Abstract
Epileptic encephalopathies account for a large proportion of the intractable early-onset epilepsies and are characterized by frequent seizures and poor developmental outcome. The epileptic encephalopathies can be loosely divided into two related groups of named syndromes. The first comprises epilepsies where continuous EEG changes directly result in cognitive and developmental dysfunction. The second includes patients where cognitive impairment is present at seizure onset and is due to the underlying etiology but the epileptic activity may then worsen the cognitive abilities over time. Recent, large-scale exome studies have begun to establish the genetic architecture of the epileptic encephalopathies, resulting in a re-consideration of the boundaries of these named syndromes. The emergence of this genetic architecture has lead to three main pathophysiological concepts to provide a mechanistic framework for these disorders. In this article, we will review the classic syndromes, the most significant genetic findings, and relate both to the pathophysiological understanding of epileptic encephalopathies.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Waaler PE, Blom BH, Skeidsvoll H, Mykletun A. Prevalence, classification, and severity of epilepsy in children in western Norway. Epilepsia. 2000;41:802–10.
Berg AT 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;51:676–85.
Howell KB, Harvey AS, Archer JS. Epileptic encephalopathy: use and misuse of a clinically and conceptually important concept. Epilepsia. 2016;57:343–7.
Ohtahara S, Ohtsuka Y, Oka E. Epileptic encephalopathies in early infancy. Indian J Pediatr. 1997;64:603–12.
Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression-bursts, Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev. 2002;24:13–23.
Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res. 2006;70:2–5.
Wilmshurst JM et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia. 2015;56:1185–97.
Saitsu H et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782–8.
Deprez L et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology. 2010;75:1159–65.
Saitsu H et al. STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. Epilepsia. 2010;51:2397–405.
Mignot C et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia. 2011;52:1820–7.
Milh M et al. Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations. Epilepsia. 2011;52:1828–34.
Carvill GL et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82:1245–53.
Stamberger H et al. STXBP1 encephalopathy A neurodevelopmental disorder including epilepsy. Neurology. 2016;86:954–62.
Biervert C. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279:403–6.
Singh N et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:231–6.
Weckhuysen S et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology. 2013;81:1697–703.
Saitsu H et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol. 2012;72:298.
Kato M et al. Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia. 2013;54:1282–7.
Nakamura K et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology. 2013;81:992–8.
Heron SE et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002;360:851–2.
Berkovic SF et al. Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann Neurol. 2004;55:550–7.
Aicardi J, Goutieres F. [Neonatal myoclonic encephalopathy (author’s transl)]. Rev Electroencephalogr Neurophysiol Clin. 1978;8:99–101.
Dalla Bernardina B et al. Early myoclonic epileptic encephalopathy (E.M.E.E.). Eur J Pediatr. 1983;140:248–52.
Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol. 2003;20:398–407.
Molinari F et al. Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet. 2005;76:334–9.
Kato M et al. PIGA mutations cause early-onset epileptic encephalopathies and distinctive features. Neurology. 2014;82:1587–96.
Hansen J et al. De novo mutations in SIK1 cause a spectrum of developmental epilepsies. Am J Hum Genet. 2015;96:682–90.
Eling P, Renier WO, Pomper J, Baram TZ. The mystery of the Doctor’s son, or the riddle of West syndrome. Neurology. 2002;58:953–5.
Lux AL et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol. 2005;4:712–7.
Osborne JP 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;51:2168–74.
•• Allen AS et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–21. Collaborative large-scale exome study revealing the signicance of de novo mutations in epileptic encephalopathies.
•• EuroEPINOMICS-RES Consortium, E. P. & Genome Project, E. C. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014;95:360–70. Collaborative large-scale exome study revealing the signicance of de novo mutations in epileptic encephalopathies.
Kalscheuer VM et al. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet. 2003;72:1401–11.
Klein KM et al. A distinctive seizure type in patients with CDKL5 mutations: hypermotor-tonic-spasms sequence. Neurology. 2011;76:1436–8.
Jähn J et al. CDKL5 mutations as a cause of severe epilepsy in infancy: clinical and electroencephalographic long-term course in 4 patients. J Child Neurol. 2013;28:937–41.
Evans JC et al. Early onset seizures and Rett-like features associated with mutations in CDKL5. Eur J Hum Genet. 2005;13:1113–20.
Strømme P et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet. 2002;30:441–5.
Kato M, Das S, Petras K, Sawaishi Y, Dobyns WB. Polyalanine expansion of ARX associated with cryptogenic West syndrome. Neurology. 2003;61:267–76.
Kato M et al. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat. 2004;23:147–59.
Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011;52:3–9.
Bender AC, Morse RP, Scott RC, Holmes GL, Lenck-Santini PP. SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav. 2012;23:177–86.
Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y. A long-term follow-up study of Dravet syndrome up to adulthood. 2010;51:1043–52.
Claes L et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327–32.
Sugawara T et al. Frequent mutations of SCN1A in severe myoclonic epilepsy in infancy. Neurology. 2002;58:1122–4.
Djémié T et al. Pitfalls in genetic testing: the story of missed SCN1A mutations. Mol Genet Genomic Med. 2016;1–8. doi:10.1002/mgg3.217.
Mulley JC et al. SCN1A mutations and epilepsy. Hum Mutat. 2005;25:535–42.
Depienne C et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2009;46:183–91.
• Meng H et al. The SCN1A mutation database: updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Hum Mutat. 2015;36:573–80. This is the most up-to-date listing and consideration of mutations and phenotypes in SCN1A related epilepsy, which is the most common genetic casue of the EEs.
Harkin LA et al. Truncation of the GABA A-receptor g2 subunit in a family with generalized epilepsy with febrile seizures plus. 2002;530–6.
Depienne C et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009;5:e1000381.
Suls A et al. 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;93:967–75.
Nava C et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46:640–5.
Hirose S et al. SCN1A testing for epilepsy: application in clinical practice. Epilepsia. 2013;54:946–52.
Gastaut H et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as ‘petit-mal variant’) or Lennox syndrome. Epilepsia. 1966;7:85–138.
Arzimanoglou A et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. Lancet Neurol. 2009;8:82–93.
Kaminska A et al. Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res. 1999;36:15–29.
Filippini M, Boni A, Dazzani G, Guerra A, Gobbi G. Neuropsychological findings: myoclonic astatic epilepsy (MAE) and Lennox-Gastaut syndrome (LGS). Epilepsia. 2006;47:56–9.
Hoffmann-Riem M et al. Nonconvulsive status epilepticus—a possible cause of mental retardation in patients with Lennox-Gastaut syndrome. Neuropediatrics. 2000;31:169–74.
Zupanc ML. Clinical evaluation and diagnosis of severe epilepsy syndromes of early childhood. J Child Neurol. 2009;24:6S–14S.
Lund C, Brodtkorb E, Øye AM, Røsby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav. 2014;33:18–21.
Jallon P, Loiseau P. Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE Study. 2001;42:464–75.
DeLorenzo RJ et al. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46:1029–35.
Wasterlain CG, Fujikawa DG, Penix L, Sankar R. Pathophysiological mechanisms of brain damage from status epilepticus. Epilepsia. 1993;34 Suppl 1:S37–53.
Walker MC. Diagnosis and treatment of nonconvulsive status epilepticus. CNS Drugs. 2001;15:931–9.
Wallace RH et al. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28:49–52.
Jouvenceau A et al. Early report human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet. 2001;358:801–7.
Cossette P et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31:184–9.
Lu J et al. Mutation screen of the GABAA receptor gamma 2 subunit gene in Chinese patients with childhood absence epilepsy. Neurosci Lett. 2002;332:75–8.
Imbrici P et al. Dysfunction of the brain calcium channel Cav2.1 in absence epilepsy and episodic ataxia. Brain. 2004;127:2682–92.
Maljevic S et al. A mutation in the GABAA receptor α1-subunit is associated with absence epilepsy. Ann Neurol. 2006;59:983–7.
Suls A et al. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol. 2009;66:415–9.
Arsov T et al. Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia. 2012;53:e204–7.
Muhle H et al. The role of SLC2A1 in early onset and childhood absence epilepsies. Epilepsy Res. 2013;105:229–33.
Mullen SA et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol. 2011;68:1152–5.
Larsen J et al. The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome. Epilepsia. 2015;56:e203–8.
Helbig I et al. 15Q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet. 2009;41:160–2.
Dibbens LM et al. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet. 2009;18:3626–31.
de Kovel CGF et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 2010;133:23–32.
Mullen SA et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 2013;81:1507–14.
Helbig I et al. Structural genomic variation in childhood epilepsies with complex phenotypes. Eur J Hum Genet. 2014;22:896–901.
Patry G, Lyagoubi S, Tassinari CA. Subclinical ‘electrical status epilepticus’ induced by sleep in children. Arch Neurol. 1971;24:242–52.
Doose H, Neubauer B, Carlson G. Children with benign focal sharp waves. Neuropdatrics. 1996;227–41.
Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957;7:8–1241.
•• Lemke JR et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067–72. One of three studies published in the same issue of Nature Genetics highlighting the importance of mutations in GRIN2A as gene for epilepsy-aphasia syndromes.
•• Carvill GL et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45:1073–6. One of three studies published in the same issue of Nature Genetics highlighting the importance of mutations in GRIN2A as gene for epilepsy-aphasia syndromes.
•• Lesca G et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013;45:1061–6. One of three studies published in the same issue of Nature Genetics highlighting the importance of mutations in GRIN2A as gene for epilepsy-aphasia syndromes.
Ptáček LJ et al. Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell. 1991;67:1021–7.
Ptáček LJ. Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscul Disord. 1997;7:250–5.
Yu FH et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci. 2006;9:1142–9.
Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol. 2010;588:1849–59.
Liu Y et al. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol. 2013;74:128–39.
Swanson DA, Steel JM, Valle D. Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release. Genomics. 1998;48:373–6.
Verhage M et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. 2000;287:864–9.
Weimer RM et al. Defects in synaptic vesicle docking in unc-18 mutants. Nat Neurosci. 2003;6:1023–30.
Chen Y et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol. 2003;54:239–43.
Ferguson SM et al. A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science. 2007;316:570–4.
Hayashi et al. Cell- and stimulus-dependent heterogeneity of synaptic vesicle endocytic recycling mechanisms revealed by studies of dynamin 1-null neurons. Proc Natl Acad Sci U S A. 2008;105:2175–80.
• Dhindsa RS et al. Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet. 2015;1:1–9. This is a nice recent example of how to determine the underlying pathophysiological deficiencies in specific genetic EEs.
Kato M, Dobyns WB. X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, ‘interneuronopathy’. J Child Neurol. 2005;20:392–7.
Anderson SA, Eisenstat DD, Shi L, Rubenstein JL. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science. 1997;278:474–6.
Kitamura K et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet. 2002;32:359–69.
Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet. 2003;12 Spec No:R89–96.
Bonneau D et al. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann Neurol. 2002;51:340–9.
McKenzie O et al. Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. Neuroscience. 2007;146:236–47.
Fulp CT et al. Identification of Arx transcriptional targets in the developing basal forebrain. Hum Mol Genet. 2008;17:3740–60.
Colasante G et al. ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. Cereb Cortex. 2015;25:322–35.
Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr. 2003;15:567–71.
Friocourt. Mutations in ARX result in several defects involving GABAergic neurons. Front Cell Neurosci. 2010;4:1–11.
Nasrallah MP et al. Differential effects of a polyalanine tract expansion in Arx on neural development and gene expression. Hum Mol Genet. 2012;21:1090–8.
Helbig KL et al. Genetic risk perception and reproductive decision making among people with epilepsy. Epilepsia. 2010;51:1874–7.
Lemke JR et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012;53:1387–98.
Acknowledgements
Markus von Deimling was supported by funds of the Stiftung zur Förderung der medizinischen Forschung of the University of Kiel and by a grant from the German Research Foundation (DFG, HE5415/5-1, HE5415/6-1). Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE).
Eric D. Marsh was supported by NIH/NINDS - R01 NS082761-01. Dr. Marsh has also received a grant from GW Pharma, advisory board fees from Stanley Brothers Social Enterprises, and support from Neuren Pharmaceuticals.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
None of the authors have anything to declare related to this review
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Pediatric Neurology
Rights and permissions
About this article
Cite this article
von Deimling, M., Helbig, I. & Marsh, E.D. Epileptic Encephalopathies—Clinical Syndromes and Pathophysiological Concepts. Curr Neurol Neurosci Rep 17, 10 (2017). https://doi.org/10.1007/s11910-017-0720-7
Published:
DOI: https://doi.org/10.1007/s11910-017-0720-7