Sleep Disorders in Rett Syndrome and Rett-Related Disorders: A Narrative Review

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 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.

Cardiac autonomic control in Rett syndrome: Insights from heart rate variability analysis

“…According to the 2010 revised criteria, regression is a key element for diagnosis along with four main criteria ( Hagberg, 2002 ): (1) partial or complete loss of acquired purposeful hand skills, (2) partial or complete loss of acquired spoken language, (3) gait abnormalities (impaired -dyspraxic- or absence of ability), (4) stereotypic hand movements (such as hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatism) ( Jeffrey et al, 2010 ). Four stages compose the typical clinical course of Rett syndrome ( Hagberg, 2002 ; Cosentino et al, 2019 ; Tascini et al, 2022 ). The first phase (6–18 months) is characterized by a slowdown in the development and is followed by a second stage (1–4 years) distinguished by skill regression, profound loss of acquired communication and hand use skills, and autistic-like behavior.…”

“…During the last part of their life, patients undergo a worsening motor performance ( Hagberg, 2002 ; Cosentino et al, 2019 ; Tascini et al, 2022 ). “Atypical or variant” Rett is defined by the presence of many of the clinical characteristics of RTT but not completely satisfied.…”

“…These variants range from milder conditions with a later age of onset to more severe manifestations ( Chahrour and Zoghbi, 2007 ). Among the atypical forms, the preserved speech variant (Zappella variant) mainly caused by MECP2 mutations, the congenital variant (Rolando variant) closely related to mutations in the FOXG1 gene, and the early seizures variant (Hanefeld variant) associated with mutations in CDKL5 gene ( Operto et al, 2019 ; Tascini et al, 2022 ) are described. Males with MECP2 mutations present further diagnostic and classification challenges.…”

“…Rett syndrome (RTT), OMIM #312750, is a rare neurological disorder characterized by severe cognitive, social, and physical impairments, mainly affecting females ( Jeffrey et al, 2010 ; Tascini et al, 2022 ), being the second most prevalent genetic cause of intellectual disability in girls (incidence of 1/10,000) ( Borloz et al, 2021 ). First described in the 1960s by Andreas Rett ( Rett, 1966 ; Jeffrey et al, 2010 ), the syndrome was subsequently clinically characterized by Hagberg in classical and atypical RTT forms ( Hagberg et al, 1983 ; Hagberg, 2002 ; Tascini et al, 2022 ). Amir et al (1999) identified the genetic cause of RTT as a loss of function mutation in the gene Methyl-CpG-binding protein 2 (MECP2).…”

“… Amir et al (1999) identified the genetic cause of RTT as a loss of function mutation in the gene Methyl-CpG-binding protein 2 (MECP2). More than 800 de novo mutations of MECP2 gene are responsible for 95% cases of classical RTT ( Tascini et al, 2022 ) and 50–70% of AR in which other genes, such as cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) gene, are also involved ( Guerrini and Parrini, 2012 ; Tascini et al, 2022 ). Nevertheless, RTT continues to be primarily a clinical diagnosis, as MECP2 mutations are neither necessary nor sufficient for the diagnosis ( Ramirez et al, 2020 ).…”