Genetische Ursachen von Epilepsien

Stefan Wolking; Holger Lerche

doi:10.1055/a-0952-6908

Nervenheilkunde, Table of Contents

Nervenheilkunde 2019; 38(12): 902-910
DOI: 10.1055/a-0952-6908

Schwerpunkt

Genetische Ursachen von Epilepsien

Neue Erkenntnisse und praktische Anwendung heute und in ZukunftGenetic causes of epilepsy

Stefan Wolking

¹Neurologie mit Schwerpunkt für Epileptologie, Hertie-Institut für klinische Hirnforschung, Universitätsklinikum Tübingen

²Department of Neurosciences, CHUM Research Center, University of Montreal

,

Holger Lerche∗

¹Neurologie mit Schwerpunkt für Epileptologie, Hertie-Institut für klinische Hirnforschung, Universitätsklinikum Tübingen

› Author Affiliations

Abstract

ZUSAMMENFASSUNG

Die Erkenntnisse über genetische Ursachen von Epilepsien haben in den vergangenen Jahren rasant zugenommen. Neben epileptischen Enzephalopathien stehen mittlerweile die genetischen generalisierten sowie die nicht läsionellen fokalen Epilepsien stärker im Fokus. An die genetische Ursache angepasste Behandlungswege im Sinne der ‚Precision Medicine‘ eröffnen zunehmend individualisierte Therapieoptionen. Die Pharmakogenetik könnte zudem die Vorhersage von Therapieansprechen bzw. Nebenwirkungen unterstützen und somit die Therapiesicherheit erhöhen. Genetische Diagnostik ist für eine zunehmende Anzahl von Epilepsiepatienten sinnvoll und wird weiter an Bedeutung zunehmen.

ABSTRACT

The knowledge about genetic causes of epilepsies has quickly expanded in the last years. Besides developmental and epileptic encephalopathies, genetic generalized epilepsies and non-acquired focal epilepsies enter the limelight. The advent of precision medicine, i.e. therapies adapted to specific genetic causes, opens up individualized treatment options. Pharmacogenomics might help to predict treatment response and adverse drug reactions and thus improve patient safety. Genetic diagnostics is a valuable tool for an increasing share of patients with epilepsy and will become more important in the near future.

Schlüsselwörter

Genetische generalisiete Epilepsien - fokale nicht-läsionelle Epilepsien - Precision Medicine - Pharmakogenetik

Key words

Genetic generalized epilepsies - non-acquired focal epilepsies - precision medicine - pharmacogenomics

Full Text

References

Literatur
1 McTague A, Howell KB, Cross JH. et al The genetic landscape of the epileptic encephalopathies of infancy and childhood. The Lancet Neurology 2016; 15 (03) 304-16
2 Dravet C, Guerrini R. Dravet syndrome. Montrouge: J. Libbey Eurotext; 2011
3 Marini C, Scheffer IE, Nabbout R. et al The genetics of Dravet syndrome. Epilepsia 2011; 52 (Suppl. 02) 24-9
4 Wolking S, Weber Y. Genetik der epileptischen Enzephalopathien. Aktuelle Neurologie 2015; 42 (08) 473-81
5 Depienne C, Bouteiller D, Keren B. et al Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet 2009; 5 (02) e1000381
6 Harkin LA, Bowser DN, Dibbens LM. et al Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 2002; 70 (02) 530-6
7 Wolff M, Johannesen KM, Hedrich UBS. et al Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017; 140 (05) 1316-36
8 Escayg A, MacDonald BT, Meisler MH. et al Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS + 2. Nat Genet 2000; 24 (04) 343-5
9 Dichgans M, Freilinger T, Eckstein G. et al Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005; 366 9483 371-7
10 Zuberi SM, Brunklaus A, Birch R. et al Genotype-phenotype associations in SCN1A-related epilepsies. Neurology 2011; 76 (07) 594-600
11 Schubert J, Siekierska A, Langlois M. et al Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nature Genetics 2014; 46 (12) 1327-32
12 Wolking S, May P, Mei D. et al Clinical spectrum of STX1B -related epileptic disorders. Neurology 2019: 10 1212/WNL.0000000000007089
13 Weber YG, Biskup S, Helbig KL. et al The role of genetic testing in epilepsy diagnosis and management. Expert Review of Molecular Diagnostics 2017; 17 (08) 739-50
14 Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett 2018; 667: 27-39
15 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 (04) 512-21
16 Wolking S, Lerche H. Häufige Epilepsieformen im Kindes- und Erwachsenenalter: Anfallserkrankungen. InFo Neurologie & Psychiatrie 2014; 16 (10) 42-52
17 Wallace RH, Marini C, Petrou S. et al Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 2001; 28 (01) 49-52
18 Cossette P, Liu L, Brisebois K. et al Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002; 31 (02) 184-9
19 Striano P, Weber YG, Toliat MR. et al GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 2012; 78 (08) 557-62
20 Kirov G. CNVs in neuropsychiatric disorders. Human Molecular Genetics 2015; 24 R1 R45-9
21 de Kovel CGF, Trucks H, Helbig I. et al Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133 (01) 23-3
22 Szafranski P, Von Allmen GK, Graham BH. et al 6q22.1 microdeletion and susceptibility to pediatric epilepsy. Eur J Hum Genet 2015; 23 (02) 173-9
23 Mullen SA, Carvill GL, Bellows S. et al Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 2013; 81 (17) 1507-14
24 Monlong J, Girard SL, Meloche C. et al Global characterization of copy number variants in epilepsy patients from whole genome sequencing. PLoS Genet 2018; 14 (04) e1007285
25 International League Against Epilepsy Consortium on Complex Epilepsies Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 2018; 9 (01) 5269
26 Epi4K consortium, Epilepsy Phenome/Genome Project Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol 2017; 16 (02) 135-43
27 May P, Girard S, Harrer M. et al Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol 2018; 17 (08) 699-708
28 International Schizophrenia Consortium Purcell SM, Wray NR. et al Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460 7256 748-52
29 Weiner DJ, Wigdor EM, Ripke S. et al Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat Genet 2017; 49 (07) 978-85
30 Scheffer IE, Bhatia KP, Lopes-Cendes I. et al Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain 1995; 118 Pt 1 61-73
31 Winawer MR, Ottman R, Hauser WA. et al Autosomal dominant partial epilepsy with auditory features: defining the phenotype. Neurology 2000; 54 (11) 2173-6
32 Steinlein OK, Mulley JC, Propping P. et al A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995; 11 (02) 201-3
33 Berkovic SF, Izzillo P, McMahon JM. et al LGI1 mutations in temporal lobe epilepsies. Neurology 2004; 62 (07) 1115-9
34 Baldassari S, Picard F, Verbeek NE. et al The landscape of epilepsy-related GATOR1 variants. Genetics in Medicine [Internet]. 2018 Aug 10 [cited 2019 Feb 6] http://www.nature.com/articles/s41436-018-0060-2
35 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149 (02) 274-93
36 Dibbens LM, de Vries B, Donatello S. et al Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 2013; 45 (05) 546-51
37 Picard F, Makrythanasis P, Navarro V. et al DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology 2014; 82 (23) 2101-6
38 Striano P, Serioli E, Santulli L. et al DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia 2015; 56 (10) e168-171
39 Lal D, Reinthaler EM, Schubert J. et al DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol 2014; 75 (05) 788-92
40 Scheffer IE, Heron SE, Regan BM. et al Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol 2014; 75 (05) 782-7
41 Baulac S, Ishida S, Marsan E. et al Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol 2015; 77 (04) 675-83
42 Møller RS, Weckhuysen S, Chipaux M. et al Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Neurol Genet 2016; 2 (06) e118
43 Weckhuysen S, Marsan E, Lambrecq V. et al Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 2016; 57 (06) 994-1003
44 Feng Y-CA, Howrigan DP, Abbott LE. et al Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals. bioRxiv [Internet]. 2019 Jan 21 [cited 2019 Apr 15] http://biorxiv.org/lookup/doi/10.1101/525683
45 EpiPM Consortium A roadmap for precision medicine in the epilepsies. Lancet Neurol 2015; 14 (12) 1219-28
46 Deng X, Nakamura Y. Cancer Precision Medicine: From Cancer Screening to Drug Selection and Personalized Immunotherapy. Trends in Pharmacological Sciences 2017; 38 (01) 15-24
47 De Vivo DC, Trifiletti RR, Jacobson RI. et al Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991; 325 (10) 703-9
48 Suls A, Mullen SA, Weber YG. et al Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Annals of Neurology 2009; 66 (03) 415-9
49 Wolking S, Becker F, Bast T. et al Focal epilepsy in Glucose transporter type 1 (Glut1) defects: case reports and a review of literature. J Neurol 2014; 261 (10) 1881-6
50 Suls A, Dedeken P, Goffin K. et al Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 2008; 131 (07) 1831-44
51 Weber YG, Kamm C, Suls A. et al Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 2011; 77 (10) 959-64
52 Klepper J. GLUT1 deficiency syndrome in clinical practice. Epilepsy Research 2012; 100 (03) 272-7
53 Guerrini R, Dravet C, Genton P. et al Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 1998; 39 (05) 508-12
54 Connolly HM, Crary JL, McGoon MD. et al Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337 (09) 581-8
55 Ceulemans B, Boel M, Leyssens K. et al Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53 (07) 1131-9
56 Ceulemans B, Schoonjans A-S. Marchau. et al Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. Epilepsia 2016; 57 (07) e129-134
57 Berkovic SF, Heron SE, Giordano L. et al Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol 2004; 55 (04) 550-7
58 Nakamura K, Kato M, Osaka H. et al Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013; 81 (11) 992-8
59 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) 958-66
60 Lemke JR, Lal D, Reinthaler EM. et al Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nature Genetics 2013; 45 (09) 1067-72
61 Pierson TM, Yuan H, Marsh ED. et al GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014; 1 (03) 190-8
62 Platzer K, Yuan H, Schütz H. et al GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 2017; 54 (07) 460-70
63 Barcia G, Fleming MR, Deligniere A. et al De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet 2012; 44 (11) 1255-9
64 Bearden D, Strong A, Ehnot J. et al Targeted treatment of migrating partial seizures of infancy with quinidine: MPSI and Quinidine. Annals of Neurology 2014; 76 (03) 457-61
65 Mullen SA, Carney PW, Roten A. et al Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine. Neurology 2018; 90 (01) e67-72
66 French JA, Lawson JA, Yapici Z. et al Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2019; 388 10056 2153-63
67 Myers KA, Scheffer IE. DEPDC5 as a potential therapeutic target for epilepsy. Expert Opinion on Therapeutic Targets 2017; 21 (06) 591-600
68 Maljevic S, Reid CA, Petrou S. Models for discovery of targeted therapy in genetic epileptic encephalopathies. Journal of Neurochemistry 2017; 143 (01) 30-48
69 Wood MJA, Talbot K, Bowerman M. Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape. Human Molecular Genetics 2017; 26 R2 R151-9
70 Hsiao J, Yuan TY, Tsai MS. et al Upregulation of Haploinsufficient Gene Expression in the Brain by Targeting a Long Non-coding RNA Improves Seizure Phenotype in a Model of Dravet Syndrome. EBioMedicine 2016; 9: 257-77
71 Mallal S, Phillips E, Carosi G. et al HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008; 358 (06) 568-79
72 Chung W-H, Hung S-I, Hong H-S. et al Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428 6982 486
73 McCormack M, Alfirevic A, Bourgeois S. et al HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011; 364 (12) 1134-43
74 Chung W-H, Chang W-C, Lee Y-S. et al Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA 2014; 312 (05) 525-34
75 McCormack M, Gui H, Ingason A. et al Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology 2018; 90 (04) e332-41
76 Amstutz U, Shear NH, Rieder MJ. et al Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia 2014; 55 (04) 496-506
77 Chen P, Lin J-J, Lu C-S, Ong C-T. et al Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 2011; 364 (12) 1126-33
78 Chen Z, Liew D, Kwan P. Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions. Neurology 2014; 83 (22) 2077-84
79 Glauser TA, Holland K, O’Brien V. et al Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy. Ann Neurol 2017; 81 (03) 444-53
80 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 (04) 393-9
81 Heron SE, Smith KR, Bahlo M. et al Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012; 44 (11) 1188-90
82 Singh NA, Charlier C, Stauffer D. et al A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998; 18 (01) 25-9
83 Weckhuysen S, Mandelstam S, Suls A. et al KCNQ2 encephalopathy: Emerging phenotype of a neonatal epileptic encephalopathy. Annals of Neurology 2012; 71 (01) 15-25
84 Kato M, Yamagata T, Kubota M. et al Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013; 54 (07) 1282-7
85 Horvath R, Hudson G, Ferrari G. et al Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 2006; 129 Pt 7 1674-84
86 Engelsen BA, Tzoulis C, Karlsen B. et al POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain 2008; 131 Pt 3 818-28
87 Larsen J, Carvill GL, Gardella E. et al The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015; 84 (05) 480-9
88 Johannesen KM, Gardella E, Encinas AC. et al The spectrum of intermediate SCN8A-related epilepsy. Epilepsia 2010; 60 (05) 830-44
89 Gardella E, Becker F, Møller RS. et al Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 2018; 79 (03) 428-36
90 Boerma RS, Braun KP, van den Broek MPH. et al Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach. Neurotherapeutics 2016; 13 (01) 192-7
91 Klepper J, Leiendecker B. Glut1 Deficiency Syndrome and Novel Ketogenic Diets. Journal of Child Neurology 2013; 28 (08) b1045-8