Epilepsy Mechanisms in Down Syndrome: Genetic and Pathophysiological Perspectives Across the Lifespan

Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability. Seizures are a frequent comorbidity in individuals with Down syndrome and can exert significant negative consequences on cognitive capacity and quality of life. In Down syndrome, seizures cluster at two extremes of the lifespan. In the first year of life, infantile epileptic spasms syndrome affects 5-10% of children with Down syndrome. The second peak occurs after age 30 years, when myoclonic seizures appear at the time of onset of Down syndrome-related dementia of the Alzheimer type (late-onset myoclonic epilepsy in Down syndrome or LOMEDS). While epilepsy at these two disparate time points has been long recognized in the Down syndrome population, the mechanisms underlying seizure pathogenesis have not been studied in detail. For example, it is not known whether the brain developmental abnormalities that characterize Down syndrome are primarily responsible for the epilepsies or whether distinct mechanisms underlie seizures at the two ages. This narrative review addresses possible mechanisms of seizure propensity across the lifespan, with special reference to potential age-specific treatments.