CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Genetics of autosomal dominant and sporadic lateral temporal epilepsy

Autosomal dominant lateral temporal epilepsy (ADLTE) is a focal epileptic syndrome of genetic origin characterized by seizures with prominent auditory aura. It is caused by mutations in the LGI1 gene in about half of the families that segregate the syndrome. Sporadic (non familial) cases with idiopathic lateral temporal epilepsy (LTE) are clinically indistinguishable from most ADLTE patients. De novo LGI1 mutations are found in about 2% of sporadic LTE cases, providing a link between familial and sporadic patients with LTE. LGI1 is mainly expressed in neurons and shows no homology with known ion channel genes. Therefore, ADLTE represents a paradigm for the class of idiopathic epilepsies not related to ion channel mutations.

This group significantly contributed to identifying LGI1 as a causative gene for ADLTE, to characterizing LGI1 mutations, and to defining the clinical spectrum of both familial and sporadic LTE forms. Particularly, we demonstrated the genetic heterogeneity of ADLTE, described the non-familial idiopathic LTE syndrome, and identified de novo LGI1 mutations in sporadic LTE patients. We also showed that a form of reflex epilepsy termed telephone-induced partial epilepsy can be regarded as an LTE subtype as it is sometimes caused by mutations in LGI1. In collaboration with over 15 Italian epilepsy centres, we have so far collected and studied over 30 ADLTE families (111 patients) and about 150 sporadic LTE cases. By testing this patient population, we excluded several candidate genes and gene polymorphisms as susceptibility factors to LTE.

In addition, we characterized the basic biochemical properties of the Lgi1 protein, and, more recently, analysed the subcellular distribution of Lgi1 in rat cortex by immunohistochemistry and immunoelectron microscopy. In collaboration with other groups, we also showed that LGI1 may be involved in the regulation of proliferation and survival of neuroblastoma cells in vitro, suggesting that it may exert similar functions in the developing brain, and found a subtle lesion of probable developmental origin in the left temporal cortex of ADLTE patients carrying LGI1 mutations by voxel-based diffusion tensor imaging.

The main goal of our future research is to identify additional genes involved in ADLTE. This will be achieved by performing genome-wide analysis of a pool of Italian and American families without mutations in LGI1 to identify new ADLTE loci and, subsequently, by searching for the mutated genes in the chromosome regions mapped.

Publications

  • Di Bonaventura C, Carni M, Diani E, Fattouch J, Vaudano EA, Egeo G, Pantano P, Maraviglia B, Bozzao L, Manfredi M, Prencipe M, Giallonardo TA, Nobile C (2009) Drug resistant ADLTE and recurrent partial status epilepticus with dysphasic features in a family with a novel LGI1mutation: electroclinical, genetic, and EEG/fMRI findings. Epilepsia 50:2481-6.
  • Nobile C, Michelucci R, Andreazza S, Pasini E, Tosatto SC, Striano P (2009) LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum. Mutat. 30:530-6.
  • Striano P, de Falco A, Diani E, Bovo G, Furlan S, Vitiello L, Pinardi F, Striano S, Michelucci R, de Falco FA, Nobile C (2008) A novel loss-of-function LGI1 mutation linked to autosomal dominant lateral temporal epilepsy. Arch. Neurol. 65:939-42.
  • Diani E, Di Bonaventura C, Mecarelli O, Gambardella A, Elia M, Bovo G, Bisulli F, Pinardi F, Binelli S, Egeo G, Castellotti B, Striano P, Striano S, Bianchi A, Ferlazzo E, Vianello V, Coppola G, Aguglia U, Tinuper P, Giallonardo AT, Michelucci R, Nobile C (2008) Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins. Epilepsy Res. 80:1-8.
  • Tessa C, Michelucci R, Nobile C, Giannelli M, Della Nave R, Testoni S, Bianucci D, Tinuper P, Bisulli F, Sofia V, De Feo MR, Giallonardo AT, Tassinari CA, Mascalchi M (2007) Structural anomaly of left lateral temporal lobe in epilepsy due to mutated LGI1. Neurology 69:1298-300.
  • Michelucci R, Mecarelli O, Bovo G, Bisulli F, Testoni S, Striano P, Striano S, Tinuper P, Nobile C (2007) A de novo LGI1 mutation causing idiopathic partial epilepsy with telephone-induced seizures. Neurology 68:2150-1.
  • Furlan S, Roncaroli F, Forner F, Vitiello L, Calabria E, Piquer-Sirerol S, Valle G, Perez-Tur J, Michelucci R, Nobile C (2006) The LGI1/epitempin gene encodes two protein isoforms differentially expressed in human brain. J. Neurochem. 98:985-91.
  • Ayerdi-Izquierdo A, Stavrides G, Sellés-Martínez JJ, Larrea L, Bovo G, López de Munain A, Bisulli F, Martí-Massó JF, Michelucci R, Poza JJ, Tinuper P, Stephani U, Striano P, Striano S, Staub E, Sarafidou T, Hinzmann B, Moschonas N, Siebert R, Deloukas P, Nobile C, Pérez-Tur J (2006) Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy. Epilepsy Res. 70:118-26.
  • Bisulli F, Tinuper P, Scudellaro E, Naldi I, Bagattin A, Avoni P, Michelucci R, Nobile C (2004) A de novo LGI1 mutation in sporadic partial epilepsy with auditory features. Ann. Neurol. 56:455-6.
  • Bisulli F, Tinuper P, Avoni P, Striano P, Striano S, d'Orsi G, Vignatelli L, Bagattin A, Scudellaro E, Florindo I, Nobile C, Tassinari CA, Baruzzi A, Michelucci R (2004) Idiopathic partial epilepsy with auditory features (IPEAF): a clinical and genetic study of 53 sporadic cases. Brain 127:1343-52.
  • Michelucci R, Poza JJ, Sofia V, de Feo MR, Binelli S, Bisulli F, Scudellaro E, Simionati B, Zimbello R, D'Orsi G, Passarelli D, Avoni P, Avanzini G, Tinuper P, Biondi R, Valle G, Mautner VF, Stephani U, Tassinari CA, Moschonas NK, Siebert R, Lopez de Munain A, Perez-Tur J, Nobile C (2003) Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families. Epilepsia 44:1289-97.

Grants

1999-present: Temporal lobe epilepsy: identification, clinical characterization, and genetic analysis of families with mendelian inheritance. Funded by the Genetic Commission of the Italian League Against Epilepsy (LICE).

Collaborations

LICE collaborative group on epilepsy genetics

  • M. Mascalchi, University of Florence, Italy.
  • J. Perez-Tur, CSIC-Institut de Biomedicina de Valencia, Spain.
  • S. Tosatto, University of Padua, Italy.
  • C. Zancanaro/M. Malatesta, University of Verona, Italy.
  • R. Ottman, Columbia University, New York, USA.

 

PI photo

Carlo Nobile

Contact information

email  E-mail

email  049 8276072

Participating staff

Erica Diani

Sandra Furlan

Giorgia Busolin