A new locus for familial temporal lobe epilepsy on chromosome 3q.

BACKGROUND: Temporal lobe epilepsy (TLE) is a common and heterogeneous focal epilepsy syndrome with a complex etiology, involving both environmental and genetic factors. Several familial forms of TLE have been described, including familial lateral TLE (FLTLE), familial mesial TLE (FMTLE) without hippocampal sclerosis, and FMTLE with hippocampal sclerosis. Mutations have been identified only in the leucine-rich, glioma-inactivated 1 (LGI1) gene on chromosome 10q22-q24 in FLTLE. Several loci have been mapped in families with FMTLE, but responsible genes have not been found. We report clinical evaluation in a large family with FMTLE and a new genetic locus. METHODS: We conducted a genome-wide scan using 10cM-spaced microsatellite markers on a family with TLE. Seven individuals had TLE without antecedent FS; four other individuals had FS during childhood, but no subsequent epilepsy. Patients with TLE had infrequent simple partial, complex partial and secondarily generalized seizures that generally responded well to treatment. The proband had no hippocampal sclerosis. The mode of inheritance appeared to be autosomal dominant with incomplete penetrance. Linkage analysis was performed using the Genehunter software. Regions with LOD score>1 and those that were poorly informative in the first-pass scan were further genotyped. RESULTS: Linkage was identified on chromosome 3q25-q26 in a 13cM region flanked by markers D3S1584 and D3S3520, with a peak LOD score of 3.23. This interval does not correspond to any previously known locus for familial epilepsy or FS. KCNAB1, encoding a voltage-gated, shaker-related potassium channel, and NLGN1, encoding a member of a family of neuronal cell surface protein were excluded as disease causing mutations. CONCLUSION: We identified a novel locus for familial TLE with FS, providing additional evidence of the complexity and genetic heterogeneity of familial focal epilepsy.

Suggestive evidence for a new locus for epilepsy with heterogeneous phenotypes on chromosome 17q.

PURPOSE: To characterize the clinical features and molecular genetic background in a family with various epilepsy phenotypes including febrile seizures, childhood absence epilepsy, and possible temporal lobe epilepsy. METHODS: Clinical data were collected. DNA and RNA were extracted from peripheral blood. A genome-wide microsatellite marker scan was performed and regions with a multipoint location score > or =1.5 were fine mapped. Functional candidate genes identified from databases and by comparing gene expression profiles of genes between affected and unaffected individuals were sequenced. Copy number variation was evaluated with array-based comparative genomic hybridization. RESULTS: The seizure phenotype was benign. Inheritance was consistent with an autosomal dominant model and reduced penetrance. The highest two-point LOD score of 2.8 was identified at marker D17S1606 in a 37cM interval on chromosome 17q12-q24. Loci on 5q11.2 and on 18p11-q11, showed LOD scores > or =1.5 after fine mapping. Sequencing of nine ion-channel genes and two (RPIP8 and SLC25A39) differentially expressed genes from 17q12-q24, as well as IMPA2 from 18p11-q11 did not reveal a pathogenic alteration. No clinically relevant copy number variation was identified. CONCLUSIONS: Our findings suggest complex inheritance of seizure susceptibility in the family with contribution from three loci, including a possible new locus on chromosome 17q. The underlying molecular defects remain unknown.