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From the Department of Neurology (P.H., M.B., B.A.-K.), Center for Human Genetics Research (P.H., K.T., Y.B., J.L.H.), and Department of Molecular Physiology and Biophysics (J.L.H.), Vanderbilt University, Nashville, TN; Department of Neurology (E.A., F.A., D.D.), McGill University, Montreal, Canada; and Department of Neurology (L.C., M.P.), Université Libre de Bruxelles, Brussels, Belgium.
Address correspondence and reprint requests to Dr. Peter Hedera, Department of Neurology, Vanderbilt University, 465 21st Avenue South, 6140 MRB III, Nashville, TN 37232- 8552 peter.hedera{at}vanderbilt.edu
Purpose: To report results of linkage analysis in a large family with autosomal dominant (AD) familial mesial temporal lobe epilepsy (FMTLE).
Background: Although FMTLE is a heterogeneous syndrome, one important subgroup is characterized by a relatively benign course, absence of antecedent febrile seizures, and absence of hippocampal sclerosis. These patients have predominantly simple partial seizures (SPS) and infrequent complex partial seizures (CPS), and intense and frequent déjà vu phenomenon may be the only manifestation of this epilepsy syndrome. No linkage has been described in this form of FMTLE.
Methods: We identified a four-generation kindred with several affected members meeting criteria for FMTLE and enrolled 21 individuals who gave informed consent. Every individual was personally interviewed and examined; EEG and MRI studies were performed on three affected subjects. DNA was extracted from every enrolled individual. We performed a genome-wide search using an 8 cM panel and fine mapping was performed in the regions with a multipoint lod score >1. We sequenced the highest priority candidate genes.
Results: Inheritance was consistent with AD mode with reduced penetrance. Eleven individuals were classified as affected with FMTLE and we also identified two living asymptomatic individuals who had affected offspring. Seizure semiologies included predominantly SPS with déjà vu feeling, infrequent CPS, and rare secondarily generalized tonic-clonic seizures. No structural abnormalities, including hippocampal sclerosis, were detected on MRI performed on three individuals. Genetic analysis detected a group of markers with lod score >3 on chromosome 4q13.2–q21.3 spanning a 7 cM region. No ion channel genes are predicted to be localized within this locus. We sequenced all coding exons of sodium bicarbonate cotransporter (SLC4A) gene, which plays an important role in tissue excitability, and cyclin I (CCNI), because of its role in the cell migration and possibility of subtle cortical abnormalities. No disease-causing mutations were identified in these genes.
Conclusion: We report identification of a genetic locus for familial mesial temporal lobe epilepsy. The identification of a disease-causing gene will contribute to our understanding of the pathogenesis of temporal lobe epilepsies.
This article was previously published in electronic format as an Expedited E-Pub on March 21, 2007, at www.neurology.org.
Supported by NIH K08NS42743 to PH, and in part by GCRC Grant RR00095 to the VUMC General Clinical Research Center.
Disclosure: The authors report no conflicts of interest.
Received September 21,2006.Accepted in final form February 7, 2007.
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