application): Epilepsy is a common disorder in humans with an overall lifetime prevalence rate approaching 20/1000 individuals. It is a significant health problem especially in children and adolescents. Epilepsy is characterized by recurrent seizures which are the consequence of paroxysmal disturbances in the electrical activity of the brain. The molecular pathogenesis for most forms of human epilepsy is unknown. The applicants propose to advance the understanding of the basic molecular mechanisms of human idiopathic generalized epilepsies (IGEs) by identifying the gene responsible for an inherited form of IGE, benign familial neonatal convulsions (BFNC). The BFNC gene maps to human chromosome 20 very close to the telomere of the long arm. They have continued to augment their BFNC family resources to provide sufficient material for genetic and mutational analysis. They have identified five candidate disease genes, including voltage-gated ion channels and neurotransmitter receptors, which map close to the BFNC locus. All five of these candidates were eliminated when no mutations were found in the collection of BFNC patients. They have narrowed the genetic localization of this gene to a very small chromosomal region. Within this region they have identified a small, less than 130 kb deletion, that co-segregates with the BFNC locus in a large family. They propose to test the hypothesis that all or part of the BFNC gene lies within this deletion using standard positional cloning techniques. Discovery of the gene for BFNC would provide insight into the molecular mechanism of human epilepsies and insights into the general control of neuronal excitability, especially as it relates to the regulation of gene expression at birth and early infancy. Cloning of this gene may aid in the identification of disease genes in other, more common forms of IGE. The goal is to identify the BFNC gene, understand its function, and propose rational treatment based on this discovery.
