Abstract
The number of genes underlying monogenic epilepsies in human and animal models continues to grow as the clinical syndromes for a variety of heritable epilepsies yield to neurogenetic analysis. Interestingly, the diversity of co-morbid phenotypes linked to single epilepsy gene defects is also expanding. While many rare familial idiopathic epilepsy disorders are typically defined as "pure" seizure syndromes, many occur in the context of more complex clinical symptomatology. This is not surprising, since genes that alter cortical excitability are expressed in diverse brain networks, as well as in other tissues. In this brief review, two such genes are described. The gene encoding amyloid precursor protein along with related genes contributing to the accumulation of an aberrant peptide cleavage product, Aβ42, has now been placed in a molecular pathway mediating both the dementia of Alzheimer's Disease and seizures. A second gene, KCNQ1, encoding one of the voltage-sensitive ion channels contributing to membrane repolarisation in the heart, is co-expressed in both heart and brain where mutations contribute to cardiac arrhythmias, early mortality, and seizures. KCNQ1, a member of the cardiac LQTS gene family, is the first validated candidate gene for sudden unexplained death in epilepsy (SUDEP). The new strategy of searching for epilepsy genes linked to non-epileptic co-morbidity is providing illuminating examples of the role of neuronal network hyperexcitability in explaining the clinical spectrum of complex human neurological disorders that feature seizures.
