Sleep problems in children with Angelman Syndrome: The effect of a behavioral intervention program

Heus, Karen G. C. B. Bindels‐de; Hooven‐Radstaake, Maartje ten; Legerstee, Jeroen S.; Hoopen, Leontine W. ten; Dieleman, Gwen; Moll, Henriëtte A.; Mous, Sabine E.; Wit, Marie‐Claire Y. de

doi:10.1016/j.ridd.2023.104444

Cited by 12 publications

(4 citation statements)

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“…We also utilized the oscillatory power to obtain power spectral densities (PSD) of each frequency wave, identifying greater absolute power in Syngap1 +/mice, and elevated delta and theta power, compared WT age and sex matched control subjects. Elevated delta power is currently being used as a biomarker in clinical trials for other genetic NDDs, such as the Angelman Syndrome trial using GTX-102 30,[61][62][63][64][65] . Increased spike trains in vivo during EEG show similar patterns of activity to the HD-MEA outputs of increased bursts and shorter latency between bursts with Syngap1 +/primary neurons.…”

Section: Discussionmentioning

confidence: 99%

Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability

Silverman,

Fenton,

Haouchine

et al. 2024

Preprint

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Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability, motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicting the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the mouse model from the Huganir laboratory, corroborated earlier reported behaviors including robust hyperactivity and deficits in learning and memory in young adults. In extension, we report impairments in slow wave sleep, a critical component of the domain of sleep. We characterized Syngap1+/- mice by using neurophysiology collected with wireless, telemetric electroencephalography (EEG). Syngap1+/- mice also exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta frequency band. For the first time, we illustrated how primary neurons from Syngap1+/- mice function and display increased network firing activity, greater bursts, and shorter inter-burst intervals between peaks by employing high density microelectrode arrays (HD-MEA). Our reported data bridge in-vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development of and efficacy assessment of targeted treatments for SRID.

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Section: Discussionmentioning

confidence: 99%

Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability

Silverman,

Fenton,

Haouchine

et al. 2024

Preprint

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“…Interventions aimed at decreasing child emotional/behavioural problems could, for example, involve identifying new and adaptive ways for the child to express their emotions using Augmented and Aided Communication. Sleeping problems may be reduced through behavioural interventions (Allen et al 2013;Bindels-de Heus et al 2023) or sleep medication (Braam et al 2008). Parenting stress could also be directly targeted, for example, through mindfulness interventions (Neece 2014), teaching adaptive coping styles or by validating and supporting parents in prioritising their own sleep and well-being and help them organise respite care for their child.…”

Section: Discussionmentioning

confidence: 99%

Child characteristics associated with child quality of life and parenting stress in Angelman syndrome

Hagenaar,

Bindels‐de Heus,

Lubbers

et al. 2023

J intellect Disabil Res

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BackgroundAngelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and behavioural issues. Little is known on child health‐related quality of life (HRQoL) in AS. AS family studies have reported elevated parenting stress and a high impact of the child's syndrome on the parent. It is unclear which factors influence child HRQoL and parenting stress/impact in AS.MethodsWe collected data prospectively through standardised clinical assessments of children with AS at the ENCORE Expertise centre for Angelman Syndrome at the Erasmus MC Sophia Children's Hospital. A linear regression analysis was conducted for the following outcome variables: (1) child HRQoL (Infant and Toddler Quality of Life Questionnaire); (2) the impact of the child's syndrome on the parent (Infant and Toddler Quality of Life Questionnaire); and (3) parenting stress (Parenting Stress Index). Predictor variables were child genotype, epilepsy, sleeping problems (Sleep Disturbance Scale for Children), cognitive developmental level (Bayley Cognition Scale), autistic features (Autism Diagnostic Observation Schedule) and emotional/behavioural problems (Child Behaviour Checklist). Covariates were sex, age and socio‐economic status.ResultsThe study sample consisted of 73 children with AS, mean age = 9.1 years, range = 2–18 years. Emotional/behavioural problems were the strongest significant predictor of lowered child HRQoL. Internalising problems were driving this effect. In addition, having the deletion genotype and higher age was related to lower child HRQoL. Sleeping problems were related to a higher impact of the child's syndrome on the parent. Finally, emotional/behavioural problems were associated with higher parenting stress. Cognitive developmental level, autistic features and epilepsy were not a significant predictor of child HRQoL and parenting stress/impact.ConclusionsThese results suggest that interventions aimed at increasing child HRQoL and decreasing parenting stress/impact in AS should focus on child emotional/behavioural problems and sleeping problems, using a family‐centred approach.

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“…We also utilized the oscillatory power to obtain power spectral densities of each frequency wave, discovering greater overall power in Syngap1 +/− mice, and elevated delta and theta power. Elevated delta power is being used as a biomarker in clinical trials for other NDDs, such as Angelman Syndrome clinical trials [25,[51][52][53][54][55]. Increased spike trains during in vivo EEG show similar patterns of activity to the increased numbers of bursts and shorter latency bursts using micro-electrode arrays (MEA) on Syngap1 +/− primary neurons.…”

Section: Discussionmentioning

confidence: 99%

Hyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutations

Silverman,

Fenton,

Haouchine

et al. 2023

Preprint

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SYNGAP1 is a critical gene for neuronal development, synaptic structure, and function. Although rare, the disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability. Without functional SynGAP1 protein, patients present with intellectual disability, motor impairments, and epilepsy. Previous work using mouse models with a variety of germline and conditional mutations has helped delineate SynGAP1’s critical roles in neuronal structure and function, as well as key biochemical signaling pathways essential to synapse integrity. Homozygous loss of SYNGAP1 is embryonically lethal. Heterozygous mutations of SynGAP1 result in a broad range of phenotypes including increased locomotor activity, impaired working spatial memory, impaired cued fear memory, and increased stereotypic behavior. Our in vivo functional data, using the original germline mutation mouse line from the Huganir laboratory, corroborated robust hyperactivity and learning and memory deficits. Here, we describe impairments in the translational biomarker domain of sleep, characterized using neurophysiological data collected with wireless telemetric electroencephalography (EEG). We discovered Syngap1+/− mice exhibited elevated spike trains in both number and duration, in addition to elevated power, most notably in the delta power band. Primary neurons from Syngap1+/− mice displayed increased network firing activity, greater spikes per burst, and shorter inter-burst intervals between peaks using high density micro-electrode arrays (HD-MEA). This work is translational, innovative, and highly significant as it outlines functional impairments in Syngap1 mutant mice. Simultaneously, the work utilized untethered, wireless neurophysiology that can discover potential biomarkers of Syngap1R-ID, for clinical trials, as it has done with other NDDs. Our work is substantial forward progress toward translational work for SynGAP1R-ID as it bridges in-vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate multiple quantitative, translational biomarkers in vivo and in vitro for the development of treatments for SYNGAP1-related intellectual disability.

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Sleep problems in children with Angelman Syndrome: The effect of a behavioral intervention program

Cited by 12 publications

References 53 publications

Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability

Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-Related Intellectual Disability

Child characteristics associated with child quality of life and parenting stress in Angelman syndrome

Hyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutations

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