Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12–30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome. To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12). Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls. This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG—routinely ordered for epilepsy monitoring—opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology. We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions.

中文翻译：

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15q11.2-13.1重复（Dup15q）综合征患儿睡眠生理异常

自闭症谱系障碍 (ASD) 中的睡眠障碍是一种常见且令人烦恼的合并症。这些之间的临床异质性需要研究与特定遗传病因相关的机制。15q11.2-13.1（Dup15q 综合征）的重复对智力障碍和 ASD 等神经发育障碍 (NDD) 以及睡眠障碍具有高度渗透性。15q 区域的基因，特别是 UBE3A 和一组 GABAA 受体基因，对神经发育、突触蛋白合成和降解以及抑制性神经传递至关重要。在清醒脑电图 (EEG) 期间，患有 Dup15q 综合征的儿童表现出增加的 β 波段振荡 (12-30 Hz)，这可能反映了异常的 GABA 能神经传递。健康的睡眠节律，是强大的认知发展所必需的，也高度依赖 GABA 能神经传递。因此，我们假设 Dup15q 综合征儿童的睡眠生理学会异常。为了检验 Dup15q 综合征中升高的 β 振荡在睡眠中持续存在以及 NREM 睡眠节律会被打乱的假设，我们计算了：(1) β 功率，(2) 纺锤体密度，和 (3) 慢波睡眠 (SWS) 的百分比) 在一组患有 Dup15q 综合征的儿童 (n = 15) 的夜间睡眠脑电图记录中，并将它们与年龄匹配的神经型儿童 (n = 12) 进行比较。与年龄匹配的神经典型对照组相比，患有 Dup15q 综合征的儿童表现出异常的睡眠生理，β 功率升高、纺锤体密度降低以及 SWS 减少或缺失。该研究依赖于无法进行睡眠分期的临床脑电图。然而，考虑到在这一人群中收集临床多导睡眠图具有挑战性，因此能够在临床 EEG 上量化这些生物标志物（通常用于癫痫监测）为更大规模的研究打开了大门。虽然与罕见遗传疾病的其他人类研究相当，但更大的样本将允许检查可能影响睡眠生理学的癫痫发作严重程度、药物和发育年龄的作用。我们已经确定了 Dup15q 综合征中睡眠中断的三个定量 EEG 生物标志物，这是一种对 ASD 具有高度渗透性的遗传状况。这项研究的见解不仅促进了对定义 Dup15q 综合征的病理生理学的更大机制理解，而且为研究睡眠与认知之间的关联奠定了基础。