Santulli, Lia (2016) LATERAL TEMPORAL EPILEPSY ASSOCIATED WITH LGI1 MUTATIONS: A CLINICAL, GENETIC AND FUNCTIONAL STUDY. [Tesi di dottorato]

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Introduction. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene or epitempin cause autosomal dominant lateral temporal epilepsy (ADLTE), an epileptic syndrome characterized by focal seizures with prominent auditory symptoms and benign clinical course. Lgi1 function is not completely defined and it seems to mediate proteins to proteins interactions in synapses. To date, 38 LGI1 mutations have been described and most of them inhibit protein secretion (loss-of-function). In the present study we aimed to better define the clinical phenotype of ADLTE associated with LGI1 mutations and to further investigate the pathogenic mechanisms underlying the syndrome. Particularly we evaluated the functional effect of some identified mutations. Methods. Families were selected on the basis of an ADLTE diagnosis according to defined diagnostic criteria. Almost all the affected individuals were submitted to clinical assessment, video-electroencephalogram (EEG) monitoring and magnetic resonance imaging (MRI). A positron emission tomography (PET) and a psychiatric assessment by means of validated psychometric scales were obtained in some individuals. Genetic analysis included LGI1 sequencing and multiple ligation-dependant probe amplification (MLPA) assay in patients without point mutations. The expression of Lgi1 mutant proteins was evaluated in cultured cells by a secretion assay. The interaction of extracellular Lgi1 mutated proteins with ADAM 22/23 receptors (a Disintegrine and Metallopeptidase domain family) was investigated by means of both co-transfection and immunofluorescence and co-immunoprecipitation assays. Results. Four families out of eight identified were included into the study. Three presented missense mutations and one a microdeletion. PET study demonstrated a mild hypermetabolism of the right temporal lobe in patients compared to controls at SPM analysis. Psychiatric assessment provided evidence for a psychiatric diagnosis in most of the patients and for higher level of impulsiveness in patients compared to a control group. Two mutations (R406C; T380A) were showed to not impair completely protein secretion. However they reduced Lgi1 binding to ADAM22/23 receptors. Discussion and conclusions. We described four families with different LGI1 mutations. In our patients we noticed a prevalence of ictal symptoms different from auditory auras higher than previously reported in other series. A psychiatric comorbidity was also present and seems to emerge as a new aspect in some ADLTE families. As to genetic aspects we found a microdeletion in one family, confirming the possibility of copy number variations (CNVs) as causative mutations. The functional study demonstrated a pathogenic mechanism different from inhibition of secretion for two mutations suggesting a possible role of the ADAM22/23 receptors in the pathogenesis of this condition.

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