Neuropsychological disturbances in frontal lobe epilepsy due to mutated nicotinic receptors Fabienne Picard a, * , Alan J Pegna b , Venke Arntsberg c , Nadia Lucas d , Izabela Kaczmarek e , Olga Todica f , Carmelina Chiriaco g , Margitta Seeck a , Eylert Brodtkorb h a Department of Neurology, University Hospital and Medical School of Geneva, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland b Neuropsychology Unit, Department of Neurology, University Hospital and Medical School of Geneva, Geneva, Switzerland c Psychiatric Centre, Neuropsychological Service, Helgeland Hospital, Mosjøen, Norway d Laboratory of Neurology and Imaging of Cognition, University Hospital and Medical School of Geneva, Geneva, Switzerland e Developmental Neurology, Clinical Hospital 2, Poznan, Poland f Department of Neurology, University of Duisberg-Essen, Essen, Germany g Institute of Neurology, Magna Graecia University of Catanzaro, Catanzaro, Italy h Department of Neuroscience, Norwegian University of Science and Technology, and Department of Neurology and Clinical Neurophysiology, St. Olav’s Hospital, Trondheim, Norway article info Article history: Received 29 September 2008 Accepted 14 November 2008 Available online 6 December 2008 Keywords: Autosomal dominant nocturnal frontal lobe epilepsy Epilepsy Neuropsychology Cognition Nicotinic receptor Genetics abstract Mutations in nicotinic receptor subunits have been identified in some families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Normal intelligence has currently been considered the rule, although anecdotal cases with intellectual disability have been reported. We aimed to evaluate the fre- quency and degree of neuropsychological disorders in ADNFLE associated with nicotinic receptor muta- tions by testing 11 subjects from four families with a comprehensive neuropsychological assessment. General intellectual function was below the normal range in 45% of the subjects. All were abnormal in one or more executive task. Memory was either more affected than executive functions or equally affected in two thirds of subjects, suggesting a frontotemporal pattern of cognitive impairment. Cognitive dysfunction appears to be an integral part of the broad phenotype of ADNFLE with nicotinic receptor mutations, a fact that has been underestimated until now. The cognitive disorder affects executive func- tions as well as memory in most subjects. Ó 2008 Elsevier Inc. All rights reserved. 1. Introduction Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an inherited nonlesional partial epilepsy syndrome, with more than 100 families reported. To date, mutations have been found in three different subunits (a4, b2, and a2) of the neuronal nico- tinic acetylcholine receptor (nAChR). In total, seven different muta- tions have been identified, in 15 families [1,2]. A normal interictal clinical neurological examination, including normal intelligence, was one of the features originally described, and the majority of la- ter reports emphasized normal intellectual function in patients with ADNFLE [3–7]. Conceivably, a neuropsychological approach could possibly contribute to differentiate patients with nocturnal frontal lobe epilepsy (NFLE) of genetic origin from patients with lesional forms. However, neuropsychological deficits have sporad- ically been described in some families. The aim of the present study was to estimate the frequency and extent of neuropsycho- logical disturbances in ADNFLE. Eleven individuals originating from four unrelated ADNFLE families, each carrying a different nic- otinic receptor mutation, were assessed using a comprehensive neuropsychological evaluation in the search for cognitive deficits. 2. Methods 2.1. Patients Eleven adults from four different families with a detected nico- tinic receptor mutation were studied (Table 1). The families came from Poland, Norway, Germany, and Italy [8–11]. The nAChR muta- tion was different in each family: three mutations affected the a4 subunit (S252L, S248F, and T265I) and one the b2 subunit (V287L). Nine individuals had epilepsy, eight of whom received antiepilep- tic medication, and two were mutation carriers never diagnosed with seizures. Events predisposing to brain dysfunction (e.g., head trauma) were not reported by any of the patients. Seven individu- als were still experiencing seizures at the time of the study, but some of them took only low doses of antiepileptic drugs or had poor compliance. All these individuals were described in previous reports as having a normal clinical neurological examination. In 1525-5050/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2008.11.003 * Corresponding author. Fax: +41 22 372 82 99. E-mail address: Fabienne.Picard1@hcuge.ch (F. Picard). Epilepsy & Behavior 14 (2009) 354–359 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh