Epileptic Encephalopathies in Childhood: The Role of Genetic Testing

Johannes R. Lemke; Steffen Syrbe

doi:10.1055/s-0035-1552623

Seminars in Neurology, Table of Contents

Semin Neurol 2015; 35(03): 310-322
DOI: 10.1055/s-0035-1552623

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epileptic Encephalopathies in Childhood: The Role of Genetic Testing

Johannes R. Lemke

¹Institute of Human Genetics, University of Leipzig, Leipzig, Germany

,

Steffen Syrbe

²Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany

› Author Affiliations

Abstract

The epileptic encephalopathies comprise a heterogeneous group of neurodevelopmental disorders characterized by marked epileptic activity associated with developmental regression. The genetic confirmation and classification of a clinical diagnosis in an individual may provide certainty in treatment decisions, prognosis, and evaluation of seizure recurrence risks and may also prevent unnecessary diagnostic investigations. Furthermore, without genetic testing it is challenging to classify the epileptic encephalopathies based on clinical and electroencephalogram features alone.

The significant gain of knowledge of the past few years associated with improvement in genetic analyses allows for precise diagnoses in an increasing number of patients. As a consequence, known encephalopathies have been associated with even broader phenotypic ranges and novel entities constantly expand the spectrum of these disorders. Accordingly, many entities of this heterogeneous spectrum escape a precise classification using current nomenclatures.

Keywords

epileptic encephalopathy - infantile epilepsy - molecular genetic testing

Full Text

References

References
1 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 (4) 676-685
2 Mizrahi EMM. Early severe neonatal and infantile epilepsies. In: Bureau M, Genton P, Dravet CH, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, , eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 5th ed. London: John Libbey Eurotext Ltd; 2012
3 Aicardi J, Goutieres F. [Neonatal myoclonic encephalopathy (author's transl)]. Rev Electroencephalogr Neurophysiol Clin 1978; 8 (1) 99-101
4 Aicardi J. Epilepsy in brain-injured children. Dev Med Child Neurol 1990; 32 (3) 191-202
5 Plecko B. Pyridoxine and pyridoxalphosphate-dependent epilepsies. Handb Clin Neurol 2013; 113: 1811-1817
6 Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol 2003; 20 (6) 398-407
7 Murakami N, Ohtsuka Y, Ohtahara S. Early infantile epileptic syndromes with suppression-bursts: early myoclonic encephalopathy vs. Ohtahara syndrome. Jpn J Psychiatry Neurol 1993; 47 (2) 197-200
8 Panayiotopoulos CP. The epilepsies: seizures, syndromes and management. Oxfordshire, UK: Bladon Medical Publishing; 2005
9 Hirose M, Haginoya K, Yokoyama H , et al. Functional cortical deafferentation from the subcortical structures in a patient with early myoclonic encephalopathy: a functional neuroimaging study. Epilepsia 2010; 51 (4) 699-702
10 Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res 2006; 70 (Suppl. 01) S58-S67
11 Backx L, Ceulemans B, Vermeesch JR, Devriendt K, Van Esch H. Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur J Hum Genet 2009; 17 (3) 378-382
12 Kato M, Saitsu H, Murakami Y , et al. PIGA mutations cause early-onset epileptic encephalopathies and distinctive features. Neurology 2014; 82 (18) 1587-1596
13 Ohtahara S, Ishida T, Oka E, Yamatogy Y, Inoue H. On the specific age dependent epileptic syndrome: the early-infantile epileptic encephalopathy with suppression-burst. No To Hattatsu 1976; 8: 270-279
14 Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev 2002; 24 (1) 13-23
15 Kato M, Saitoh S, Kamei A , et al. A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). Am J Hum Genet 2007; 81 (2) 361-366
16 Giordano L, Sartori S, Russo S , et al. Familial Ohtahara syndrome due to a novel ARX gene mutation. Am J Med Genet A 2010; 152A (12) 3133-3137
17 Uyanik G, Aigner L, Martin P , et al. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 2003; 61 (2) 232-235
18 Guerrini R, Moro F, Kato M , et al. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology 2007; 69 (5) 427-433
19 Weckhuysen S, Holmgren P, Hendrickx R , et al. Reduction of seizure frequency after epilepsy surgery in a patient with STXBP1 encephalopathy and clinical description of six novel mutation carriers. Epilepsia 2013; 54 (5) e74-e80
20 Deprez L, Weckhuysen S, Holmgren P , et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology 2010; 75 (13) 1159-1165
21 Weckhuysen S, Mandelstam S, Suls A , et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol 2012; 71 (1) 15-25
22 Weckhuysen S, Ivanovic V, Hendrickx R , et al; KCNQ2 Study Group. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 2013; 81 (19) 1697-1703
23 Saitsu H, Kato M, Osaka H , et al. CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia. Epilepsia 2012; 53 (8) 1441-1449
24 Nakamura K, Kodera H, Akita T , et al. De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy. Am J Hum Genet 2013; 93 (3) 496-505
25 Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 1995; 36 (10) 1017-1024
26 Coppola G. Malignant migrating partial seizures in infancy: an epilepsy syndrome of unknown etiology. Epilepsia 2009; 50 (Suppl. 05) 49-51
27 McTague A, Appleton R, Avula S , et al. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum. Brain 2013; 136 (Pt 5) 1578-1591
28 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) 1255-1259
29 Ishii A, Shioda M, Okumura A , et al. A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy. Gene 2013; 531 (2) 467-471
30 Ohba C, Kato M, Takahashi S , et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014; 55 (7) 994-1000
31 Poduri A, Heinzen EL, Chitsazzadeh V , et al. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol 2013; 74 (6) 873-882
32 Dhamija R, Wirrell E, Falcao G, Kirmani S, Wong-Kisiel LC. Novel de novo SCN2A mutation in a child with migrating focal seizures of infancy. Pediatr Neurol 2013; 49 (6) 486-488
33 Coppola G, Veggiotti P, Del Giudice EM , et al. Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy. Brain Dev 2006; 28 (2) 76-79
34 Lux AL, Osborne JP. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: consensus statement of the West Delphi group. Epilepsia 2004; 45 (11) 1416-1428
35 Jóźwiak S, Kotulska K, Domańska-Pakieła D , et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011; 15 (5) 424-431
36 Nabbout R, Dulac O. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol 2003; 20 (6) 393-397
37 Mettin RR, Merkenschlager A, Bernhard MK , et al. Wide spectrum of clinical manifestations in children with tuberous sclerosis complex—follow-up of 20 children. Brain Dev 2014; 36 (4) 306-314
38 Osborne JP, Lux AL, Edwards SW , et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia 2010; 51 (10) 2168-2174
39 Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms. Pediatr Neurol 2011; 45 (6) 355-367
40 Kurian MA, Meyer E, Vassallo G , et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain 2010; 133 (10) 2964-2970
41 Edvardson S, Baumann AM, Mühlenhoff M , et al. West syndrome caused by ST3Gal-III deficiency. Epilepsia 2013; 54 (2) e24-e27
42 Allen AS, Berkovic SF, Cossette P , et al; Epi4K Consortium; Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 2013; 501 (7466) 217-221
43 Euro E-RESC ; EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 2014; 95 (4) 360-370
44 Lemke JR, Hendrickx R, Geider K , et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol 2014; 75 (1) 147-154
45 Dravet C. Les epilepsies graves de l'enfant. Vie Med 1978; 8: 543-548
46 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
47 Dravet C, Bureau M, Oguni H, Cokar O, Guerrini R. Dravet syndrome. (Severe myoclonic epilepsy in infancy). In: Bureau M, Genton P, Dravet CH, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, , eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 5th ed. London: John Libbey Eurotext Ltd; 2012
48 Dalla Bernardina B, Capovilla G, Gattoni MB, Colamaria V, Bondavalli S, Bureau M. [Severe infant myoclonic epilepsy (author's transl)]. Rev Electroencephalogr Neurophysiol Clin 1982; 12 (1) 21-25
49 Bureau M, Dalla Bernardina B. Electroencephalographic characteristics of Dravet syndrome. Epilepsia 2011; 52 (Suppl. 02) 13-23
50 Orosz I, McCormick D, Zamponi N , et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia 2014; 55 (10) 1576-1584
51 Rodda JM, Scheffer IE, McMahon JM, Berkovic SF, Graham HK. Progressive gait deterioration in adolescents with Dravet syndrome. Arch Neurol 2012; 69 (7) 873-878
52 Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001; 68 (6) 1327-1332
53 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 (2) e1000381
54 Carvill GL, Weckhuysen S, McMahon JM , et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology 2014; 82 (14) 1245-1253
55 Suls A, Jaehn JA, Kecskés A , et al; EuroEPINOMICS RES Consortium. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet 2013; 93 (5) 967-975
56 Nava C, Dalle C, Rastetter A , et al; EuroEPINOMICS RES Consortium. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet 2014; 46 (6) 640-645
57 Singh NA, Pappas C, Dahle EJ , et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet 2009; 5 (9) e1000649
58 Lemke JR, Riesch E, Scheurenbrand T , et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 2012; 53 (8) 1387-1398
59 Lennox WG, Davis JP. Clinical correlates of the fast and the slow spike-wave electroencephalogram. Pediatrics 1950; 5 (4) 626-644
60 Gastaut H, Roger J, Soulayrol R , et al. [Epileptic encephalopathy of children with diffuse slow spikes and waves (alias “petit mal variant”) or Lennox syndrome]. Ann Pediatr (Paris) 1966; 13 (8) 489-499
61 Crespel A, Gelisse P, Nikanorova M, Ferlazzo E, Genton P. Lennox-Gastaut syndrome. In: Bureau M, Genton P, Dravet CH, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, , eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 5th ed. London: John Libbey Eurotext Ltd; 2012
62 Lund C, Brodtkorb E, Øye AM, Røsby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav 2014; 33: 18-21
63 Kruse R. [The myoclonic astatic petit mal. Clinical course of small epileptic seizures in childhood. With an introduction by Prof. Dr. Dietrich Janz]. Monogr Gesamtgeb Neurol Psychiatr 1968; 124: 1-126
64 Doose H, Gerken H, Leonhardt R, Völzke E, Völz C. Centrencephalic myoclonic-astatic petit mal. Clinical and genetic investigation. Neuropadiatrie 1970; 2 (1) 59-78
65 Oguni H, Tanaka T, Hayashi K , et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics 2002; 33 (3) 122-132
66 Kaminska A, Ickowicz A, Plouin P, Bru MF, Dellatolas G, Dulac O. Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res 1999; 36 (1) 15-29
67 Wallace RH, Wang DW, Singh R , et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998; 19 (4) 366-370
68 Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 2010; 75 (5) 432-440
69 Carvill GL, McMahon JM, Schneider A , et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet 2015; 96 (5) 808-815
70 Syrbe S, Hedrich UB, Riesch E , et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 2015; 4 (4) 393-399
71 Patry G, Lyagoubi S, Tassinari CA. Subclinical “electrical status epilepticus” induced by sleep in children. A clinical and electroencephalographic study of six cases. Arch Neurol 1971; 24 (3) 242-252
72 Tassinari CA, Daniele O, Gambarelli F, Bureau-Paillas M, Robaglia L, Cicirata F. [Excessive 7-14-sec positive spikes during REM sleep in monozygotic non-epileptic twins with speech retardation (author's transl)]. Rev Electroencephalogr Neurophysiol Clin 1977; 7 (2) 192-193
73 Tassinari CA. Encephalopathy related to status epilepticus during slow sleep (ESES) including Landau-Kleffner syndrome. In: Bureau M, Genton P, Dravet CH, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, , eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 5th ed. London: John Libbey Eurotext Ltd; 2012
74 Tovia E, Goldberg-Stern H, Ben Zeev B , et al. The prevalence of atypical presentations and comorbidities of benign childhood epilepsy with centrotemporal spikes. Epilepsia 2011; 52 (8) 1483-1488
75 Lemke JR, Lal D, Reinthaler EM , et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet 2013; 45 (9) 1067-1072
76 Lesca G, Rudolf G, Bruneau N , et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013; 45 (9) 1061-1066
77 Carvill GL, Regan BM, Yendle SC , et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013; 45 (9) 1073-1076
78 Rauch A, Wieczorek D, Graf E , et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012; 380 (9854) 1674-1682
79 Milligan CJ, Li M, Gazina EV , et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014; 75 (4) 581-590
80 Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76 (3) 457-461
81 Orhan G, Bock M, Schepers D , et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol 2014; 75 (3) 382-394
82 Pierson TM, Yuan H, Marsh ED , et al; PhD for the NISC Comparative Sequencing Program. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014; 1 (3) 190-198