AUTHOR=Tascini Giorgia , Dell'Isola Giovanni Battista , Mencaroni Elisabetta , Di Cara Giuseppe , Striano Pasquale , Verrotti Alberto TITLE=Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review JOURNAL=Frontiers in Neurology VOLUME=Volume 13 - 2022 YEAR=2022 URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.817195 DOI=10.3389/fneur.2022.817195 ISSN=1664-2295 ABSTRACT=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 (classical Rett), while 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 is between 16-42% in children. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first seven 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 characterized CDKL5 Deficiency Disorder (CDD), although scoliosis and respiratory irregularities are relatively less frequent. In addition, sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with bruxism, screaming or laughing spells, hypotonia shifting to progressive spasticity, 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. Moreover, 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.