Difficulties in the diagnosis, prognosis and treatment of genetic epileptic encephalopathies: the view of a neurologist

Belousova E.D.; Sharkov A.A.

doi:https://doi.org/10.17116/jnevro201911911234

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Abstract:

Genetic epileptic encephalopathies are a rather wide spectrum of childhood epilepsies with onset of epilepsy in the first 1.5—2 years of life, regression or delayed psychomotor and speech development and «massive» epileptiform activity on electroencephalogram (EEG). The review discusses the difficulties of choosing the optimal method of genetic examination, problems with the interpretation of the results obtained, the formulation of the diagnosis, the determination of the prognosis of the course and targeted therapy. It is emphasized that the interpretation of the identified genetic variants is not an easy task, requiring close interaction between specialists in molecular genetics, bioinformatics, neurology and clinical genetics. The possibilities of targeted treatment of genetic epileptic encephalopathies are still limited, but knowledge of the genetic cause of epilepsy allows making a more informed choice of the treatment.

Keywords:

early epileptic encephalopathies

genetic diagnosis

new generation sequencing

prognosis

target therapy

Authors:

Belousova E.D.

Moskovskiĭ NII pediatrii i detskoĭ khirurgii

SPIN RSCI: 6594-3049
Scopus AuthorID: 24767524000
ORCID: 0000-0003-3594-6974

Sharkov A.A.

Veltischev Research and Clincal Institute of Pediatrics in Pirogov Russian National Research Medical University, Moscow, Russia

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References:

Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. https://doi.org/10.1111/epi.13709
Castro-Gago M, Blanco-Barca MO, Gómez-Lado C, Eirís-Puñal J, Campos-González Y, Arenas-Barbero J. Respiratory chain complex I deficiency in an infant with Ohtahara syndrome. Brain. 2009;31:322-325. https://doi.org/10.1016/j.braindev.2008.05.009
Myers KA, Johnstone D, Dyment DA. Epilepsy Genetics: current knowledge, applications and future directions. Clin Genet. 2019;95(1):95-111. https://doi.org/10.1111/cge.13414
Sharkov AA, Sharkova IV, Belousova ED, Dadali EL. Genetics and treatment of early infantile epileptic encephalopathies. Zhurnal Nevrologii i Psihiatrii im. S.S. Korsakova. 2016;116(9-2):67-73. https://doi.org/10.17116/jnevro20161169267-73
Patel J, Mercimek-Mahmutoglu S. Epileptic Encephalopathy in Childhood: A Stepwise Approach for Identification of Underlying Genetic Causes. Indian J Pediatr. 2016;83(10):1164-1174. https://doi.org/10.1007/s12098-015-1979-9
Mercimek-Mahmutoglu S, Patel J, Cordeiro D, Hewson S, Callen D, Donner EJ, Hahn CD, Kannu P, Kobayashi J, Minassian BA, Moharir M, Siriwardena K, Weiss SK, Weksberg R, Snead OC. Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015;56(5):707-716. https://doi.org/10.1111/epi.12954
Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: Beyond SCN1A. Epilepsia. 2017;58(11):1807-1816. https://doi.org/10.1111/epi.13889
Dadali EL, Sharkova IV, Sharkov AA, Akimova IA. Kliniko-geneticheskiye osobennosti i sovremennyye sposoby diagnostiki nasledstvennykh epilepsiy. V sbornike: Molekulyarno-biologicheskiye tekhnologii v meditsinskoy praktike. Novosibirsk: Akademizdat; 2016.
Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017;101(5):664-685. https://doi.org/10.1016/j.ajhg.2017.09.008
Hardies K, Weckhuysen S, De Jonghe P, Suls A. Lessons learned from gene identification studies in Mendelian epilepsy disorders. Eur J Hum Genet. 2016;24(7):961-967. https://doi.org/10.1038/ejhg.2015.251
Richards S, Aziz N, Bale S Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-423. https://doi.org/10.1016/j.jmoldx.2016.10.002
Zhou B, Ho SS, Zhang X, Pattni R, Haraksingh RR, Urban AE. Whole-genome sequencing analysis of CNV using low-coverage and paired-end strategies is efficient and outperforms array-based CNV analysis. J Med Genet. 2018;55(11):735-743. https://doi.org/10.1136/jmedgenet-2018-105272
Tyburczy ME, Dies KA, Glass J, Camposano S, Chekaluk Y, Thorner AR, Lin L, Krueger D, Franz DN, Thiele EA, Sahin M, Kwiatkowski DJ. Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet. 2015;11(11):e1005637. https://doi.org/10.1371/journal.pgen.1005637
Nakayama T, Ishii A, Yoshida T, Nasu H, Shimojima K, Yamamoto T, Kure S, Hirose S. Somatic mosaic deletions involving SCN1A cause Dravet syndrome. Am J Med Genet A. 2018;176(3):657-662. https://doi.org/10.1002/ajmg.a.38596
Milh M, Lacoste C, Cacciagli P, Abidi A, Sutera-Sardo J, Tzelepis I, Colin E, Badens C, Afenjar A, Coeslier AD, Dailland T, Lesca G, Philip N, Villard L. Variable clinical expression in patients with mosaicism for KCNQ2 mutations. Am J Med Genet A. 2015;167A(10):2314-2318. https://doi.org/10.1002/ajmg.a.37152
Xu X, Yang X, Wu Q, Liu A, Yang X, Ye AY, Huang AY, Li J, Wang M, Yu Z, Wang S, Zhang Z, Wu X, Wei L, Zhang Y. Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of «de novo» SCN1A Mutations in Children with Dravet Syndrome. Hum Mutat. 2015;36(9):861-872. https://doi.org/10.1002/humu.22819
Ishii A, Watkins JC, Chen D, Hirose S, Hammer MF. Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome. Epilepsia. 2017;58(2):282-290. https://doi.org/10.1111/epi.13639
World Health Organization. International Classification of Diseases (ICD 11). Geneva: The World Health Organization; 2018.
Kivity S, Oliver KL, Afawi Z, Damiano JA, Arsov T, Damiano JA, Arsov T, Bahlo M, Berkovic SF. SCN1A clinical spectrum includes the self-limited focal epilepsies of childhood. Epilepsy Res. 2017;131:9-14. https://doi.org/10.1016/j.eplepsyres.2017.01.012
Sadleir LG, Mountier EI, Gill D. Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype. Neurology. 2017;89(10):1035-1042. https://doi.org/10.1212/WNL.0000000000004331
Miceli F, Soldovieri MV, Joshi N, Weckhuysen S, Cooper E, Taglialatela M. KCNQ2-Related Disorders. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2018.
Hawkins NA, Martin MS, Frankel WN, Kearney JA, Escayg A. Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus. Neurobiol Dis. 2011;41:655-660. https://doi.org/10.1016/j.nbd.2010.11.016
Jiang T, Shen Y, Chen H, Yuan Z, Mao S, Gao F. Clinical and molecular analysis of epilepsy related genes in patients with Dravet syndrome. Medicine (Baltimore). 2018;97(50):13565. https://doi.org/10.1097/MD.0000000000013565
Wang L, Fu X, Peng X, Xiao Z, Li Z, Chen G, Wang X. DNA Methylation Profiling Reveals Correlation of Differential Methylation Patterns with Gene Expression in Human Epilepsy. J Mol Neurosci. 2016;59(1):68-77. https://doi.org/10.1007/s12031-016-0735-6
Tiwari D, Peariso K, Gross C. MicroRNA-induced silencing in epilepsy: Opportunities and challenges for clinical application. Dev Dyn. 2018;247(1):94-110. https://doi.org/10.1002/dvdy.24582
Gross C, Tiwari D. Regulation of Ion Channels by MicroRNAs and the Implication for Epilepsy. Curr Neurol Neurosci Rep. 2018;18(9):60. https://doi.org/10.1007/s11910-018-0870-2
Younus I, Reddy DS. Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy. Pharmacol Ther. 2017;177:108-122. https://doi.org/10.1016/j.pharmthera.2017.03.002
van der Poest CEA, Sahin M, Peters JM. Vigabatrin for Epileptic Spasms and Tonic Seizures in Tuberous Sclerosis Complex. J Child Neurol. 2018;33(8):519-524. https://doi.org/10.1177/0883073818768309
Daci A, Bozalija A, Jashari F, Krasniqi S. Individualizing Treatment Approaches for Epileptic Patients with Glucose Transporter Type1 (GLUT-1) Deficiency. Int J Mol Sci. 2018;19(1):122. https://doi.org/10.3390/ijms19010122
Luk’yanova EG, Ayvazyan SO, Osipova KV, Sushko LM, Kozhanova TV, Zhilina SS, Meshcheryakova TI, Prityko AG. Sindrom defitsita transportera glyukozy 1 tipa (GLUT1) i primeneniye ketogennoy diyety v lechenii bolezni de vivo. Quantum Satis. 2017;1(3-4):83-89.
Nikolaeva EA, Semyachkina AN. Modern opportunities for the treatment of hereditary diseases in children. Russian Journal of Perinatology and Pediatrics. 2018;63(4):6-14 https://doi.org/10.21508/1027-4065-2018-63-4-6-14
Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A. CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018;378(20):1898-1907. https://doi.org/10.1056/NEJMoa1712649
Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T. Golas G, Simeonov DR, Holloman C, Tankovic A, Karamchandani MM, Schreiber JM, GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190-198. https://doi.org/10.1002/acn3.39
Mullen SA, Carney PW, Roten A, Ching M, Lightfoot PA. Ching M, Lightfoot PA, Churilov L, Nair U, Li M, Berkovic SF, Petrou S, Scheffer IE. Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology. 2018;90(1):67-72. https://doi.org/10.1212/WNL.0000000000004769
Brigo F, Striano P, Balagura G, Belcastro V. Emerging drugs for the treatment of Dravet syndrome. Expert Opin Emerg Drugs. 2018;23(4):261-269. https://doi.org/10.1080/14728214.2018.1552937
Dilena R, Striano P, Traverso M, Viri M, Cristofori G, Viri M, Cristofori G, Tadini L, Barbieri S, Romeo A, Zara F. Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation. Brain Dev. 2016;38(1):128-131. https://doi.org/10.1016/j.braindev.2015.07.002