YWHAG-related epileptic encephalopathy (DEE56) is a rare genetic syndrome, affecting less than 50 known individuals, manifested by intellectual disability, epilepsy, and behavioral disorders. YWHAG encodes for the protein 14-3-3γ, involved in cell cycle regulation and signal transduction. 14-3-3 proteins are affected in neurodevelopmental disorders, such as Down Syndrome and Williams Syndrome, and neurodegenerative diseases, including Creutzfeldt-Jakob Disease and Parkinson’s Disease. Though sleep disorders have been described in up to 39% of individuals with DEE56, there is no literature on the characteristics or management of sleep in this population.

We present the case of a 10-year-old girl with intractable epilepsy and intellectual disability in the setting of DEE56, due to a heterozygous de novo YWHAG missense variant: c.169C>T p.(R57C). Her sleep disturbance began early in life, manifested by deficits in sleep initiation and maintenance, prolonged nighttime awakenings, and daytime somnolence. We discuss behavioral and pharmacologic sleep interventions utilized and present a medication regimen, which resulted in both improved sleep and seizure control.

Sleep and epilepsy have a bidirectional relationship and epileptiform activity during sleep can impair cognition, but little research has been done to characterize the clinical phenotype of sleep in epilepsy, especially in genetic epileptic encephalopathies (EEs). We present a review of the literature on what is known about the physiologic basis for sleep disturbances in several genetic disorders and specific sleep phenotypes currently characterized in neurodevelopmental disorders. Such characterization has not been done for individuals with YWHAG variants, and there is no literature discussing effective management of sleep in EEs.

This case highlights the importance of sleep management in genetic EEs and need for thorough characterization of sleep phenotypes in YWHAG and other rare genetic neurodevelopmental disorders. Understanding the physiology behind the sleep disturbances may offer timely and targeted treatment approaches for these conditions.