The role of altered translation in intellectual disability and epilepsy

A very high proportion of cases of intellectual disability are genetic in origin and are associated with the occurrence of epileptic seizures during childhood. These two disorders together effect more than 5% of the world's population. One feature linking the two diseases is that learning and memory require the synthesis of new synaptic components and ion channels, while maintenance of overall excitability also requires synthesis of similar proteins in response to altered neuronal stimulation. Many of these disorders result from mutations in proteins that regulate mRNA processing, translation initiation, translation elongation, mRNA stability or upstream translation modulators. One theme that emerges on reviewing this field is that mutations in proteins that regulate changes in translation following neuronal stimulation are more likely to result in epilepsy with intellectual disability than general translation regulators with no known role in activity-dependent changes. This is consistent with the notion that activity-dependent translation in neurons differs from that in other cells types in that the changes in local cellular composition, morphology and connectivity that occur generally in response to stimuli are directly coupled to local synaptic activity and persist for months or years after the original stimulus.