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Twelve Novel Mutations Identified

Claudio Zucca, MD; Francesca Redaelli, PhD; Roberta Epifanio, MD; Nicoletta Zanotta, MD; Antonino Romeo, MD; Monica Lodi, MD; Pierangelo Veggiotti, MD; Giovanni Airoldi, PhD; Chris Panzeri, PhD; Romina Romaniello, MD; Gianni De Polo, MD; Paolo Bonanni, MD; Simonetta Cardinali, MD; Cinzia Baschirotto, BS; Loreto Martorell, PhD; Renato Borgatti, MD; Nereo Bresolin, MD; Maria Teresa Bassi, PhD

Arch Neurol. 2008;65(4):489-494.

Background  Sodium channel alpha 1 subunit gene, SCN1A, is the gene encoding the neuronal voltage-gated sodium channel 1 subunit (Na_v1.1) and is mutated in different forms of epilepsy. Mutations in this gene were observed in more than 70% of patients with severe myoclonic epilepsy of infancy (SMEI) and were also found in different types of infantile epileptic encephalopathy.

Objective  To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause).

Design  Clinical characterization and molecular genetic analysis of a cohort of patients.

Setting  University hospitals, rehabilitation centers, and molecular biology laboratories.

Patients  Sixty unrelated patients with cryptogenic epileptic syndromes.

Main Outcome Measures  Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening.

Results  No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative.

Conclusions  These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.

Author Affiliations: Clinical Neurophysiology Unit (Drs Zucca, Epifanio, and Zanotta), Laboratory of Molecular Biology (Drs Redaelli, Airoldi, Panzeri, Bresolin, and Bassi and Ms Baschirotto), and Department of Neurorehabilitation (Drs Romaniello and Borgatti), E. Medea Scientific Institute, Lecco, Italy; Epilepsy Center, Department of Child Neuropsychiatry and Neurophysiology, Fatebenefratelli e Oftalmico Hospital, Milan, Italy (Drs Romeo and Lodi); Department of Child Neurology and Psychiatry, IRCCS C. Mondino Foundation, University of Pavia, Pavia, Italy (Dr Veggiotti); Clinical Neurphysiology Unit, E. Medea Scientific Institute, Conegliano, Italy (Drs De Polo and Bonanni); Child Neuropsychiatry Unit, Azienda Ospedaliera G. Salvini, Garbagnate Milanese, Milan (Dr Cardinali); Molecular Genetics Section, Sant Joan de Déu Hospital, Barcelona, Spain (Dr Martorell); and Dino Ferrari Center, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Department of Neurological Sciences, University of Milan, Milan (Dr Bresolin).