Mutational analysis of inherited epilepsies

Abstract

Single-gene mutations in mice initiate specific heritable neuronal diseases featuring different patterns of epilepsy. Thirteen chromosomal loci for convulsive seizures and four loci for spike-wave seizures have been assigned. Within this genetic framework, a few general principles are emerging. Mutations located on different chromosomes may result in identical seizure patterns. Interactions between specific genes, demonstrated by the synthesis of compound heterozygotes, can express intermediate syndromes. Interactions with unknown genes in the background can mask neurological disease expression. Analysis of the cellular phenotypes of epileptic mutants is a direct strategy to define naturally occurring defects in central synaptic pathways involved in cortical synchronization. In one allele of the tottering locus, a pathogenetic lesion linking noradrenergic hyperinnervation with cortical spike-wave discharges has been identified. The tottering gene initiates an overgrowth within all target innervation areas of axon terminals originating from the locus coeruleus (LC). Selective neonatal denervation of the excess noradrenergic axons permanently prevents the subsequent appearance of cortical spike-wave seizures in the adult animal. Partial lesions of central noradrenergic afferent fibers in adults temporarily reverse the seizure disorder. Other criteria defining the relationship between the mutant gene and the electrophysiologic traits and the role of central noradrenergic pathways in neuronal synchronization are reviewed. Isolating and tracing the developmental expression of epileptic mutations permits a formal classification of gene-linked excitability defects, a derivation of basic rules governing their inheritance, and the design of strategies to correct the gene error. By allowing phenotypic comparisons with over 60 known human inherited neurological diseases associated with seizures, these models may directly contribute to advances in the clinical management of epileptic gene expression.