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NEUROLOGY 2009;73:1046-1053
© 2009 American Academy of Neurology

De novo mutations of voltage-gated sodium channel {alpha}II gene SCN2A in intractable epilepsies

I. Ogiwara, PhD, K. Ito, PhD, Y. Sawaishi, MD, PhD, H. Osaka, MD, PhD, E. Mazaki, MS, I. Inoue, MS, M. Montal, MD, PhD, T. Hashikawa, PhD, T. Shike, MD, T. Fujiwara, MD, PhD, Y. Inoue, MD, PhD, M. Kaneda, MD, PhD and K. Yamakawa, PhD

From the Laboratories for Neurogenetics (I.O., K.I., E.M., I.I., M.K., K.Y.) and Neural Architecture (T.H.), RIKEN Brain Science Institute, Wako; Department of Comparative Pathophysiology (K.I.), Graduate School of Agricultural and Life Sciences, the University of Tokyo; Department of Pediatrics (Y.S.), Akita University School of Medicine; Division of Neurology (H.O.), Kanagawa Children’s Medical Center, Japan; Section of Neurobiology (M.M.), Division of Biological Sciences, University of California San Diego; National Epilepsy Center (T.S., Y.I., F.T.), Shizuoka Institute of Epilepsy and Neurological Disorders; and Department of Physiology (M.K.), Keio University School of Medicine, Japan.

Address correspondence and reprint requests to Dr. Kazuhiro Yamakawa, Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan yamakawa{at}brain.riken.jp

Background: Mutations of voltage-gated sodium channel {alpha}II gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances.

Methods: We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Nav1.2 channels containing identified mutations.

Results: We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (a ~18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (a ~22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused a ~14-mV hyperpolarizing shift in the voltage dependence of activation.

Conclusions: The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.

Abbreviations: BFNIS = benign familial neonatal-infantile seizures; EMA = epilepsy with myoclonic absence; FLE = frontal lobe epilepsy; GEFS+ = generalized epilepsy with febrile seizures plus; IS = infantile spasms; OLE = occipital lobe epilepsy; PE = partial epilepsy; SMEB = borderline severe myoclonic epilepsy in infancy; SMEI = severe myoclonic epilepsy in infancy; VGSC = voltage-gated sodium channel; WT = wild-type.

Supplemental data at www.neurology.org

Supported by grants from the RIKEN Brain Science Institute, the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the NIH (GM-49711).

Disclosure: The authors report no disclosures.

Received February 25, 2009. Accepted in final form June 18, 2009.






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