Review

Authors: Stephanie M Kyle, Neeti Vashi, Monica J Justice...

Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of in the central nervous system. However, the variety of phenotypes identified in mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

Topics: Animals; Brain; Disease Models, Animal; Disease Progression; Drug Repositioning; Female; History, 20th Century; Humans; Lipid Metabolism; Lovastatin; Methyl-CpG-Binding Protein 2; Mice; Mutation; Quality of Life; Rett Syndrome

PubMed: 29445033
DOI: 10.1098/rsob.170216

Authors: Jeffrey L Neul, Walter E Kaufmann, Daniel G Glaze...

OBJECTIVE

Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl-CpG-binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials.

METHOD

RettSearch members, representing the majority of the international clinical RTT specialists, participated in an iterative process to come to a consensus on a revised and simplified clinical diagnostic criteria for RTT.

RESULTS

The clinical criteria required for the diagnosis of classic and atypical RTT were clarified and simplified. Guidelines for the diagnosis and molecular evaluation of specific variant forms of RTT were developed.

INTERPRETATION

These revised criteria provide clarity regarding the key features required for the diagnosis of RTT and reinforce the concept that RTT is a clinical diagnosis based on distinct clinical criteria, independent of molecular findings. We recommend that these criteria and guidelines be utilized in any proposed clinical research.

Topics: Animals; Humans; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome; Terminology as Topic

PubMed: 21154482
DOI: 10.1002/ana.22124

Review

Authors: Silvia Vidal, Clara Xiol, Ainhoa Pascual-Alonso...

Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities, and is one of the most prevalent causes of intellectual disability in females. More than fifty years after the first publication on Rett syndrome, and almost two decades since the first report linking RTT to the gene, the research community's effort is focused on obtaining a better understanding of the genetics and the complex biology of RTT and Rett-like phenotypes without mutations. Herein, we review the current molecular genetic studies, which investigate the genetic causes of RTT or Rett-like phenotypes which overlap with other genetic disorders and document the swift evolution of the techniques and methodologies employed. This review also underlines the clinical and genetic heterogeneity of the Rett syndrome spectrum and provides an overview of the RTT-related genes described to date, many of which are involved in epigenetic gene regulation, neurotransmitter action or RNA transcription/translation. Finally, it discusses the importance of including both phenotypic and genetic diagnosis to provide proper genetic counselling from a patient's perspective and the appropriate treatment.

Topics: Animals; Gene Expression Regulation; Genetic Heterogeneity; Humans; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome; Signal Transduction

PubMed: 31409060
DOI: 10.3390/ijms20163925

Meta-Analysis Review

Authors: Uarda Petriti, Daniel C Dudman, Emil Scosyrev...

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

Review

Authors: Sandra Vilvarajan, Madeleine McDonald, Lyndal Douglas...

Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being symptomatic and supportive. This study provides a comprehensive review of the clinical features, comorbidities and multidisciplinary management of a well-characterized cohort of females with classical Rett syndrome. We aim to improve awareness and understanding of Rett syndrome amongst pediatricians, pediatric subspecialists and allied health professionals to enable early diagnosis and a streamlined enrolment approach for future clinical trials. Rett syndrome, a complex X-linked condition, affecting mainly females, is due to pathogenic variants of the gene in most affected individuals. The Rett syndrome Multidisciplinary Management clinic at The Children's Hospital at Westmead, Sydney, Australia, was established in 2000. This retrospective analysis of individuals who attended the clinic from 2000 to 2020 was performed to identify the incidence and predicted age of onset of Rett syndrome related comorbidities, disease progression and to review management principles. Data collected included age of Rett syndrome diagnosis, genotype, clinical features and medical comorbidities, such as sleep disturbance, seizures, breathing irregularities, scoliosis, mobility, hand stereotypies, hand function, constipation, feeding ability, use of gastrostomy, communication skills, QTc prolongation, anthropometry, and bruxism. Analysis of 103 girls who fulfilled the clinical diagnostic criteria for classical Rett syndrome with a pathogenic variant of the gene showed a median age of diagnosis of 3 years. The most frequent variant was c.502 C>T.

Topics: Female; Humans; Child; Child, Preschool; Male; Rett Syndrome; Retrospective Studies; Scoliosis; Constipation; Seizures

PubMed: 37628658
DOI: 10.3390/genes14081607

Review

Authors: Shervin Pejhan, Mojgan Rastegar

Rett Syndrome (RTT) is a severe, rare, and progressive developmental disorder with patients displaying neurological regression and autism spectrum features. The affected individuals are primarily young females, and more than 95% of patients carry mutation(s) in the Methyl-CpG-Binding Protein 2 ( gene. While the majority of RTT patients have mutations (classical RTT), a small fraction of the patients (atypical RTT) may carry genetic mutations in other genes such as the cyclin-dependent kinase-like 5 ( and . Due to the neurological basis of RTT symptoms, MeCP2 function was originally studied in nerve cells (neurons). However, later research highlighted its importance in other cell types of the brain including glia. In this regard, scientists benefitted from modeling the disease using many different cellular systems and transgenic mice with loss- or gain-of-function mutations. Additionally, limited research in human postmortem brain tissues provided invaluable findings in RTT pathobiology and disease mechanism. MeCP2 expression in the brain is tightly regulated, and its altered expression leads to abnormal brain function, implicating MeCP2 in some cases of autism spectrum disorders. In certain disease conditions, MeCP2 homeostasis control is impaired, the regulation of which in rodents involves a regulatory microRNA () and brain-derived neurotrophic factor (BDNF). Here, we will provide an overview of recent advances in understanding the underlying mechanism of disease in RTT and the associated genetic mutations in the gene along with the pathobiology of the disease, the role of the two most studied protein variants (MeCP2E1 and MeCP2E2 isoforms), and the regulatory mechanisms that control MeCP2 homeostasis network in the brain, including BDNF and .

Topics: Animals; Brain-Derived Neurotrophic Factor; Epigenesis, Genetic; Homeostasis; Humans; Methyl-CpG-Binding Protein 2; Rett Syndrome; Signal Transduction

PubMed: 33429932
DOI: 10.3390/biom11010075

Review

Authors: Nicolas Panayotis, Yann Ehinger, Marie Solenne Felix...

Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome. WHAT THIS PAPER ADDS: Recent advances shed light on the promises of gene replacement therapy with new vectors designed to control the levels of MeCP2 expression. New developments in DNA/RNA editing approaches or reactivation of the silenced X chromosome open the possibility to re-express the native MeCP2 locus at endogenous levels. Current strategies still face limitations in transduction efficiency and future work is needed to improve brain delivery.

Topics: Mice; Animals; Humans; Rett Syndrome; Art Therapy; Methyl-CpG-Binding Protein 2; Brain; Mutation; Neurons

PubMed: 36056801
DOI: 10.1111/dmcn.15383

Randomized Controlled Trial

Authors: Jeffrey L Neul, Alan K Percy, Timothy A Benke...

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen's d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

Topics: Female; Humans; Rett Syndrome; Treatment Outcome; Glutamates; Double-Blind Method

PubMed: 37291210
DOI: 10.1038/s41591-023-02398-1

Review

Authors: Alan K Percy, Amitha Ananth, Jeffrey L Neul...

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation-IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype-genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected.

Topics: Rett Syndrome; Humans; Animals; Methyl-CpG-Binding Protein 2; Disease Models, Animal

PubMed: 39251501
DOI: 10.1007/s40263-024-01106-y

Review

Authors: Edoardo Bianco, Denise Rota

Rett syndrome is a progressive pediatric neurodevelopmental disorder, predominantly affecting females, characterized by a seemingly normal prenatal and perinatal period, followed by neurodevelopmental stagnation, and then rapid regression.The purpose of this study was to provide an update of the literature on the oral aspects of Rett syndrome and their possible treatment in patients suffering from this pathology. After an electronic and manual search in MEDLINE (PubMed) and the Cochrane Library, 12 articles were found, for a total of 142 patients affected by Rett syndrome. A high prevalence of bruxism, anterior open bite, ogival palate, sucking habits, and difficulties in maintaining oral hygiene was noted. There were also oral findings related to the pharmacological treatment, which included xerostomia, glossitis, erythema multiforme, gingival hyperplasia, dysphagia, and lingual paralysis. It is important for the dentist to know what problems related to the oral cavity can be encountered in a patient diagnosed with Rett syndrome and what preventive measures can be applied.

Topics: Humans; Mouth; Mouth Diseases; Rett Syndrome

PubMed: 30648368
DOI: 10.17219/dmp/99203