Abstracts

Rationale: Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is genetically heterogeneous, with LGI1 gene mutations accounting for less than 50% of ADLTE families. Additional ADLTE-related genes are unknown. It may be hypothesized that this genetic heterogeneity is caused by differences in the clinical or genetic characteristics of the families. Here we report the clinical and genetic spectrum of ADLTE in Italy. Methods: In a collaborative study of the Commission for Genetics of the Italian League against Epilepsy spanning the last 8 years we selected 33 families in which at least two members showed auditory and/or aphasic seizures, suggesting a lateral temporal onset. The probands and affected family members underwent a complete clinical, EEG and MRI study. Probands' DNAs were tested for LGI1 mutations by direct sequencing. We also calculated the clinical penetrance of LGI mutations in mutated families as well as the penetrance of the disease among proband s relatives in all pedigrees. Results: Based on genetic analysis, we subdivided the families in two main groups: 1) 9 families (38 affected subjects - 7 deceased) with LGI1 missense mutations (27 %) 2) 24 families (78 affected subjects - 14 deceased) without LGI1 mutations (73 %). The clinical features of the patients belonging to the two groups did not differ substantially as to age at onset (20 vs 18 years), frequency of auditory auras/aphasic seizures (73% vs 77%), and occurrence of tonic-clonic seizures (61% vs 63%). Interestingly only in the second group there were additional family members (8) with idiopathic generalized epilepsy whereas febrile seizures were equally distributed in both groups (4 and 6 cases respectively). The penetrance of LGI1 mutations calculated on 6 families was 58%, which is likely underestimated due to limited DNA availability. Segregation analysis of probands first and antecedent second degree relatives estimated a penetrance of 78% in mutated ADLTE families, whereas penetrance was 54% in families without LGI1 mutations. Conclusions: ADLTE is caused by LGI1 mutations in about 27% of italian families, a percentage significantly lower than hitherto reported. In the non-mutated group the penetrance is significantly lower than in mutated families, suggesting that part of the families currently classified as ADLTE may in fact exhibit complex inheritance of lateral temporal epilepsy.