Abstracts

Rationale: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a genetic form of temporal lobe epilepsy with auditory symptoms and receptive aphasia as prominent ictal manifestations. Mutations in the leucine rich, glioma inactivated 1 gene (LGI1) are found in up to 50% of families with ADPEAF, but the genes that influence risk in the remaining families have not yet been identified. We carried out genome-wide linkage analysis in 11 families with clinical symptoms consistent with ADPEAF and without LGI1 mutations, to identify chromosomal regions likely to harbor additional genes that raise risk for this syndrome. Methods: Families were included if they contained ?2 individuals with focal epilepsy with ictal auditory symptoms or receptive aphasia. Initial analyses used 390 microsatellite markers spaced at an average of 9cM throughout the genome, genotyped at the Center for Inherited Disease Research. Additional microsatellite markers were later typed in a region on chromosome 1 showing elevated LOD scores. Two-point and multipoint linkage analyses were performed as implemented in GENHUNTER2, assuming autosomal dominant inheritance with age-dependent penetrance of 67%, no sporadics, and a susceptibility allele frequency of 0.001. Two definitions of affection status were used: focal non-acquired unprovoked seizures (narrow) and any form of non-acquired unprovoked seizures (broad). Individuals with unprovoked seizures associated with structural or metabolic CNS insults were classified as unknown, and those with febrile or other acute seizures were classified as unaffected. Results: The 11 included families contained a total of 245 individuals (192 living, 53 deceased), of whom 135 were genotyped. The number of individuals per family with non-acquired epilepsy ranged from 2-7 and averaged 4.3 (focal 3.4, generalized 0.2, both 0.1, unclassifiable 0.6). Among individuals with focal epilepsy, an average of 2.7 (range 2-4) individuals per family had ictal auditory symptoms or receptive aphasia. The highest HLOD was observed for the focal epilepsy phenotype at 262cM on chromosome 1 (HLOD=2.65, alpha=0.76). HLODs were also ?1.5 in two other regions: chromosome 1, 154cM (HLOD=1.50, alpha=0.43) and chromosome 17, 121cM (HLOD=1.53, alpha=0.53). These results were strongly influenced by one large family with some clinical features atypical of ADPEAF (i.e., 3/7 individuals with epilepsy had previous febrile seizures). When this family was excluded from the analysis, the highest HLOD was on chromosome 17, 121cM (HLOD=1.82, alpha=0.63). Conclusions: The findings indicate regions to be prioritized for additional analyses to identify susceptibility genes for ADPEAF. Collaborative studies are underway to increase the sample size and include dense SNP genotyping for further analyses.