Genetische Aspekte kindlicher Epilepsiesyndrome

ZUSAMMENFASSUNG

Kindliche Epilepsiesyndrome sind Erkrankungen mit früh beginnenden epileptischen Anfällen und assoziierten Störungen der motorischen und kognitiven Entwicklung. Die Klassifikation der Epilepsiesyndrome nach elektroklinischen Kriterien bildet die Grundlage für die Therapie und die prognostische Einschätzung. Zunehmend kann eine steigende Zahl monogenen Ursachen zugeordnet werden. Die Kenntnis des genetischen Hintergrundes erlaubt so eine Einteilung nach pathophysiologischen zellulären Ursachen, kann den diagnostischen Prozess erleichtern und die Therapieentscheidung zukünftig unterstützen.

ABSTRACT

Childhood Epilepsy syndromes are neurodevelopmental disorders characterized by seizures, epileptic activity and associated comorbidities of motor and cognitive development. The classification in specific electroclinical syndromes allows for treatment decisions and prognostic counselling. Increasingly, monogenic etiologies have been identified to underly specific syndromes. This knowledge of the genetic background allows for a more precise clinical diagnosis and can help in guiding treatment and prognostic counselling.

Schlüsselwörter

Epileptische Enzephalopathie - monogene Ursache - Kinder - Panel - Exom

Keywords

Epileptic encephalopathy - monogenic etiology - children - panel - exome

• Literatur

• 1 Syrbe S. Genetische epileptische Enzephalopathien des Säuglingsalters. Zeitschrift für Epileptologie 2019; 32: 87-97
• 2 McTague A, Howell KB, Cross JH. et al The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol 2016; 15: 304-316
• 3 Lemke JR, Syrbe S. Epileptic Encephalopathies in Childhood: The Role of Genetic Testing. Semin Neurol 2015; 35: 310-322
• 4 Scheffer IE, Berkovic S, Capovilla G. et al ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 512-521
• 5 Syrbe S. Präzisionsmedizin für genetische Epilepsien – am Anfang des Weges?. Zeitschrift für Epileptologie 2021; 34: 161-167
• 6 Gaily E, Lommi M, Lapatto R. et al Incidence and outcome of epilepsy syndromes with onset in the first year of life: A retrospective population-based study. Epilepsia 2016; 57: 1594-1601
• 7 Symonds JD, Zuberi SM, Stewart K. et al Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain 2019; 142: 2303-2318
• 8 Kaplanis J, Samocha KE, Wiel L. et al Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 2020; 586: 757-762
• 9 Syrbe S, Hedrich UBS, Riesch E. et al De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 2015; 47: 393-399
• 10 Sanchez Fernandez I, Loddenkemper T, Gainza-Lein M. et al Diagnostic yield of genetic tests in epilepsy: A meta-analysis and cost-effectiveness study. Neurology. 2019
• 11 Olson HE, Kelly M, LaCoursiere CM. et al Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol 2017; 81: 419-429
• 12 Weckhuysen S, Ivanovic V, Hendrickx R. et al Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013; 81: 1697-1703
• 13 Berg AT, Berkovic SF, Brodie MJ. et al Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010; 51: 676-685
• 14 Berg AT, Chakravorty S, Koh S. et al Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms. PLoS One 2018; 13: e0193599
• 15 Syrbe S, Harms FL, Parrini E. et al Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy. Brain 2017; 140: 2322-2336
• 16 de Kovel CGF, Syrbe S, Brilstra EH. et al Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol 2017; 74: 1228-236
• 17 Krey I, Krois-Neudenberger J, Hentschel J. et al Genotype-phenotype correlation on 45 individuals with West syndrome. Eur J Paediatr Neurol 2020; 25: 134-138
• 18 Kotulska K, Kwiatkowski DJ, Curatolo P. et al Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial. Ann Neurol 2021; 89: 304-314
• 19 Bayat A, Hjalgrim H, Moller RS. The incidence of SCN1A-related Dravet syndrome in Denmark is 1:22,000: a population-based study from 2004 to 2009. Epilepsia 2015; 56: e36-39
• 20 Brunklaus A, Ellis R, Reavey E. et al Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 2012; 135: 2329-2336
• 21 Fitzgerald MP, Fiannacca M, Smith DM. et al Treatment Responsiveness in KCNT1-Related Epilepsy. Neurotherapeutics 2019; 16: 848-857
• 22 Fitzgerald MP SD, Møller RS, McGinnis E. et al Response to treatment in patients with KCNT1-related epilepsy. Abstracts presented at AES Annual Meetings. 2017
• 23 Burgess R, Wang S, McTague A. et al The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures. Ann Neurol 2019; 86: 821-831
• 24 Oguni H, Tanaka T, Hayashi K. et al Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics 2002; 33: 122-132
• 25 Oguni H. Epilepsy with myoclonic-atonic seizures, also known as Doose syndrome: Modification of the diagnostic criteria. Eur J Paediatr Neurol 2022; 36: 37-50
• 26 Gillentine MA, Wang T, Hoekzema K. et al Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders. Genome Med 2021; 13: 63
• 27 Semino F, Schroter J, Willemsen MH. et al Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder. Hum Mutat 2021; 42: 1094-1100
• 28 Sonnek B, Doring JH, Mutze U. et al Clinical spectrum and treatment outcome of 95 children with continuous spikes and waves during sleep (CSWS). Eur J Paediatr Neurol. 2020
• 29 Doring JH, Schroter J, Jungling J. et al Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders. Int J Mol Sci 2021: 22
• 30 Schroter J, Popp B, Brennenstuhl H. et al Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies. Eur J Hum Genet 2022; 30: 298-306
• 31 Schroter J, Doring JH, Garbade SF. et al Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies. Genet Med 2021; 23: 516-523
• 32 Imbrici P, Liantonio A, Camerino GM. et al Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery. Front Pharmacol 2016; 07: 121
• 33 Sisodiya SM.. Precision medicine and therapies of the future. Epilepsia. 2020
• 34 Sands TT, Balestri M, Bellini G. et al Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia 2016; 57: 2019-2030
• 35 Soto D, Olivella M, Grau C. et al L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy. Sci Signal 2019: 12
• 36 Krey I, von Spiczak S, Johannesen KM. et al L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants. Neurotherapeutics. 2022
• 37 Wolff M, Johannesen KM, Hedrich UBS. et al Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017; 140: 1316-1336
• 38 Millichap JJ, Park KL, Tsuchida T. et al KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2016; 02: e96
• 39 Zhao S, Yudin Y, Rohacs T. Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms. Elife 2020: 9
• 40 Dyment DA, Terhal PA, Rustad CF. et al De novo substitutions of TRPM3 cause intellectual disability and epilepsy. Eur J Hum Genet 2019; 27: 1611-1618
• 41 Saffari A, Brosse I, Wiemer-Kruel A. et al Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age – a multicenter retrospective study. Orphanet J Rare Dis 2019; 14: 96
• 42 Venot Q, Blanc T, Rabia SH. et al Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 2018; 558: 540-546
• 43 Guiberson NGL, Pineda A, Abramov D. et al Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones. Nat Commun 2018; 09: 3986
• 44 Yokoi N, Fukata Y, Kase D. et al Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy. Nat Med 2015; 21: 19-26
• 45 Schulz A, Ajayi T, Specchio N. et al Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med 2018; 378: 1898-1907
• 46 Johannesen KM, Liu Y, Koko M. et al Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain. 2021
• 47 Mulkey SB, Ben-Zeev B, Nicolai J. et al Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H. Epilepsia 2017; 58: 436-445
• 48 Bonardi CM, Heyne HO, Fiannacca M. et al KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum. Brain 2021; 144: 3635-3650
• 49 Stamberger H, Nikanorova M, Willemsen MH. et al STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology 2016; 86: 954-962
• 50 Bahi-Buisson N, Villeneuve N, Caietta E. et al Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships. Am J Med Genet A 2012; 158 A 1612-1619