Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

Center for Genomics and Transcriptomics GmbH Tübingen Germany

Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid Spain

Child and Adolescent Department Pediatric Neurology University Hospitals Geneva Switzerland

Child Neurology Department 2nd Faculty of Medicine Charles University Motol Hospital Prague Czech Republic

Cologne Center for Genomics University of Colgone Cologne Germany

Danish Epilepsy Center Dianalund Denmark

Department of Clinical and Experimental Epilepsy University College London Institute of Neurology Queen Square London WC1N 3BG UK

Department of Diagnostics Institute of Human Genetics University of Leipzig Leipzig Germany

Department of Medical Genetics Institute of Mother and Child Warsaw Poland

Department of Molecular Biology and Genetics Bogazici University Istanbul Turkey

Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

Department of Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

Department of Neurology Antwerp University Hospital University of Antwerp Antwerp Belgium

Department of Neuropediatrics Christian Albrechts University of Kiel Germany

Department of Neuropediatrics University of Tübingen Tübingen Germany

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

Division of Human Genetics University Children's Hospital Inselspital Bern Switzerland

Division of Neurology Children's Hospital of Philadelphia Philadelphia USA

Division of Neuropediatrics University Children's Hospital Inselspital Bern Switzerland

Division of Pediatric Endocrinology University Children's Hospital Inselspital Bern Switzerland

Dr JT MacDonald Department for Human Genetics Hussman Institute for Human Genomics University of Miami Miami USA

Epilepsy Society Chalfont St Peter Bucks SL9 0RJ UK

Folkhälsan Institute of Genetics Helsinki Helsinki Finland

German Research Center for Neurodegenerative Diseases Tübingen Germany

Gulhane Military Medical School Division of Child Neurology Ankara Turkey

Institute for Molecular Medicine Finland University of Helsinki Helsinki Finland

Institute for Regional Health Services University of Southern Denmark Odense Denmark

Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium

Luxembourg Centre for Systems Biomedicine University of Luxembourg Esch sur Alzette Luxembourg

Neurogenetics group Department of Molecular Genetics VIB Antwerp Belgium

Neurology Lab and Epilepsy Unit Department of Neurology IIS Fundación Jiménez Díaz UAM Madrid Spain

Neuroscience Center University of Helsinki Helsinki Finland

Pediatric Neurology Children's Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Pediatric Neurology Clinic 2 Department of Neurology Pediatric Neurology Psychiatry and Neurosurgery Carol Davila University of Medicine Sector 4 Bucharest Romania

Pediatric Neurology Clinic Professor Doctor Alexandru Obregia Clinical Hospital Sector 4 Bucharest Romania

Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry Massachusetts General Hospital Boston MA 02114 USA

Research Program's Unit Molecular Neurology University of Helsinki Helsinki Finland

Swiss Epilepsy Center Zürich Switzerland

Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton UK

Clin Genet. 2015 Aug;88(2):137-9. doi: 10.1111/cge.12615. PubMed

Zobrazit více v PubMed

Capovilla G, Wolf P, Beccaria F, Avanzini G. The history of the concept of epileptic encephalopathy. Epilepsia. 2013;54(Suppl 8):2–5. PubMed

Guerrini R, Pellock JM. Age-related epileptic encephalopathies. Handb Clin Neurol. 2012;107:179–93. PubMed

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. PubMed PMC

Nava C, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014;46:640–5. PubMed

Epi KC, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217–21. PubMed PMC

Lerche H, et al. Ion channels in genetic and acquired forms of epilepsy. J Physiol. 2013;591:753–64. PubMed PMC

Lai HC, Jan LY. The distribution and targeting of neuronal voltage-gated ion channels. Nature Reviews Neuroscience. 2006;7:548–562. PubMed

Biervert C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279:403–6. PubMed

Charlier C, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet. 1998;18:53–5. PubMed

Singh NA, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18:25–9. PubMed

Weckhuysen S, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71:15–25. PubMed

Orhan G, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75:382–94. PubMed

Browne DL, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994;8:136–40. PubMed

Wuttke TV, et al. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology. 2007;69:2045–53. PubMed

Dedek K, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci U S A. 2001;98:12272–7. PubMed PMC

Irani SR, et al. Antibodies to KV1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010;133:2734–48. PubMed PMC

Lemke JR, et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia. 2012;53:1387–98. PubMed

Lubbers WJ, et al. Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide. J Neurol Neurosurg Psychiatry. 1995;59:400–5. PubMed PMC

Pena SD, Coimbra RL. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genet. 2015;87:e1–3. PubMed

Xie G, et al. A new KV1.2 channelopathy underlying cerebellar ataxia. J Biol Chem. 2010;285:32160–73. PubMed PMC

Brew HM, et al. Seizures and reduced life span in mice lacking the potassium channel subunit KV1.2, but hypoexcitability and enlarged KV1 currents in auditory neurons. J Neurophysiol. 2007;98:1501–25. PubMed

Jan LY, Jan YN. Voltage-gated potassium channels and the diversity of electrical signalling. J Physiol. 2012;590:2591–9. PubMed PMC

Holmgren M, Shin KS, Yellen G. The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge. Neuron. 1998;21:617–21. PubMed

Long SB, Campbell EB, Mackinnon R. Voltage sensor of KV1.2: structural basis of electromechanical coupling. Science. 2005;309:903–8. PubMed

Labro AJ, Raes AL, Bellens I, Ottschytsch N, Snyders DJ. Gating of shaker-type channels requires the flexibility of S6 caused by prolines. J Biol Chem. 2003;278:50724–31. PubMed

Chen X, Wang Q, Ni F, Ma J. Structure of the full-length Shaker potassium channel KV1.2 by normal-mode-based X-ray crystallographic refinement. Proc Natl Acad Sci U S A. 2010;107:11352–7. PubMed PMC

Klein A, Boltshauser E, Jen J, Baloh RW. Episodic ataxia type 1 with distal weakness: a novel manifestation of a potassium channelopathy. Neuropediatrics. 2004;35:147–9. PubMed

Nybo K. Molecular biology techniques Q&A. Western blot: protein migration. Biotechniques. 2012;53:23–4. PubMed

Lorincz A, Nusser Z. Cell-type-dependent molecular composition of the axon initial segment. J Neurosci. 2008;28:14329–40. PubMed PMC

Wang H, Kunkel DD, Schwartzkroin PA, Tempel BL. Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain. J Neurosci. 1994;14:4588–99. PubMed PMC

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. PubMed PMC

Suls A, et al. Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients. Hum Mutat. 2006;27:914–20. PubMed

Wang H, Kunkel DD, Martin TM, Schwartzkroin PA, Tempel BL. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature. 1993;365:75–9. PubMed

Liu X, Jian X, Boerwinkle E. dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations. Hum Mutat. 2013;34:E2393–402. PubMed PMC

Kong A, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5. PubMed PMC

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5