||Lucy Treiman, PhD Barrow Epilepsy Genetics Research
Epilepsy and the associated seizure disorders are some of the most prevalent human neurological disorders. They are being diagnosed in 2% to 4% of the U.S. population, that is in 4 to 8 million individuals. Most of these patients can be treated successfully with medication to control their seizure activity. Those whose seizures are not controlled or those who have an ongoing seizure-inducing condition that requires constant surgical intervention suffer a debilitating compromise in the quality of their lives.
Epilepsy is usually a chronic condition characterized by the recurrence of spontaneous seizures. These seizures may be generalized, involving both hemispheres of the brain simultaneously, or partial, arising from epileptic activity in a specific area or focus of the brain. The generalized seizures are most frequently associated with idiopathic epilepsies which have no specific structural pathology and account for 30 to 40% of all epilepsies.
The specific genes for some of these dominantly inherited epilepsies have recently been mapped. Juvenile myoclonic epilepsy has been mapped to human Chromosome 6, benign familial neonatal convulsions to Chromosome 20, and progressive myoclonus epilepsy to Chromosome 21.
Approximately 70% of epilepsies are attributable to a significant specific brain pathology. While most of these disorders appear to be associated with traumatic brain injury, tumor, stroke, or hemorrhage, susceptibility to these conditions in some instances appears to have a strong underlying genetic component. Identification of the gene or genes that can cause or contribute to the inherited epilepsies will allow earlier, more accurate detection of people at risk for developing seizures before they become symptomatic. In the future, such studies may allow the development of effective preventive measures that will keep these potentially devastating conditions from becoming a problem.
Identifying Cerebral Cavernous Malformation Genes, CCM1, CCM2 and CCM3
Cerebral cavernous malformations (CCMs) are collections of large, closely clustered blood vessels that are separated from one another by a single layer of the cells that normally line blood vessels, the endothelium. This lack of support tissue means that these blood vessels are very weak and prone to leak blood or hemorrhage. CCMs have been found in the brain, retina, adrenal gland, skin, liver, and other internal organs. CCMs are most dangerous when found in the brain. Epilepsy is one of the most common symptoms of CCM, occurring in 50% to 85% of symptomatic patients.
At least some CCMs are known to be inherited in an autosomal dominant fashion. That is, children of an affected individual have a 50% chance of inheriting the gene that may cause the CCMs. Recently, several CCM loci (CCM1, CCM2, and CCM3) have been mapped.
A collaborative research effort involving investigators from the Barrow Neurological Institute, the National Institutes of Health, and Duke University, the CCM Consortium, has identified the CCM1 gene as KRIT1, a gene of unknown function that may be involved in cell proliferation. Investigators with the CCM Consortium are investigating the neuroanatomical and physiological implications of this discovery.
The DNA Diagnostics Laboratory at St. Joseph's hospital offers a diagnostic test for the common Hispanic CCM1 gene mutation. In association with investigators at Yale Universities, the CCM Consortium continues to fine map the intervals where the CCM2 and CCM3 genes may be found with the ultimate goal of identifying these unknown genes.
|Jie Wu, MD, PhD Epilepsy Research, Cellular Neurophysiology
Genetics of Familial Febrile Convulsions
Convulsions associated with fever are the most common form of seizures in children. Studies indicate that between 2 to 5% of all children experience an febrile convulsion before the age of 5 years. This figure is as high as 15% in certain Pacific populations. As many as 7% of children who experience febrile convulsions develop nonfebrile seizures and epilepsy later in life. This rate is 2 to 10 times higher than the rate in the general population. Some of these patients develop hippocampal sclerosis, a primary cause of idiopathic temporal lobe epilepsy.
There is a significant genetic component for susceptibility to febrile convulsions. Children from families with a history of febrile convulsions have a 3-fold greater risk for experiencing febrile convulsions. Locations for three potential febrile convulsion genes have been recently published.
The first locus (FEB1) was reported on chromosome 8q in a single Australian family. Another autosomal dominant febrile convulsion locus (FEB2) on chromosome 19p was identified in a large midwestern family. Neither of these genes has yet been identified.
A third gene, FEB3, which is located on chromosome 19q, has been identified in a well-defined clinical subset of families afflicted with generalized epilepsy with febrile seizures plus (GEFS+). Children in these families experience febrile convulsions after 6 years of age and have a higher level of afebrile generalized seizures later in life. FEB3 has been identified as a mutation in the voltage-gated sodium channel b1 subunit gene, SCN1B.
The potential long-term ramification of febrile seizures make understanding the familial form of the disease and preventing febrile convulsions in this clinically significant subpopulation an important biomedical priority. Preventing the development of febrile convulsions or ameliorating the damage they can cause in even a small percentage of the patient population will positively affect the lives of tens to hundreds of thousands of people throughout the world.
Barrow is involved in a collaborative effort with investigators from Bowman-Grey School of Medicine, Children's Hospital in Philadelphia, Columbia University and the University of Minnesota to collect families with febrile seizure to identify the genes involved.