DS-related disorders. We searched PubMed and SCOPUS for all the published cases related to gene mutations of until October 20, 2021. The results reported by each study were summarized narratively. The PubMed and SCOPUS search yielded 2,889 items. A total of 453 studies published between 2005 and 2020 met the final inclusion criteria. Overall, 303 studies on DS, 93 on GEFS+, three on Doose syndrome, nine on the epilepsy of infancy with migrating focal seizures (EIMFS), six on the West syndrome, two on the Lennox-Gastaut syndrome (LGS), one on the Rett syndrome, seven on the nonsyndromic epileptic encephalopathy (NEE), 19 on hemiplegia migraine, six on autism spectrum disorder (ASD), two on nonepileptic -related sudden deaths, and two on the arthrogryposis multiplex congenital were included. Aside from DS, also causes other epileptic encephalopathies, such as GEFS+, Doose syndrome, EIMFS, West syndrome, LGS, Rett syndrome, and NEE. In addition to epilepsy, hemiplegic migraine, ASD, sudden death, and arthrogryposis multiplex congenital can also be caused by mutations of .
PubMed: 35002916
DOI: 10.3389/fneur.2021.743726 -
Brain Sciences Jun 2020Rett syndrome is a rare genetic disorder that affects brain development and causes severe mental and physical disability. This systematic review analyzes the most recent... (Review)
Review
Rett syndrome is a rare genetic disorder that affects brain development and causes severe mental and physical disability. This systematic review analyzes the most recent evidence concerning the role of physical therapy in the management of individuals with Rett syndrome. The review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A total of 17319 studies were found in the main scientific databases. Applying the inclusion/exclusion criteria, 22 studies were admitted to the final phase of the review. Level of evidence of the included studies was assessed using the Oxford Centre for Evidence-Based Medicine-Levels of Evidence guide. Nine approaches to physical therapy for patients with Rett syndrome were identified: applied behavior analysis, conductive education, environmental enrichment, traditional physiotherapy with or without aids, hydrotherapy, treadmill, music therapy, computerized systems, and sensory-based treatment. It has been reported that patients had clinically benefited from the analysed approaches despite the fact that they did not have strong research evidence. According to the results, a multimodal individualized physical therapy program should be regularly recommended to patients with Rett syndrome in order to preserve autonomy and to improve quality of life. However, more high-quality studies are needed to confirm these findings.
PubMed: 32630125
DOI: 10.3390/brainsci10070410 -
International Journal of Environmental... Jan 2021Rett Syndrome is an x linked developmental disorder which becomes apparent in females after 6 to 18 months of age. It leads to severe impairments including loss of... (Review)
Review
Rett Syndrome is an x linked developmental disorder which becomes apparent in females after 6 to 18 months of age. It leads to severe impairments including loss of speech, loss of hand movements/manual dexterity, characteristic hand movements such as hang wringing and intellectual disability/learning problems. This systematic review was carried out to identify the dental manifestation of Rett syndrome and to shed light on treatment options available for oral health problems associated with Rett syndrome. A systematic literature search was conducted on the PubMed, Scopus, Biomed, Web of Science, Embase, Google Scholars, Cochrane and CINAHL using the following entries: Rett syndrome ( = 3790), Oral health and Rett syndrome ( = 17), dental health of Rett syndrome patients ( = 13), and the MeSH terms listed below: Rett syndrome and Oral Health ( = 17), Rett syndrome and dentistry ( = 29). The final review included 22 search articles. The most common oral findings was bruxism. Masseteric hypertrophy was also reported. Anterior open bite and non-physiological tooth wear was observed. Other oral manifestations of Rett syndrome included mouth breathing, tongue thrusting, digit/thumb sucking, high arch palate. Increased awareness and dental education amongst dentists and assistants regarding the dental manifestations of Rett syndrome and similar neurodevelopmental disorders is required to improve the level of care and empathy they can provide to these differently able patients. Research on dental aspects of Rett is scarce and this remains a neglected topic.
Topics: Bruxism; Female; Hand; Humans; Rett Syndrome; Speech
PubMed: 33525609
DOI: 10.3390/ijerph18031162 -
Psychiatry and Clinical Neurosciences Dec 2021This systematic review identified and thematically appraised clinical evidence of movement disorders in patients with Rett syndrome (RTT). (Review)
Review
AIM
This systematic review identified and thematically appraised clinical evidence of movement disorders in patients with Rett syndrome (RTT).
METHOD
Using PRISMA criteria, six electronic databases were searched from inception to April 2021. A thematic analysis was then undertaken on the extracted data to identify potential themes.
RESULTS
Following the thematic analysis, six themes emerged: (i) clinical features of abnormal movement behaviors; (ii) mutational profile and its impact on movement disorders; (iii) symptoms and stressors that impact on movement disorders; (iv) possible underlying neurobiological mechanisms; (v) quality of life and movement disorders; and (vi) treatment of movement disorders. Current guidelines for managing movement disorders in general were then reviewed to provide possible treatment recommendations for RTT.
CONCLUSION
Our study offers an enriched data set for clinical investigations and treatment of fine and gross motor issues in RTT. A detailed understanding of genotype-phenotype relationships of movement disorders allows for more robust genetic counseling for families but can also assist healthcare professionals in terms of monitoring disease progression in RTT. The synthesis also showed that environmental enrichment would be beneficial for improving some aspects of movement disorders. The cerebellum, basal ganglia, alongside dysregulation of the cortico-basal ganglia-thalamo-cortical loop, are likely anatomical targets. A review of treatments for movement disorders also helped to provide recommendations for treating and managing movement disorders in patients with RTT.
Topics: Animals; Humans; Movement Disorders; Mutation; Quality of Life; Rett Syndrome
PubMed: 34472659
DOI: 10.1111/pcn.13299 -
International Journal of Molecular... May 2023This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies,... (Review)
Review
This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution.
Topics: Humans; Rett Syndrome; Gene Editing; Tissue Distribution; Methyl-CpG-Binding Protein 2; Brain; Genetic Therapy
PubMed: 37240368
DOI: 10.3390/ijms24109023 -
Journal of Psychiatry & Neuroscience :... May 2020Rett syndrome (RTT), a debilitating neuropsychiatric disorder that begins in early childhood, is characterized by impairments in the autonomic nervous system that can...
BACKGROUND
Rett syndrome (RTT), a debilitating neuropsychiatric disorder that begins in early childhood, is characterized by impairments in the autonomic nervous system that can lead to sudden unexpected death. This study explores the mechanisms of autonomic dysfunction to identify potential risk factors for sudden death in patients with RTT.
METHODS
Following the Reporting Items for Systematic Review and Meta-Analyses (PRISMA) criteria, we undertook comprehensive systematic reviews using the PubMed, Scopus, Cochrane, PsycINFO, Embase and Web of Science databases.
RESULTS
We identified and critically appraised 39 articles for autonomic dysfunction and 5 for sudden death that satisfied the eligibility criteria. Following thematic analysis, we identified 7 themes: breathing irregularities, abnormal spontaneous brainstem activations, heart rate variability metrics, QTc changes, vagal imbalance, fluctuation in peptides and serotonergic neurotransmission. We grouped these 7 themes into 3 final themes: (A) brainstem modulation of breathing, (B) electrical instability of the cardiovascular system and (C) neurochemical changes contributing to autonomic decline. We described key evidence relating to each theme and identified important areas that could improve the clinical management of patients with RTT.
LIMITATIONS
The heterogeneity of the methods used to assess autonomic function increased the difficulty of making inferences from the different studies.
CONCLUSION
This study identified the important mediators of autonomic dysfunction and sudden death in patients with RTT. We proposed brainstem mechanisms and emphasized risk factors that increase brainstem vulnerability. We discussed clinical management to reduce sudden death and future directions for this vulnerable population.
Topics: Autonomic Nervous System; Autonomic Nervous System Diseases; Brain Stem; Death, Sudden; Humans; Rett Syndrome; Risk Factors
PubMed: 31702122
DOI: 10.1503/jpn.190033 -
BMC Pediatrics Mar 2024Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly impacts females. It presents with loss of acquired skills, impaired communication, and stereotypic hand movements. Given the limited treatment options for Rett syndrome, there is a dire need for effective interventions.
OBJECTIVE
To evaluate the safety and efficacy of trofinetide in Randomized Controlled Trials (RCTs) that report on Rett syndrome patients.
METHODS
We identified 109 articles from four databases (Scopus, PubMed, Web of Science, and Cochrane CENTRAL). After removing the duplicates, we narrowed them down to 59 articles for further assessment. We included RCTs that evaluated the efficacy and safety of trofinetide in patients with Rett syndrome. Three studies were eligible for inclusion. Two independent reviewers evaluated the identified studies' titles, abstracts, and full texts, extracting pertinent data. We assessed the quality of the studies using the Cochrane Risk of Bias (RoB) 2.0 tool. We then conducted a meta-analysis using the fixed effects model in the case of insignificant heterogeneity; otherwise, we used the random effects model. Based on the nature of the outcome, we analyzed the mean difference or the odds ratio. Analysis was conducted using RevMan version 5.3.
RESULTS
Among the analyzed outcomes in 181 patients in the trofinetide group and 134 patients in the placebo group, significant improvement in Rett Syndrome Behavior Questionnaire (RSBQ) scores was observed at 200 mg dosage (overall mean difference: -3.53, p = 0.001). Clinical Global Impression-Improvement (CGI-I) scores improved considerably at 200 mg dosage (overall mean difference: -0.34, p < 0.0001). No substantial changes were observed in Motor Behavioral Assessment (MBA) or Top 3 Caregiver Concerns. We evaluated Treatment Emergent Adverse Events (TEAEs) across the various dosages and noted significant associations with diarrhea (200 mg), vomiting (200 mg), and irritability (200 mg). However, we did not find a significant association between any of the dosages and the incidence of decreased appetite.
CONCLUSION
Trofinetide demonstrated potential in improving RSBQ and CGI-I scores at 200 mg dosage. Although no substantial changes were found in MBA and top 3 caregiver concerns. Adverse events were linked to specific dosages.
Topics: Female; Humans; Rett Syndrome; Randomized Controlled Trials as Topic; Glutamates; Diarrhea
PubMed: 38521908
DOI: 10.1186/s12887-024-04526-3 -
Frontiers in Neuroscience 2024Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent...
Functional contribution of the intestinal microbiome in autism spectrum disorder, attention deficit hyperactivity disorder, and Rett syndrome: a systematic review of pediatric and adult studies.
INTRODUCTION
Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent studies have shown the presence of gut microbiota alterations in neurodevelopmental disorders. Here we performed a systematic review of alterations of the intestinal microbiota composition and function in pediatric and adult patients affected by autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Rett syndrome (RETT).
METHODS
We searched selected keywords in the online databases of PubMed, Cochrane, and OVID (January 1980 to December 2021) with secondary review of references of eligible articles. Two reviewers independently performed critical appraisals on the included articles using the Critical Appraisal Skills Program for each study design.
RESULTS
Our systematic review identified 18, 7, and 3 original articles describing intestinal microbiota profiles in ASD, ADHD, and RETT, respectively. Decreased Firmicutes and increased Bacteroidetes were observed in the gut microbiota of individuals affected by ASD and ADHD. Proinflammatory cytokines, short-chain fatty acids and neurotransmitter levels were altered in ASD and RETT. Constipation and visceral pain were related to changes in the gut microbiota in patients affected by ASD and RETT. Hyperactivity and impulsivity were negatively correlated with (phylum Firmicutes) and positively correlated with sp. (phylum Bacteroidetes) in ADHD subjects. Five studies explored microbiota-or diet-targeted interventions in ASD and ADHD. Probiotic treatments with sp. and fecal microbiota transplantation from healthy donors reduced constipation and ameliorated ASD symptoms in affected children. Perinatal administration of sp. prevented the onset of Asperger and ADHD symptoms in adolescence. Micronutrient supplementation improved disease symptomatology in ADHD without causing significant changes in microbiota communities' composition.
DISCUSSION
Several discrepancies were found among the included studies, primarily due to sample size, variations in dietary practices, and a high prevalence of functional gastrointestinal symptoms. Further studies employing longitudinal study designs, larger sample sizes and multi-omics technologies are warranted to identify the functional contribution of the intestinal microbiota in developmental trajectories of the human brain and neurobehavior.
SYSTEMATIC REVIEW REGISTRATION
https://clinicaltrials.gov/, CRD42020158734.
PubMed: 38516317
DOI: 10.3389/fnins.2024.1341656 -
Frontiers in Neurology 2020To systematically identify and critically appraise studies that investigate the autonomic characteristics of Sudden Unexpected Death in Epilepsy (SUDEP) in the...
Autonomic Characteristics of Sudden Unexpected Death in Epilepsy in Children-A Systematic Review of Studies and Their Relevance to the Management of Epilepsy in Rett Syndrome.
To systematically identify and critically appraise studies that investigate the autonomic characteristics of Sudden Unexpected Death in Epilepsy (SUDEP) in the pediatric population. We also wanted to explore how this information would be relevant to the management of epilepsy in patients with Rett Syndrome. Using PRISMA guidelines, a systematic review of PubMed, Scopus, Cochrane, PsycINFO, Embase, and Web of Science databases was performed to identify eligible studies. After extracting data from the included studies, a thematic analysis was undertaken to identify emerging themes. A quality appraisal was also done to assess the quality of the included studies. The systematic search revealed 41 records, and 15 full-text articles on the autonomic characteristics of SUDEP in children were included in the final analysis. Following thematic analysis, three themes were identified (I) modulation in sympathovagal tone, (II) pre- and post-ictal autonomic changes, and (III) other markers of autonomic dysregulation in children with epilepsy. Modulation in sympathovagal tone emerged as the theme with the highest frequency followed by pre- and post-ictal autonomic changes. While the themes provide additional insight into the management of epilepsy in the Rett Syndrome population, the quality of evidence concerning the autonomic characteristics of SUDEP in the pediatric population was low and underscores the importance of much needed research in this area. The mechanism of SUDEP in the pediatric population is complex and involves an interplay between several components of the autonomic nervous system. While direct clinical inferences regarding pediatric SUDEP could not be made, the thematic analysis does suggest that in vulnerable populations such as Rett Syndrome, where there is already a pervasive autonomic dysregulation, pro-active surveillance of the autonomic profile in this patient group would be useful to better manage epilepsy and reduce the SUDEP risk.
PubMed: 33613425
DOI: 10.3389/fneur.2020.632510