SCN2A-Related Early-Onset Epileptic Encephalopathy Responsive to Phenobarbital

Abstract

Voltage-gated sodium channels (Nav) are critical regulators of neuronal excitability. Genes for the α-subunits of three sodium channel subtypes—SCN1A, SCN2A, and SCN3A—are all located on chromosome 2q24. A full-term boy with an unremarkable birth history presented at 1 month of age with unusual movements that had started on day of life 2. Exam was notable for lack of visual attention, hypotonia, and hyperreflexia. Electroencephalogram (EEG) showed an invariant burst suppression with multifocal spikes, ictal episodes with bicycling movements associated with buildups of rhythmic activity, and epileptic spasms. Work-up revealed a 1.77-Mb duplication at locus 2q24.3, encompassing the entirety of SCN2A and SCN3A, but not SCN1A. Phenobarbital led to rapid resolution of the clinical seizures and EEG background normalized other than rare sharp waves. Early-onset epileptic encephalopathy (EOEE), with neonatal seizures, burst suppression, and reversibility with phenobarbital, is part of the enlarging spectrum of Nav channelopathies. The delayed diagnosis provided an unusual opportunity to view the early natural history of this disorder and its remarkable responsiveness to barbiturate therapy. The clinical and EEG response to phenobarbital implicates seizures as the cause of the encephalopathy.

Keywords

voltage-gated sodium channels - early-onset epileptic encephalopathy - 2q24 - reversibility

• References

• 1 Goeggel Simonetti B, Rieubland C, Courage C , et al. Duplication of the sodium channel gene cluster on 2q24 in children with early onset epilepsy. Epilepsia 2012; 53 (12) 2128-2134
• 2 Oliva M, Berkovic SF, Petrou S. Sodium channels and the neurobiology of epilepsy. Epilepsia 2012; 53 (11) 1849-1859
• 3 Shi X, Yasumoto S, Kurahashi H , et al. Clinical spectrum of SCN2A mutations. Brain Dev 2012; 34 (7) 541-545
• 4 Nakamura K, Kato M, Osaka H , et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013; 81 (11) 992-998
• 5 Raymond G, Wohler E, Dinsmore C , et al. An interstitial duplication at 2q24.3 involving the SCN1A, SCN2A, SCN3A genes associated with infantile epilepsy. Am J Med Genet A 2011; 155A (4) 920-923
• 6 Heron SE, Scheffer IE, Grinton BE , et al. Familial neonatal seizures with intellectual disability caused by a microduplication of chromosome 2q24.3. Epilepsia 2010; 51 (9) 1865-1869
• 7 Okumura A, Yamamoto T, Shimojima K , et al. Refractory neonatal epilepsy with a de novo duplication of chromosome 2q24.2q24.3. Epilepsia 2011; 52 (7) e66-e69
• 8 Vecchi M, Cassina M, Casarin A , et al. Infantile epilepsy associated with mosaic 2q24 duplication including SCN2A and SCN3A. Seizure 2011; 20 (10) 813-816
• 9 Sanders SJ, Murtha MT, Gupta AR , et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485 (7397) 237-241
• 10 Neale BM, Kou Y, Liu L , et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485 (7397) 242-245
• 11 Celle ME, Cuoco C, Porta S, Gimelli G, Tassano E. Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features, psychomotor delay, microcephaly and no history of seizures. Gene 2013; 532 (2) 294-296
• 12 Krumm N, O'Roak BJ, Shendure J, Eichler EE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci 2014; 37 (2) 95-105