Objectives: Epilepsy genetics has undergone a revolution in the past 19 years since the discovery of the first gene for epilepsy. The story of our increasing knowledge and how it impacts on patient care is presented with reference to recent discoveries. Understanding the significance of a genetic variant is challenging both in terms of molecular pathogenicity and in how this finding fits into the rubric of causation. In some cases, it may only be a contributing susceptibility factor; whereas in others, it explains the patient's disease.
Methods: A brief overview of the clinicomolecular approaches is discussed in the context of the discovery of epilepsy genes. These include family studies and, more recently, next generation sequencing using multigene panels and whole exome sequencing.
Results: Recent studies illustrating the way in which epilepsy genetics is changing clinical practice are described. A particular focus is DEPDC5, the first gene for nonlesional focal epilepsy likely to be relevant to sporadic patients with focal epilepsies and those from small families, in contrast to rare large families with autosomal dominant focal epilepsies. As DEPDC5 is a negative regulator of the mammalian target of rapamycin (mTOR) pathway, it is likely that some patients with DEPDC5 mutations may have malformations of cortical development akin to the two-hit hypothesis suggested in tuberous sclerosis. The greatest impact of epilepsy genetics at a clinical level is for patients with epileptic encephalopathies as many have de novo mutations-a rapidly expanding list of causative genes is being found.
Conclusion: Epilepsy genetics is changing clinical practice enabling diagnosis in many patients, informing our understanding of comorbidities, prognosis, and genetic counseling. Importantly, a genetic finding may impact on treatment choices. At a biological level, new insights promise to lead to the development of novel therapies and bring together the seemingly disparate genetics of nonlesional epilepsies and epilepsies associated with cortical malformations.
Georg Thieme Verlag KG Stuttgart · New York.