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.
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.
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.
These findings may facilitate planning of therapeutic trials in this indication in terms of target sample size and accrual times.

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.

OBJECTIVE: To present a cohort of 8 males and perform a systematic review of all published cases with a single copy of MECP2 carrying a pathogenic variant.
METHODS: We reviewed medical records of males with a single copy of MECP2 carrying a pathogenic variant. We searched in Medline (Pubmed) and Embase to collect all articles which included well-characterized males with a single copy of MECP2 carrying a pathogenic or likely pathogenic variant in MECP2 (1999-2020).
RESULTS: The literature search yielded a total of 3,185 publications, of which 58 were included in our systematic review. We were able to collect information on 27 published patients with severe neonatal encephalopathy, 47 individuals with isolated or familial mental retardation X-linked 13 (XLMR13), as well as 24 individuals with isolated or familial Pyramidal signs, parkinsonism, and macroorchidism (PPM-X). In our cohort, we met eight individuals aged 4 to 19-year-old at the last evaluation. Three MECP2-associated phenotypes were seen in male carriers of a single copy of the gene: severe neonatal encephalopathy (n = 5); X-linked intellectual deficiency 13 (n = 2); and pyramidal signs, parkinsonism, and macroorchidism (PPM-X) (n = 1). Two novel de novo variants [p.(Gly252Argfs∗7) and p.(Tyr132Cys)] were detected.
CONCLUSIONS: In males, the MECP2 pathogenic variants can be associated with different phenotypes, including neonatal severe encephalopathy, intellectual deficiency, or late-onset parkinsonism and spasticity. The typical RS phenotype is not expected in males, except in those with Klinefelter syndrome or somatic mosaicism for MECP2.

Systematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).
Pubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.
ERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.
While there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.
The review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.

Rett Syndrome (RTT) is a neurological disorder mainly associated with mutations in the X-linked gene coding for the methyl-CpG binding protein 2 (MECP2). To assist in studying MECP2\'s function, researchers have generated Mecp2 mouse mutants showing that MECP2\'s product (MeCP2) mostly functions as a transcriptional regulator. During the last two decades, these models have been used to determine the genes that are regulated by MeCP2, slowly dissecting the etiological mechanisms underlying RTT. In the present review, we describe the findings of these transcriptomic studies, and highlight differences between them, and discuss how studies on these genetic models can sharpen our understanding of the human disorder. We conclude that - while there\'s large variability regarding the number of differentially expressed genes identified - there are overlapping features that inform on the biology of RTT.

Rett syndrome (RTT) is a unique neurodevelopmental disorder that primarily affects females resulting in severe cognitive and physical disabilities. Despite the commendable collective efforts of the research community to better understand the genetics and underlying biology of RTT, there is still no cure. However, in the past 50 years, since the first report of RTT, steady progress has been made in the accumulation of clinical and molecular information resulting in the identification of a number of genes associated with RTT and associated phenotypes, improved diagnostic criteria, natural history studies, curation of a number of databases capturing genotypic and phenotypic data, a number of promising clinical trials and exciting novel therapeutic options which are currently being tested in laboratory and clinical settings. This Review focuses on the current knowledge of the clinical aspects of RTT, with particular attention being paid to clinical trials and the comorbidities of the disorder as well as the genetic etiology and the recognition of new diseases genes.

OBJECTIVE: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious.
METHODS: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012.
RESULTS: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements.
CONCLUSIONS: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT.