Sleep disruption and neuropsychiatric features in Angelman syndrome: insights into underlying neurobiology.

Abstract

Sleep disorders are a core feature of Angelman syndrome (AS), affecting approximately 80% of individuals. They typically manifest as insomnia and disrupted sleep-wake cycles and contribute substantially to the burden experienced by affected individuals and their families. AS is caused by loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, which encodes the E3 ubiquitin ligase E6AP, a protein essential for synaptic development and function. In individuals with a maternal 15q11-q13 deletion, concomitant deletion of neighboring non-imprinted genes, including GABRB3, GABRA5, GABRG3, ATP10A, and HERC2, may also contribute to the phenotype. Evidence from animal models further indicates that UBE3A plays a key role in sleep homeostasis and circadian rhythm regulation, including through interactions with core clock genes such as BMAL1. In this narrative review, we examine the role of UBE3A in sleep regulation and outline the principal sleep disturbances observed in AS, integrating findings from both preclinical models and human studies, while also considering genotype-phenotype correlations for the main clinical manifestations. The available evidence suggests that sleep disruption may be closely linked to the core neurological and behavioral features of AS, particularly epilepsy and behavioral abnormalities, through shared pathophysiological mechanisms related to UBE3A deficiency. Early identification and management of sleep disturbances may therefore represent a potentially modifiable factor for improving behavioral outcomes, seizure control, and overall quality of life in individuals with AS. In addition, sleep measures should be considered as potentially relevant clinical endpoints in ongoing trials of emerging therapeutic strategies.