Heredity in epilepsy: Neurodevelopment, comorbidity, and the neurological trait

Abstract

The genetic bases of common, nonmendelian epilepsy have been difficult to elucidate. In this article, we argue for a new approach to genetic inquiry in epilepsy. In the latter part of the 19th century, epilepsy was universally acknowledged to be part of a wider “neurological trait” that included other neuropsychiatric conditions. In recent years, studies of comorbidity have shown clear links between epilepsy and various neuropsychiatric disorders including psychosis and depression, and genetic studies of copy number variants (CNVs) have shown that in some cases, the same CNV underpins neuropsychiatric illness and epilepsy. Functional annotation analysis of the sets of genes impacted by epilepsy CNVs shows enrichment for genes involved with neural development, with gene ontological (GO) categories including “neurological system process” (P = 0.006), “synaptic transmission” (P = 0.009), and “learning or memory” (P = 0.01). These data support the view that epilepsy and some neuropsychiatric conditions share pathogenic neurodevelopmental pathways, and that epilepsy should be included in the spectrum of neurodevelopmental disorders. Yet, most current genetic research in epilepsy has restricted samples to specific types of epilepsy categorized according to the clinical classification schemes on the basis of seizure type, anatomical location, or epilepsy syndrome. These schemes are, to an extent, arbitrary and do not necessarily align with biological reality. We propose an alternative approach that makes no phenotypic assumptions beyond including epilepsy in the neurodevelopmental spectrum. A “‘value-free” strategy of reverse phenotyping may be worth exploring, starting with genetic association and looking backward at the phenotype. Finally, it should be noted that there are societal implications to associating epilepsy with other neuropsychiatric disorders, and it is vital to ensure research in this area does not result in increased stigma for patients with epilepsy.

Introduction

Published estimates of heritability for epilepsy indicate that epilepsy has a strong genetic basis [1], [2], [3], [4], yet other than a few rare mendelian forms of the disease, we know very little about the molecular genetic contributions to epilepsy. It has been suggested that genetic research efforts in the more common, sporadic forms of epilepsy have failed because of the inadequate statistical power of existing genetic association studies [5] or because the genetic formulation of epilepsy as predominantly a common variant disease is incorrect [6]. In this article we take an alternative perspective on epilepsy genetics that instead focuses on the nature of the epilepsy phenotype itself. The epilepsies referred to in this article are the common, mostly sporadic forms of epilepsy loosely termed idiopathic or cryptogenic, for which no structural or metabolic cause can be demonstrated. Drawing on the historical epilepsy literature, as well as more recent advances in epilepsy epidemiology and molecular genetics, we argue that genetic susceptibility to epilepsy should be studied from the broader perspective of epilepsy being a neurodevelopmental disorder, with shared mechanisms with other neuropsychiatric disorders. We call for a reappraisal of the epilepsy phenotype in genetic research that departs from one based solely on seizure semiology, epilepsy syndrome, or anatomical localization. We suggest that genetic inquiry of epilepsy from this mechanistic point of view may yield novel insights into the etiology of epilepsy.

Before considering the evidence for this position from modern genetics, we first mention some historical aspects of thought on the heredity of epilepsy from the mid-19th century, as the astute clinical observations made then throw an interesting light on this issue.