LATERAL TEMPORAL EPILEPSY ASSOCIATED WITH LGI1 MUTATIONS: A CLINICAL, GENETIC AND FUNCTIONAL STUDY

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

DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy

SummaryMutations in the DEPDC5 (DEP domain–containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12–37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies

Psychiatric comorbidities in patients from seven families with autosomal dominant cortical tremor, myoclonus, and epilepsy

The objective of this report was to assess the psychiatric comorbidity in a group of patients affected by autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME)

Different electroclinical picture of generalized epilepsy in two families with 15q13.3 microdeletion.

none13Coppola A;Bagnasco I;Traverso M;Brusco A;Di Gregorio E;Del Gaudio L;Santulli L;Caccavale C;Vigliano P;Minetti C;Striano S;Zara F;Striano PCoppola, A; Bagnasco, I; Traverso, M; Brusco, A; Di Gregorio, E; Del Gaudio, L; Santulli, L; Caccavale, C; Vigliano, P; Minetti, Carlo; Striano, S; Zara, F; Striano, Pasqual

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations

Purpose: In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine-rich, glioma-inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis. Methods: In a collaborative study of the Commission of Genetics of the Italian League Against Epilepsy (LICE) encompassing a 10-year period (2000-2010), we collected 33 ADLTE families, selected on the basis of the following criteria: presence of at least two members concordant for unprovoked partial seizures with prominent auditory and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a genealogic tree was built for each pedigree. The probands' DNA was tested for LGI1 mutations by direct sequencing and, if negative, were genotyped with single-nucleotide polymorphism (SNP) array to search for disease-linked copy-number variation CNV. The disease penetrance in mutated and nonmutated families was assessed as a proportion of obligate carriers who were affected. Key Findings: The 33 families included a total of 127 affected individuals (61 male, 66 female, 22 deceased). The age at onset ranged between 2 and 60 years (mean 18.7 years). Ninety-one patients (72%) had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Other symptoms included complex visual hallucinations, vertigo, and deja vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases, whereas tonic-clonic seizures occurred in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal abnormalities in 62% of cases, with a slight predominance over the left region. Magnetic resonance imaging (MRI) or computerized tomography (CT) scans were negative. LGI1 mutations (missense in nine and a microdeletion in one) were found in only 10 families (30%). The patients belonging to the mutated and not mutated groups did not differ except for penetrance estimate, which was 61.3% and 35% in the two groups, respectively (chi-square, p = 0.017). In addition, the disease risk of members of families with mutations in LGI1 was three times higher than that of members of LGI1-negative families (odds ratio [OR] 2.94, confidence interval [CI] 1.2-7.21). Significance: A large number of ADLTE families has been collected over a 10-year period in Italy, showing a typical and homogeneous phenotype. LGI1 mutations have been found in only one third of families, clinically indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a significantly lower penetrance rate and relative disease risk in non-LGI1-mutated families compared with LGI1-mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families

A prospective study of direct medical costs in a large cohort of consecutively enrolled patients with refractory epilepsy in Italy

Objective To evaluate direct medical costs and their predictors in patients with refractory epilepsy enrolled into the SOPHIE study (Study of Outcomes of PHarmacoresistance In Epilepsy) in Italy. Methods Adults and children with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers and followed for 18 months. At entry, all subjects underwent a structured interview and a medical examination, and were asked to keep records of diagnostic examinations, laboratory tests, specialist consultations, treatments, hospital admissions, and day-hospital days during follow-up. Study visits included assessments every 6 months of seizure frequency, health-related quality of life (Quality of Life in Epilepsy Inventory 31), medication-related adverse events (Adverse Event Profile) and mood state (Beck Depression Inventory-II). Cost items were priced by applying Italian tariffs. Cost estimates were adjusted to 2013 values. Results Of 1,124 enrolled individuals, 1,040 completed follow-up. Average annual cost per patient was \ue2\u82\uac 4,677. The highest cost was for antiepileptic drug (AED) treatment (50%), followed by hospital admissions (29% of overall costs). AED polytherapy, seizure frequency during follow-up, grade III pharmacoresistance, medical and psychiatric comorbidities, and occurrence of status epilepticus during follow-up were identified as significant predictors of higher costs. Age between 6 and 11 years, and genetic (idiopathic) generalized epilepsies were associated with the lowest costs. Costs showed prominent variation across centers, largely due to differences in the clinical characteristics of cohorts enrolled at each center and the prescribing of second-generation AEDs. Individual outliers associated with high costs related to hospital admissions had a major influence on costs in many centers. Significance Refractory epilepsy is associated with high costs that affect individuals and society. Costs differ across centers in relation to the characteristics of patients and the extent of use of more expensive, second-generation AEDs. Epilepsy-specific costs cannot be easily differentiated from costs related to comorbidities