Abstracts

Rationale: Autosomal dominant lateral temporal epilepsy (ADLTE) otherwise known as autosomal dominant partial epilepsy with auditory features (ADPEAF) is associated with Leucine-rich glioma inactivated 1 (LGI1) gene mutations in less than 50% of the families. Only recently heterozygous mutations of a second gene, reelin (RELN), have been detected in 7 Italian ADLTE families through single nucleotide polymorphism-array linkage analysis and whole exome sequencing (Dazzo et al, AJHG, 96, 992-1000, 2015). Here we describe the clinical phenotype of such families comparing the data with those observed in 12 LGI1-mutated pedigrees.Methods: Out of 40 Italian families with ADLTE, collected by epileptologists adhering to a collaborative study of the Commission for Genetics of the Italian League against Epilepsy encompassing a 14-year period (2000-2014), 7 (17.5%) were found to harbour heterozygous RELN mutations. The whole series also included 12 (30%) LGI1 mutated families and 21 (52.5%) non-mutated pedigrees. The families were selected on the basis of the following criteria: presence of at least two family members concordant for unprovoked partial seizures with auditory auras or aphasic symptoms, absence of any known brain pathology and normal neurological examination. The clinical, neurophysiological and neuroradiological findings of the families were analysed and a genealogical tree was built for each pedigree.Results: The 7 RELN mutated families included a total of 25 affected individuals (9 males, 16 females, 4 deceased). The age at onset ranged between 10 and 30 years (mean 20.6 years). Eighteen patients (72%) had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 64%of the cases. Other symptoms included complex visual hallucinations, vertigo, and déjà vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases whereas tonic-clonic seizures occurred in 84% of the overall series. Sudden noises could precipitate the seizures in about 8% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the vast majority of patients . The interictal EEGs showed epileptiform temporal abnormalities in 40% of cases, with a predominance over the left region. MRI or CT scans were unrevealing. These clinical findings were compared with those observed in 12 Italian LGI1 mutated families and did not differ substantially for any feature.Conclusions: RELN mutations were associated with a typical ADLTE phenotype indistinguishable from that observed in LGI1 mutated families. Our findinds support the view that ADLTE is a genetically heterogeneous condition with LGI1 and RELN mutations accounting for almost half of the families in Italy.