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.
Highlights
Attention to sleep disorders has increased especially in people suffering from neurodevelopmental disabilities such as: Rett syndrome (RTT), Down syndrome, Fragile-X syndrome, Prader-Willi syndrome, Angelman syndrome, Tuberous Sclerosis and Autistic spectrum disorders [1]
Methyl-CpG Binding protein 2 (MECP2) mutations are responsible for 95% of RTT cases and more than 50% of atypical Rett (AR)
The prevalence and elements of sleep disorders were further detailed by Boban et al in [95], in 364/461 RTT and MECP2 mutation patients registered in the international Rett syndrome phenotype database (InterRett) [95]
Summary
Attention to sleep disorders has increased especially in people suffering from neurodevelopmental disabilities such as: Rett syndrome (RTT), Down syndrome, Fragile-X syndrome, Prader-Willi syndrome, Angelman syndrome, Tuberous Sclerosis and Autistic spectrum disorders [1]. Sleep Disorders in Rett Syndrome disability (ID) (respectively 8.5–31% and 16–42%) compared to individuals with a typical development [1, 2]. Methyl-CpGbinding protein 2 (MECP2) gene mutations were first described in RTT, suggesting the monogenic origin of the disease [10, 11]. More than 800 de novo mutations of MECP2 gene are responsible for 95% cases of classical RTT. Males with MECP2 mutations range from fatal neonatal encephalopathy to classical RTT and psychiatric symptoms such as schizophrenia or bipolar disorder [16, 17]. Impairment of gross motor skills, alterations in general movements, fine movements of the face and arms, stereotypes of the hands and tremors have been described in the first months of life. The second phase (1–4 years) is characterized by skill regression over weeks or months and autistic-like behavior.
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