Single-Gene Determinants of Epilepsy Comorbidity

Abstract

Common somatic conditions are bound to occur by chance in individuals with neurological disorders as prevalent as epilepsy, but when biological links underlying the comorbidity can be uncovered, the relationship may provide clues into the origin and mechanisms of both. The expanding list of monogenic epilepsies and their associated clinical features offer a remarkable opportunity to mine the epilepsy genome for coordinate neurodevelopmental phenotypes and examine their pathogenic mechanisms. Defined single-gene-linked epilepsy syndromes identified to date include all of the most frequently cited comorbidities, such as cognitive disorders, autism, migraine, mood disorders, late-onset dementia, and even premature lethality. Gene-linked comorbidities may be aggravated by, or independent of, seizure history. Mutations in these genes establish clear biological links between abnormal neuronal synchronization and a variety of neurobehavioral disorders, and critically substantiate the definition of epilepsy as a complex spectrum disorder. Mapping the neural circuitry of epilepsy comorbidities and understanding their single-gene risk should substantially clarify this challenging aspect of clinical epilepsy management.

Figure 1.

A monogenic basis for epilepsy comorbidity. Single genes contribute to distinct biology at multiple levels of brain development. Mutations, even within the same gene, can lead to highly selective patterns of pathophysiology.

Figure 2.

Examples of genes comorbid for autism and premature lethality phenotypes. (Left) Synaptic compartment contains many genes with potential to create autism and epilepsy. Deletion of Syngap1 (left) in mouse leads to epilepsy and neurobehavioral deficits. (Right) Mutation of ion channel subunit genes (indicated by red star) expressed in the heart give rise to a variety of cardiac arrhythmias and, when expressed in brain, are proepileptogenic. Human KvLQT1 mutations lead to epilepsy, cardiac arrhythmias, and sudden unexpected death in both humans and knockin mice. SUDEP, Sudden unexpected death in epilepsy. (Top left image modified from De Rubeis et al. 2014. Left lower image from Ozkan et al. 2014; reprinted, with permission, from Elsevier © 2014. Top right image modified from Gaborit et al. 2007. Bottom right image modified from Goldman et al. 2009.)