Pediatric epilepsy genetics

Genetic epilepsies in childhood are a complex group of disorders, with heterogeneous etiologies and clinicopathologic features. This review focuses on primary genetic epilepsies, which may have variable neuropsychiatric comorbidities, but usually have no underlying gross neuropathology or evident metabolic disturbance. Epilepsy due to inherited metabolic diseases, chromosomal abnormalities, phakomatoses, or malformations of cortical development is reviewed elsewhere.

The use of high-throughput approaches to sequence DNA and to detect copy number variants is revealing a landscape of mutations in genetic epilepsies, affecting a variety of genes involved in neuronal excitability, synaptic transmission, neuronal metabolism, or network development.

A number of distinct clinical syndromes of pediatric genetic epilepsy have been described and linked to specific gene defects. Phenotypes may include, in addition to epilepsy, variable degrees of intellectual disability, elements of autism spectrum disorders, other psychiatric disorders, and motor impairment. In some cases, these comorbidities derive from uncontrolled seizure activity (epileptic encephalopathies), but in other cases they are direct, multifaceted consequences of global brain dysfunction. Mutations may be de novo, or, when inherited, show reduced penetrance and variable expressivity. Understanding the genetics of these conditions will improve diagnosis, reveal pathogenic mechanisms, and eventually lead to better treatment.