Epilepsy, especially pediatric epilepsy, is responsible for tremendous long-term health-care costs. Analysis of a few genetically inherited epileptic conditions, such as tuberous sclerosis [9], has allowed identification of key genes active in the developing cortex. Although most genetic abnormalities of the human cerebral cortex are rare and lethal, our rapidly advancing knowledge of the structure of the human genome makes it a realistic goal now to identify genes responsible for several other epileptic conditions. Some genes involved in cortical development also are part of important signaling pathways in the adult brain as well; therefore, such genes may be targets for drug development for improved medical treatment of epilepsy. This proposal focuses on two human disorders associate with intractable epilepsy. The long-term goal of the proposed research is to understand the clinical genetics of these conditions, to enable counseling to affected individuals and their families, and to identify the genetic abnormalities in affected individuals. Periventricular heterotopia (PH) is a mild congenital abnormality of the cerebral cortex associated with normal intellect and epilepsy.
Specific aim 1 is to clarify the genetics of PH, more closely localize the PH gene by analysis of tightly-linked genetic markers, and study associated clinical features that may define the disorder more clearly.
Specific aim 2 is to perform physical mapping and candidate gene analysis on DNA from PH patients, in order to identify the mutant gene. Double cortex/X-linked lissencephaly (DC/X-LIS) is a more severe congenital abnormality of the cerebral cortex that causes mental retardation and severe seizures.
Specific aim 3 is to clarify the genetics of DC/X-LIS, more closely localize the DC/X-LIS gene by analysis of tightly linked genetic markers, and study associated clinical features that may define the disorder more clearly. The DC/X-LIS gene is transected in a patient with lissencephaly who harbors a balanced translocation.
Specific aim 4 is to identify genomic DNA clones that span the breakpoint of the translocation, to identify cDNA's near that breakpoint, and to test these cDNA's as candidate genes in other DC/X-LIS patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology A Study Section (NEUA)
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Jacobs, Margaret
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Beth Israel Deaconess Medical Center
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