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Deletions involving both KCNQ2 and CHRNA4 present with benign familial neonatal seizures

From the Department of Pediatrics (H.K., J.-w.W., A.I., K.Y., T.I., S.Y., A.O., S.H.), School of Medicine, Fukuoka University; Department of Pediatrics (H.K.), Nagoya University Graduate School of Medicine, Japan; Department of Pediatrics (J.-w.W.), Qilu Hospital, Shandong University, Jinan, China; Computational Systems Biology Research Group (T. Kojima), RIKEN, Yokohama; Nakanoshima Clinic (S.W.), Sapporo; Department of Pediatrics (T. Kizawa), Iwamizawa Municipal General Hospital; Niimi Central Hospital (Y.F.); Kochi Health Sciences Center (K.K.); and Department of Neuropsychiatry (S.K.), Hirosaki University, Graduate School of Medicine, Japan.

Address correspondence and reprint requests to Prof. Shinichi Hirose, 45-1, 7-chome, Nanakuma Jonan-ku, Fukuoka 814-0180, Japan hirose{at}fukuoka-u.ac.jp

Objective: Mutations of the genes encoding subunits of potassium voltage-gated channel, KCNQ2 and KCNQ3, have been identified in patients with benign familial neonatal seizures (BFNS). This study set out to determine the frequency of microchromosomal deletions of KCNQ2 or KCNQ3 associated with BFNS.

Methods: The study subjects were patients with BFNS (n = 22). Microdeletions were sought by multiplex ligation-dependent probe amplification and then confirmed by fluorescence in situ hybridization and characterized by array-based comparative genomic hybridization.

Results: Heterozygous multiple exonic deletions of KCNQ2 were identified in 4 of 22 patients with BFNS. Concomitant deletions of adjacent genes, including nicotinic cholinergic receptor 4 (CHRNA4), were detected in 2 of the 4 cases. The clinical courses of patients with deletions of both KCNQ2 and CHRNA4 were those of typical BFNS, and none presented with the phenotype of autosomal dominant nocturnal frontal lobe epilepsy, some of which are caused by mutations of CHRNA4.

Conclusions: Our findings indicate that the clinical courses of patients with deletions of both KCNQ2 and CHRNA4 are indistinguishable from those of patients with deletions of KCNQ2 only.

Abbreviations: ADNFLE = autosomal dominant nocturnal frontal lobe epilepsy; BFNS = benign familial neonatal seizures; FISH = fluorescent in situ hybridization; MLPA = multiple ligation-dependent probe amplification; nAChR = neuronal acetylcholine receptors.

Supplemental data at www.neurology.org

This study was conducted as part of a comprehensive project organized by The Epilepsy Genetic Study Group, Japan (chairperson, S.K.), and supported in part by funding received by Dr. Hirose.

Disclosure: Author disclosures are provided at the end of the article.

Received February 23, 2009. Accepted in final form July 20, 2009.