Determinants of sleep disturbances in Rett syndrome: Novel findings in relation to genotype

Abstract

Rett syndrome is a rare but severe neurological disorder associated with a mutation in the methyl CpG binding protein 2 (MECP2) gene. Sleep problems and epilepsy are two of many comorbidities associated with this disorder. This study investigated the prevalence and determinants of sleep problems in Rett syndrome using an international sample. Families with a child with a confirmed Rett syndrome diagnosis and a MECP2 mutation registered in the International Rett Syndrome Phenotype Database (InterRett) were invited to participate. Questionnaires were returned by 364/461 (78.9%) either in web-based or paper format. Families completed the Sleep Disturbance Scale for Children and provided information on the presence, nature, and frequency of their child's sleep problems. Multivariate multinomial regression was used to investigate the relationships between selected sleep problems, age group, and genotype and linear regression for the relationships between sleep disturbance scales and a range of covariates. Night waking was the most prevalent sleep problem affecting over 80% with nearly half (48.3%) currently waking often at night. Initiating and maintaining sleep was most disturbed for younger children and those with a p.Arg294* mutation. Severe seizure activity was associated with poor sleep after adjusting for age group, mutation type, and mobility. We were surprised to find associations between the p.Arg294* mutation and some sleep disturbances given that other aspects of its phenotype are milder. These findings highlight the complexities of aberrant MECP2 function in Rett syndrome and explain some of the variation in manifestation of sleep disturbances. © 2016 Wiley Periodicals, Inc.

Clinical and biological progress over 50 years in Rett syndrome

“…2 & 3F). 169 Those with epilepsy and those not mobile were more likely to have excessive somnolence also consistent with earlier findings. 166 In one small clinical trial (n=9) melatonin appeared to improve total sleep time and efficiency in those worse at baseline without any adverse side effects.…”

“…167,168 A recent study, using InterRett for ascertainment, surveyed parents/carers of 364 genetically confirmed cases aged 2-57 years. 169 Night waking was frequent, and, consistent with previous research, those with the p.Arg294*were most likely to have problems initiating and maintaining sleep (see Figs. 2 & 3F).…”

Sleep problems in Dravet syndrome: a modifiable comorbidity

“…12 found in more than 80% of cases, may contribute to sleep disruption by dysregulation of neurological sleep networks. A similar frequency of sleep disturbance was observed in Rett syndrome, 15 although children with other developmental and epileptic encephalopathies need to be studied. Mouse models of SCN1A mutations have shown that the Na v 1.1 channel encoded by SCN1A is expressed in cells important for sleep regulation, including the GABAergic neurons in the hypothalamus, thalamic reticular nucleus, and cortex.…”

“…The high frequency of sleep disturbance may also be attributed to or compounded by refractory nocturnal seizures, and polypharmacy in children with Dravet syndrome. A similar frequency of sleep disturbance was observed in Rett syndrome, 15 although children with other developmental and epileptic encephalopathies need to be studied. Comorbidities, such as autistic features and developmental delay, frequently seen in children with Dravet syndrome, may also contribute to reports of high sleep disturbance in this population.…”

“…Mouse models of SCN1A mutations have shown that the Na v 1.1 channel encoded by SCN1A is expressed in cells important for sleep regulation, including the GABAergic neurons in the hypothalamus, thalamic reticular nucleus, and cortex. 15,17 Further analysis showed that respondents were more likely to be currently under care of clinicians at our centre and to live in the same state than the non-respondents. The high frequency of sleep disturbance may also be attributed to or compounded by refractory nocturnal seizures, and polypharmacy in children with Dravet syndrome.…”