Review article Clinical spectrum of SCN2A mutations Xiuyu Shi a,b , Sawa Yasumoto a , Hirokazu Kurahashi a,c , Eiji Nakagawa d , Tatsuya Fukasawa e , Satoshi Uchiya f , Shinichi Hirose a,⇑ a Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan b Department of Pediatrics, Chinese PLA General Hospital, Beijing, China c Department of Pediatrics, Nagoya University Graduate School of Medicine, Aichi, Japan d Department of Pediatric Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan e Department of Pediatrics, Nagoya Memorial Hospital, Nagoya, Japan f Department of Pediatrics, Mito Saiseikai General Hospital, Mito, Japan Received 15 August 2011; received in revised form 22 September 2011; accepted 26 September 2011 Abstract Mutations in SCN2A, the gene encoding a2 subunit of the neuronal sodium channel, are associated with a variety of epilepsies: benign familial neonatal–infantile seizures (BFNIS); genetic epilepsy with febrile seizures plus (GEFS+); Dravet syndrome (DS); and some intractable childhood epilepsies. More than 10 new mutations have been identified in BFNIS, all of them are missense. To date, only one nonsense mutation has been found in a patient with intractable childhood epilepsy and severe mental decline. Recently, microduplication of chromosome 2q24.3 (containing eight genes including SCN2A, SCN3A, and the 3 0 end of SCN1A) was reported in a family with dominantly inherited neonatal seizures and intellectual disability. Functional studies of SCN2A muta- tions show that they can cause divergent biophysical defects in Na V 1.2 and impair cell surface expressions. There is no consistent relationship between genotype and phenotype. Ó 2011 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Keywords: SCN2A; Benign familial neonatal–infantile seizures; Genetic epilepsy with febrile seizures plus; Intractable childhood epilepsy; Dravet syndrome 1. Introduction Voltage-gated sodium channels, comprised of a and b subunits, are the major mediators of normal neuronal firing. The a subunit includes four homologous domains (D1–D4) and exhibits significant homology with volt- age-gated potassium and calcium channels. There are at least four a subunits (SCN1A, SCN2A, SCN3A, and SCN8A) are primarily responsible for encoding sodium currents in the brain, three of them (SCN1A, SCN2A, SCN3A) are associated with a variety of epilep- sies [1–3]. Specifically, most SCN2A mutations have been identified in cases of BFNIS [2,4,5]. While Na V 1.2 mutations were thought infrequently associated with severe epilepsy, recent studies have shown SCN2A mutations in both severe myoclonic epilepsy in infancy (SMEI) and some intractable childhood epilepsies [6,7]. In addition, microduplication involving SCN2A, SCN3A, and the 3 0 end of SCN1A has been reported in a family with dominantly inherited neonatal seizures and intellectual disability [8]. All SCN2A mutations identified in BFNIS are missense mutations inherited from a single parent; most SCN2A mutations-nonsense and missense-identified in severe cases are de novo. 0387-7604/$ - see front matter Ó 2011 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. doi:10.1016/j.braindev.2011.09.016 ⇑ Corresponding author. Address: Department of Pediatrics, School of Medicine, Fukuoka University, 45-1 7-chome, Nanakuma, Jonan- ku Fukuoka 814-0180, Japan. Tel.: +81 92 801 1011 (3390), +81 92 862 1290; fax: +81 92 862 6955. E-mail address: hirose@fukuoka-u.ac.jp (S. Hirose). www.elsevier.com/locate/braindev Brain & Development 34 (2012) 541–545