Epilepsy, a common disease in humans, is a significant health problem. Genetic predilection to seizures is a major risk factor associated with epilepsy.
The aim of this proposed study is to elucidate the genetic cause for a specific type of idiopathic generalized epilepsy, benign familial neonatal convulsions (BFNC). BFNC is characterized by onset in the neonatal period, with seizures spontaneously remitting after several months. The genetic mutation responsibility for the seizures is inherited as an autosomal dominant trait. The mutated gene for BFNC is known to reside near the telomere of the long arm of chromosome 20, between the flanking markers ms214 and ms617. A region of not recombination in affected individuals can be defined in all chromosome 20-linked BFNC families by the markers RMR6, CMM6, and IP20K09. This defined region is also one where a higher than average frequency of recombination occurs. Pulsed-field gel analysis by several laboratories, including our own, have demonstrated that in this region of no recombination, a physical distance of 480kb corresponds to a genetic distance of 9cM in CEPH reference families, a 20-fold enhancement over the genome-wide average. As 7 BFNC families with 73 meiotic events in affected individuals alone are currently available for this study, and substantial progress has already been made towards the contiguous cloning in P1 vectors of the complete genomic region, the positional cloning of the BFNC gene has an excellent likelihood of success. We are confident of finding the BFNC gene by identifying mutations in cDNAs mapping physically to the region or by identifying mutations in candidate genes which map to the region. Such a candidate genes which map to the region. Such a candidate gene, a K+ ion channel gene, has recently been mapped to the distal region of chromosome 20q. Currently, the specific molecular mechanisms resulting in human epilepsy are poorly understood. Therefore the identification of the BFNC gene will be important for understanding the fundamental nature of epilepsy. Ultimately, the discovery of the molecular basis for BFNC may lead to valuable insights into the causes of other human idiopathic epilepsies as well as to more rational methods of treatment and prevention.
