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LGI1 mutations in temporal lobe epilepsies

From the Epilepsy Research Institute and Department of Medicine (Neurology) (Drs. Berkovic, Briellmann, and Scheffer, and J.M. McMahon and A.M. McIntosh), University of Melbourne, and Brain Research Institute (Dr. Briellmann), Heidelberg Repatriation Hospital, Austin Health, Heidelberg, Victoria; Centre for Medical Genetics (P. Izzillo, L.A. Harkin, and H.A. Phillips, and Drs. Wallace and Mulley), Department of Laboratory Genetics, Women’s and Children’s Hospital, Adelaide, South Australia; Department of Paediatrics (L.A. Harkin and Dr. Wallace) and Department of Molecular Biosciences (Dr. Mulley), University of Adelaide, South Australia; Department of Neurology (Drs. Mazarib, Neufeld, and Korczyn), Tel-Aviv Sourasky Medical Center, Israel; and Sieratzki Chair of Neurology (Dr. Korczyn), Tel Aviv University, Ramat Aviv, Israel.

Address correspondence and reprint requests to Dr. Samuel F. Berkovic, Director, Epilepsy Research Institute, Level 1, Neurosciences Building, Heidelberg Repatriation Hospital, Banksia Street, West Heidelberg, 3081 Victoria, Australia; e-mail: s.berkovic{at}unimelb.edu.au

Background and Objectives: A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations.

Methods: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4.

Results: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124TG; C42G) and 8 (c.1418CT; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families.

Conclusion: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

Received August 28, 2003. Accepted in final form November 4, 2003.

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