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Zeitschrift für Epileptologie

, Volume 32, Issue 4, pp 311–318 | Cite as

Gibt es operative Behandlungsoptionen bei genetischen fokalen Epilepsien?

  • Victoria San Antonio-ArceEmail author
Leitthema
  • 43 Downloads

Zusammenfassung

Genetische Ursachen von Epilepsien werden im Kontext methodischer Fortschritte der Genomanalyse zunehmend nachgewiesen. So lässt sich bei Einsatz der Hochdurchsatzsequenzierung eine genetische Ursache bei 33 % aller Epilepsien und bei 12,5 % fokaler Epilepsien nachweisen. Das Vorliegen pathogener Varianten in Epilepsie-assoziierten Genen schließt eine operative Behandlungsoption von Epilepsien jedoch nicht aus. Epilepsiechirurgie zeigte bei Patienten mit therapierefraktärer fokaler Epilepsie bei pathogenen Varianten in Genen des mTOR-Signalwegs auch bei negativem MRT-Befund gute Ergebnisse. Im Gegensatz hierzu zeigte die Epilepsiechirurgie bei Patienten mit pathogenen Varianten in anderen Epilepsie-assoziierten Genen, insbesondere in Genen, die für Ionenkanäle oder synaptische Proteine kodieren, schlechte Ergebnisse auch bei positivem MRT-Befund und hierzu konkordanten elektroklinischen Befunden. Die Identifizierung pathogener Genvarianten kann daher die diagnostischen und therapeutischen Verfahren bei Patienten mit fokaler Epilepsie beeinflussen. Weitere Daten sind erforderlich, um die Indikation für eine prächirurgische Diagnostik bei Patienten mit pathogenen Varianten in anderen Genen als den Genen des mTOR Signalwegs stellen oder ausschließen zu können. Ebenfalls wirft sich die Frage auf, in welchen Konstellationen bei strukturell erscheinenden fokalen Epilepsien eine Indikation für eine genetische Untersuchung besteht.

Schlüsselwörter

Fokale kortikale Dysplasie Epilepsiechirurgie Fehlbildung der kortikalen Entwicklung mTOR-Signalweg Ionenkanalfunktion 

Are there surgical treatment options for genetic focal epilepsies?

Abstract

In recent years, it has been recognized that many forms of epilepsy have a genetic cause. By the implementation of next generation sequencing, a genetic cause has been found in 33% of all epilepsies and in 12.5% of focal epilepsies; however, there are limited data on the outcome of epilepsy surgery in patients with pathogenic variants in epilepsy-associated genes. Epilepsy surgery has shown good results in patients with treatment refractory focal epilepsy in association with pathogenic variants of mTOR pathway genes, even in cases with negative magnetic resonance imaging (MRI) findings. In contrast, epilepsy surgery has shown poor results in patients with pathogenic variants in other epilepsy-associated genes, particularly in genes associated with ion channel function and synaptic transmission, even in the presence of lesions on MRI and concordant electroclinical findings. The identification of pathogenic genetic variants could therefore influence the diagnostic and therapeutic procedures in patients with focal epilepsy. Further data are needed to clarify or rule out the indications for presurgical evaluation in patients with pathogenic variants in genes other than those of the mTOR signaling pathway. This also raises the question of which patients should undergo genetic testing in structurally appearing focal epilepsy.

Keywords

Channelopathy Focal cortical dysplasia Epilepsy surgery Malformations of cortical development mTOR pathway 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

V. San Antonio-Arce gibt an, dass sie keinen Interessenkonflikt hat.

Dieser Beitrag beinhaltet keine vom Autor durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Akiyama M, Kobayashi K, Yoshinaga H et al (2010) A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 51:1043–1052PubMedGoogle Scholar
  2. 2.
    Bando Y, Hirano T, Tagawa Y (2014) Dysfunction of KCNK potassium channels impairs neuronal migration in the developing mouse cerebral cortex. Cereb Cortex 24:1017–1029PubMedGoogle Scholar
  3. 3.
    Barba C, Jacques T, Kahane P et al (2013) Epilepsy surgery in neurofibromatosis type 1. Epilepsy Res 105:384–395PubMedGoogle Scholar
  4. 4.
    Barba C, Parrini E, Coras R et al (2014) Co-occurring malformations of cortical development and SCN1A gene mutations. Epilepsia 55:1009–1019PubMedGoogle Scholar
  5. 5.
    Baulac S, Ishida S, Marsan E et al (2015) Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol 77:675–683PubMedGoogle Scholar
  6. 6.
    Bourgeois M, Crimmins DW, de Oliveira RS et al (2007) Surgical treatment of epilepsy in Sturge-Weber syndrome in children. J Neurosurg 106:20–28PubMedGoogle Scholar
  7. 7.
    Brodie MJ, Barry SJ, Bamagous GA et al (2002) Patterns of treatment response in newly diagnosed epilepsy. Neurology 78:1548–1554Google Scholar
  8. 8.
    Carvill GL, Crompton DE, Regan BM et al (2015) Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol Genet 1:e17PubMedPubMedCentralGoogle Scholar
  9. 9.
    Catarino CB, Kasperaviciute D, Thom M et al (2011) Genomic microdeletions associated with epilepsy: Not a contraindication to resective surgery. Epilepsia 52:1388–1392PubMedPubMedCentralGoogle Scholar
  10. 10.
    Catarino CB, Liu JY, Liagkouras I et al (2011) Dravet syndrome as epileptic encephalopathy: Evidence from long-term course and neuropathology. Brain 134:2982–3010PubMedPubMedCentralGoogle Scholar
  11. 11.
    Conti V, Pantaleo M, Barba C et al (2015) Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene. Clin Genet 88:241–247PubMedGoogle Scholar
  12. 12.
    D’Gama AM, Geng Y, Couto JA et al (2015) Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77:720–725PubMedPubMedCentralGoogle Scholar
  13. 13.
    Dibbens LM, de Vries B, Donatello S et al (2013) Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 45:546–551PubMedGoogle Scholar
  14. 14.
    Ferri L, Bisulli F, Mai R et al (2017) A stereo EEG study in a patient with sleep-related hypermotor epilepsy due to DEPDC5 mutation. Seizure 53:51–54PubMedGoogle Scholar
  15. 15.
    Gaily E, Anttonen AK, Valanne L et al (2013) Dravet syndrome: New potential genetic modifiers, imaging abnormalities, and ictal findings. Epilepsia 54:1577–1585PubMedGoogle Scholar
  16. 16.
    Helbig I, Scheffer IE, Mulley JC et al (2008) Navigating the channels and beyond: Unravelling the genetics of the epilepsies. Lancet Neurol 7:231–245PubMedGoogle Scholar
  17. 17.
    Helbig KL, Farwell Hagman KD, Shinde DN et al (2016) Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med 18(9):898–905PubMedGoogle Scholar
  18. 18.
    Hildebrand MS, Dahl H‑HM, Damiano JA et al (2013) Recent advances in the molecular genetics of epilepsy. J Med Genet 50:271–279PubMedGoogle Scholar
  19. 19.
    Ishida S, Picard F, Rudolf G et al (2013) Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet 45:552–555PubMedPubMedCentralGoogle Scholar
  20. 20.
    Jang HM, Park HR, Mun JK et al (2013) Surgical treatment of mesial temporal lobe epilepsy in a patient with neurofibromatosis type 1. J Epilepsy Res 3:35–38PubMedPubMedCentralGoogle Scholar
  21. 21.
    Jansen LA, Mirzaa GM, Ishak GE et al (2015) PI3K/AKT pathway mutations cause a spectrum of brain malformationsfrom megalencephaly to focal cortical dysplasia. Brain 138:1613–1628PubMedPubMedCentralGoogle Scholar
  22. 22.
    Lee JH, Huynh M, Silhavy JL et al (2012) De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 44:941–945PubMedPubMedCentralGoogle Scholar
  23. 23.
    Le Gal F, Korff CM, Monso-Hinard C et al (2010) A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia 51:1915–1918PubMedGoogle Scholar
  24. 24.
    Leventer RJ, Scerri T, Marsh APL et al (2015) Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR. Neurology 84:2029–2032PubMedPubMedCentralGoogle Scholar
  25. 25.
    Liu JYW, Kasperaviciute D, Martinian L et al (2012) Neuropathology of 16p13.11 deletion in epilepsy. PLoS ONE 7:e34813PubMedPubMedCentralGoogle Scholar
  26. 26.
    Mirzaa GM, Campbell CD, Solovieff N et al (2016) Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol 73:836–845PubMedPubMedCentralGoogle Scholar
  27. 27.
    Myers CT, Mefford HC (2015) Advancing epilepsy genetics in the genomic era. Genome Med 7:91PubMedPubMedCentralGoogle Scholar
  28. 28.
    Nakashima M, Saitsu H (2015) Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann Neurol 78:375–386PubMedGoogle Scholar
  29. 29.
    Ostendorf AP, Gutmann DH, Weisenberg JLZ (2013) Epilepsy in individuals with neurofibromatosis type 1. Epilepsia 54:1810–1814PubMedGoogle Scholar
  30. 30.
    Ottman R, Hirose S, Jain S et al (2010) Genetic testing in the epilepsies-report of the ILAE Genetics Commission. Epilepsia 51(4):655–670PubMedPubMedCentralGoogle Scholar
  31. 31.
    Parrini E, Conti V, Dobyns WB et al (2016) Genetic basis of brain malformations. Mol Syndromol 7(4):220–233PubMedPubMedCentralGoogle Scholar
  32. 32.
    Perucca P, Scheffer IE, Harvey AS et al (2017) Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res 131:797–798Google Scholar
  33. 33.
    Poduri A, Evrony GD, Cai X et al (2012) Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41–48PubMedPubMedCentralGoogle Scholar
  34. 34.
    Ricos MG, Hodgson BL, Pippucci T et al (2016) Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol 79:120–131PubMedGoogle Scholar
  35. 35.
    Scerri T, Riseley JR, Gillies G et al (2015) Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol 2:575–580PubMedPubMedCentralGoogle Scholar
  36. 36.
    Scheffer IE, Harkin LA, Grinton BE et al (2007) Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 130:100–109PubMedGoogle Scholar
  37. 37.
    Scheffer IE, Heron SE, Regan BM et al (2014) Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol 75:782–787PubMedGoogle Scholar
  38. 38.
    Siegler Z, Barsi P, Neuwirth M et al (2005) Hippocampal sclerosis in severe myoclonic epilepsy in infancy: A retrospective MRI study. Epilepsia 46:704–708PubMedGoogle Scholar
  39. 39.
    Skjei KL, Church EW, Harding BN et al (2015) Clinical and histopathological outcomes in patients with SCN1A mutations undergoing surgery for epilepsy. J Neurosurg Pediatr 16:1–7Google Scholar
  40. 40.
    So EL, Lee RW (2014) Epilepsy surgery in MRI-negative epilepsies. Curr Opin Neurol 27:206–212PubMedGoogle Scholar
  41. 41.
    Stephen LJ, Kwan P, Brodie MJ (2001) Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia 42(3):357–362PubMedGoogle Scholar
  42. 42.
    Stevelink R, Sanders MW, Tuinman MP et al (2018) Epilepsy surgery for patients with genetic refractory epilepsy: A systematic review. Epileptic Disord 20(2):99–115PubMedGoogle Scholar
  43. 43.
    Strauss KA, Puffenberger EG, Huentelman MJ et al (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354:1370–1377PubMedGoogle Scholar
  44. 44.
    Striano P, Mancardi MM, Biancheri R et al (2007) Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations. Epilepsia 48:1092–1096PubMedGoogle Scholar
  45. 45.
    Syrbe S (2019) Genetische epileptische Enzephalopathien des Säuglingsalters. Z Epileptol 32:87–97Google Scholar
  46. 46.
    Téllez-Zenteno JF, Ronquillo LH, Moien-Afshari F et al (2010) Surgical outcomes in lesional and non-lesional epilepsy: A systematic review and meta-analysis. Epilepsy Res 89:310–318PubMedGoogle Scholar
  47. 47.
    Tiefes AM, Hartlieb T, Tacke M et al (2019) Mesial temporal sclerosis in SCN1A-related epilepsy: Two long-term EEG case studies. Clin Eeg Neurosci 50(4):267–272PubMedGoogle Scholar
  48. 48.
    Van Poppel K, Patay Z, Roberts D et al (2012) Mesial temporal sclerosis in a cohort of children with SCN1A gene mutation. J Child Neurol 27:893–897PubMedGoogle Scholar
  49. 49.
    Weckhuysen S, Holmgren P, Hendrickx R et al (2013) Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers. Epilepsia 54:e74–e80PubMedGoogle Scholar
  50. 50.
    Weckhuysen S, Marsan E, Lambrecq V et al (2016) Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 57:994–1003PubMedGoogle Scholar
  51. 51.
    West S, Nolan SJ, Cotton J et al (2015) Surgery for epilepsy. Cochrane Database Syst Rev 7:CD10541Google Scholar
  52. 52.
    Ying Z, Wang I, Blümcke I et al (2019) A comprehensive clinico-pathological and genetic evaluation of bottom-of-sulcus focal cortical dysplasia in patients with difficult-to-localize focal epilepsy. Epileptic Disord 21(1):65–77PubMedGoogle Scholar
  53. 53.
    Zhang K, Hu WH, Zhang C et al (2013) Predictors of seizure freedom after surgical management of tuberous sclerosis complex: A systematic review and meta-analysis. Epilepsy Res 105:377–383PubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Sektion Epilepsiediagnostik im Kindes- und Jugendalter EpilepsiezentrumUniversitätsklinikum Freiburg, Mitglied des Europäischen Referenznetzwerkes (ERN) für Seltene Erkrankungen EpiCAREFreiburgDeutschland

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