Cohort of Phenotype, Genotype, and Outcome of SCN Developmental and Epileptic Encephalopathies from Southern Part of India

Abstract

The SCN encephalopathies are one of the rare early childhood intractable epileptic encephalopathies associated with pleomorphic seizures, cognitive decline, motor, and behavioral abnormalities that begin in early infancy. There is a dearth of data on phenotype and genotype of SCN encephalopathies from the Indian subcontinent, hence we are reporting clinical and molecular profile and outcome of SCN developmental and epileptic encephalopathies. This is a retrospective chart review of SCN developmental and epileptic encephalopathies in a tertiary care center, Bangalore, India between January 2015 and March 2020. All children with clinical features of SCN developmental and epileptic encephalopathies and confirmed with pathogenic variants were included. A total of 50 cases of SCN developmental and epileptic encephalopathies were analyzed, 31 of them were male and the mean age of presentation was 7.8 months. Precipitating factors for the first episode of seizure were fever and vaccination accounting for 33 and 8 children, respectively. Forty (80%) children had prolonged seizures and 15 (30%) had epileptic spasms. All children had a normal birth history and normal development before the onset of seizures, which was followed by developmental delay and regression. Thirty (60%) children had behavioral difficulties, notable hyperactivity, and autistic features. Neuroimaging and the initial electroencephalogram (EEG) were normal in all patients. The mean age of abnormal EEG was 14 months. The various subtypes of SCN variants were SCN1A in 31 children followed by SCN2A and SCN9A in eight children each and SCN1B in three children. Frameshift and nonsense mutations were associated with more severe phenotype and poor outcome compared with missense mutations. Thirty-four patients partially responded to treatment and the rest were refractory. The results of genetic testing were used to guide treatment; sodium channel blocking antiepileptic drugs were discontinued in 15 patients and sodium channel blocking agents were started in 3 patients with partial response. Three out of four children on stiripentol had a partial response. The SCN developmental and epileptic encephalopathies can present with epileptic spasms in addition to other types of seizures. Epileptic spasms are more common in nonsense and frameshift mutations. The outcome is poor in children with epileptic spasms compared with those without epileptic spasms. Genetic testing helps to select antiepileptic drugs that lead to seizure reduction.

Keywords

Dravet syndrome - SCN developmental and epileptic encephalopathies - SCN mutation - epileptic spasms

Authors' Contribution

V.K.G. did the supervision, guidance, and reviewed the manuscript. M.B. was involved in the management of the children and the preparation of the manuscript. H.V. was involved in the preparation of the manuscript. V.M.S. was involved in the diagnosis and the preparation of the manuscript. S.K.C. was involved in the diagnosis and the preparation of the manuscript. A.M. has given valuable inputs in the management of children. S.K.S. has given valuable inputs in the management of children. N.B. was involved in the diagnosis and the preparation of the manuscript.

Publication History

Received: 26 October 2020

Accepted: 03 April 2021

Article published online:
22 June 2021

• References

• 1 Scheffer IE, Nabbout R. SCN1A-related phenotypes: Epilepsy and beyond. Epilepsia 2019; 60 (Suppl. 03) S17-S24
• 2 Hattori J, Ouchida M, Ono J. et al. A screening test for the prediction of Dravet syndrome before one year of age. Epilepsia 2008; 49 (04) 626-633
• 3 Fujiwara T, Sugawara T, Mazaki-Miyazaki E. et al. Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures. Brain 2003; 126 (Pt 3): 531-546
• 4 Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: Dravet syndrome. Adv Neurol 2005; 95: 71-102
• 5 Brunklaus A, Ellis R, Reavey E, Forbes GH, Zuberi SM. Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 2012; 135 (Pt 8): 2329-2336
• 6 Incorpora G. Dravet syndrome. Ital J Pediatr 2009; 35 (01) 27
• 7 Parihar R, Ganesh S. The SCN1A gene variants and epileptic encephalopathies. J Hum Genet 2013; 58 (09) 573-580
• 8 Howell KB, McMahon JM, Carvill GL. et al. SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology 2015; 85 (11) 958-966
• 9 Mei D, Cetica V, Marini C, Guerrini R. Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies. Epilepsia 2019; 60 (Suppl. 03) S2-S7
• 10 Nieh SE, Sherr EH. Epileptic encephalopathies: new genes and new pathways. Neurotherapeutics 2014; 11 (04) 796-806
• 11 Carranza Rojo D, Hamiwka L, McMahon JM. et al. De novo SCN1A mutations in migrating partial seizures of infancy. Neurology 2011; 77 (04) 380-383
• 12 Cetica V, Chiari S, Mei D. et al. Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations. Neurology 2017; 88 (11) 1037-1044
• 13 Caraballo RH, Fejerman N. Dravet syndrome: a study of 53 patients. Epilepsy Res 2006; 70 (Suppl. 01) S231-S238
• 14 Tro-Baumann B, von Spiczak S, Lotte J. et al. A retrospective study of the relation between vaccination and occurrence of seizures in Dravet syndrome. Epilepsia 2011; 52 (01) 175-178
• 15 Oguni H, Hayashi K, Osawa M. et al. Severe myoclonic epilepsy in infancy: clinical analysis and relation to SCN1A mutations in a Japanese cohort. Adv Neurol 2005; 95: 103-117
• 16 Korff C, Laux L, Kelley K, Goldstein J, Koh S, Nordli Jr D. Dravet syndrome (severe myoclonic epilepsy in infancy): a retrospective study of 16 patients. J Child Neurol 2007; 22 (02) 185-194
• 17 Verheyen K, Wyers L, Del Felice A, Schoonjanset A-S. et al. Independent walking and cognitive development in preschool children with Dravet syndrome. 2021; 63 (04) 472-479
• 18 Ragona F, Brazzo D, De Giorgi I. et al. Dravet syndrome: early clinical manifestations and cognitive outcome in 37 Italian patients. Brain Dev 2010; 32 (01) 71-77
• 19 Kapoor D, Anand A, Sharma S. et al. Dravet syndrome: a case series. Indian J Pediatr 2021; 88 (01) 82
• 20 Do TT, Vu DM, Huynh TT. et al. SCN1A gene mutation and adaptive functioning in 18 Vietnamese children with Dravet syndrome. J Clin Neurol 2017; 13 (01) 62-70
• 21 Alame S, El-Houwayek E, Nava C, Sabbagh S, Fawaz A, Gillart AC, Hasbini D, Depienne C, Mégarbané A. Dravet Syndrome in Lebanon: First Report on Cases with SCN1A Mutations, Case Rep Med.. 2019 Jan 21;2019:5270503. doi: 10.1155/2019/5270503. PMID: 30805006; PMCID: PMC6360541.
• 22 Villeneuve N, Laguitton V, Viellard M. et al. Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome. Epilepsy Behav 2014; 31: 143-148
• 23 Petrelli C, Passamonti C, Cesaroni E. et al. Early clinical features in Dravet syndrome patients with and without SCN1A mutations. Epilepsy Res 2012; 99 (1-2): 21-27
• 24 Li BM, Liu XR, Yi YH. et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav 2011; 21 (03) 291-295
• 25 Dravet C. Severe myoclonic epilepsy in infants and its related syndromes. Epilepsia 2000; 41 (Suppl. 09) 7-10
• 26 Striano P, Mancardi MM, Biancheri R. et al. Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations. Epilepsia 2007; 48 (06) 1092-1096 DOI: 10.1111/j.1528-1167.2007.01020.x.
• 27 Catterall WA. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 2000; 26 (01) 13-25
• 28 Meng H, Xu HQ, Yu L. et al. The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat 2015; 36 (06) 573-580
• 29 Catterall WA. Sodium channel mutations and epilepsy. In: Noebels JL, Avoli M, Rogawski MA. et al, eds. Jasper's Basic Mechanisms of the Epilepsies. Bethesda, MD: National Center for Biotechnology Information; 2012: 675-687
• 30 Meisler MH, Helman G, Hammer MF. et al. SCN8A encephalopathy: research progress and prospects. Epilepsia 2016; 57 (07) 1027-1035
• 31 Fukuma G, Oguni H, Shirasaka Y. et al. Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB). Epilepsia 2004; 45 (02) 140-148
• 32 Ogiwara I, Ito K, Sawaishi Y. et al. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology 2009; 73 (13) 1046-1053
• 33 Wallace RH, Hodgson BL, Grinton BE. et al. Sodium channel alpha1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms. Neurology 2003; 61 (06) 765-769
• 34 Nakamura K, Kato M, Osaka H. et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013; 81 (11) 992-998