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Sleep in Angelman Syndrome: Data from the Natural History Study

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Up to 80% of children with neurodevelopmental disorders present with sleep disruption.  Angelman Syndrome (AS) is one such disorder in which sleep disturbance is a prominent feature. There are four described molecular etiologies for AS: deletion of the AS critical region on the maternally-inherited chromosome 15q11q13 (Del+), paternal uniparental disomy (UPD) for chromosome 15q11q13, pathogenic variants of the maternally inherited UBE3A, and imprinting defect (ImpD) where the maternal copy of UBE3A is erroneously given the paternal imprint and silenced. First-line interventions for pediatric insomnia are behavioral, but the evidence for their efficacy is weak, and they are challenging to implement, so many individuals resort to pharmacological treatments. Sleep deprivation increases parental stress levels and negatively affects the behavior, functioning, and quality of life of the affected individuals. We analyzed longitudinal sleep data from the AS Natural History Study (NHS), including the use of pharmacological treatments, to determine the prevalence of sleep problems and the adequacy of their treatment.  We also examined whether sleep disruption varied according to age and molecular subtype.

 

Methods:
Data were obtained from the AS Natural History Study (NHS), a longitudinal observational study that has enrolled individuals of all ages with a molecular diagnosis of AS since 2006. Sleep problems were captured by two detailed sleep questionnaires: a validated instrument [Schlaffragebogen für Kinder mit Neurologischen und Anderen Komplexen Erkrankungen, SNAKE], and a questionnaire developed by the investigators.

Results:
Sleep data were available on 461 individuals with AS. Among these, 147 participants completed the SNAKE questionnaire, 263 completed the investigator-designed questionnaire, and 51 completed both assessments. Overall, 85.9% of families reported sleep difficulties (80% of individuals between one and 13 years, and 90% of those older than 13 years). Families reported that at least 60% of children with AS awoke during the night more than two nights per week. There were no significant differences in sleep patterns among the different molecular etiologies of AS.

Caregivers reported that 70% of individuals Del+ and 40-55% of the non-deletion subgroups experienced physical exhaustion the day after a bad night of sleep (p=0.06). They also reported that nearly 50% of the patients with UPD and ImpD showed more aggression after a bad night of sleep, compared to approximately 30% of those with Del+ or UBE3A pathogenic variants (p=0.01).

Even though sleep disturbances were reported in 85% of the individuals, the use of sleep medication was reported in 60% of the participants. Melatonin was the most commonly used medication, in about 45% of the cohort, while diphenhydramine and clonidine were each used in approximately 15% of individuals.

The analysis of the SNAKE questionnaire revealed considerable fluctuations in the sleep scores over time, with clear periods of worsening sleep, indicated by higher scores, and intervals of improvement with lower scores. Notably, these changes occurred independently of medication use.

 

Conclusion:


Sleep disturbance is a significant problem for individuals with AS and their families; adequate treatments remain an unmet clinical need. Future studies are needed to elucidate the contributors to the inconsistent sleep pattern and the effectiveness of pharmacological agents. Understanding potential barriers to the use of pharmacological treatment is essential to guide the medical care of patients with AS.

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