Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome

Claire Bar^{1

2}, Mathieu Kuchenbuch^{1

2}, Giulia Barcia^{2

3}, Amy Schneider⁴, Mélanie Jennesson⁵, Gwenaël Le Guyader^{6

7}, Gaetan Lesca^{8

9}, Cyril Mignot^{10

11}, Martino Montomoli¹², Elena Parrini¹², Hervé Isnard¹³, Anne Rolland¹⁴, Boris Keren¹¹, Alexandra Afenjar¹⁵, Nathalie Dorison^{16

17}, Lynette G Sadleir¹⁸, Delphine Breuillard^{1

2}, Raphael Levy¹⁹, Marlène Rio^{3

20}, Sophie Dupont^{10

21}, Susanna Negrin²², Alberto Danieli²², Emmanuel Scalais²³, Anne De Saint Martin²⁴, Salima El Chehadeh²⁵, Jamel Chelly²⁵, Alice Poisson²⁶, Anne-Sophie Lebre²⁷, Anca Nica^{28

29}, Sylvie Odent^{30

31}, Tayeb Sekhara³², Vesna Brankovic³³, Alice Goldenberg³⁴, Pascal Vrielynck³⁵, Damien Lederer³⁶, Hélène Maurey³⁷, Gaetano Terrone³⁸, Claude Besmond³⁹, Laurence Hubert³⁹, Patrick Berquin⁴⁰, Thierry Billette de Villemeur¹⁷, Bertrand Isidor⁴¹, Jeremy L Freeman^{42

43}, Heather C Mefford⁴⁴, Candace T Myers⁴⁴, Katherine B Howell^{42

43}, Andrés Rodríguez-Sacristán Cascajo^{45

46}, Pierre Meyer^{47

48}, David Genevieve⁴⁹, Agnès Guët⁵⁰, Diane Doummar¹⁷, Julien Durigneux⁴², Marieke F van Dooren⁵¹, Marie Claire Y de Wit⁵², Marion Gerard⁵³, Isabelle Marey¹¹, Arnold Munnich^{2

3}, Renzo Guerrini¹², Ingrid E Scheffer^{4

42

43

54}, Edor Kabashi², Rima Nabbout^{1

2}

Affiliations

¹ Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France.
² Imagine Institute, Mixed Unit of Research 1163, University of Paris, Sorbonne University, Paris, France.
³ Department of Clinical Genetics, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
⁴ Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
⁵ Department of Pediatrics, American Memorial Hospital, Reims, France.
⁶ Department of Genetics, Poitiers University Hospital Center, Poitiers Cedex, France.
⁷ EA3808-NEUVACOD Neurovascular and Cognitive Disorders Unit, University of Poitiers, Poitiers, France.
⁸ Department of Genetics, Lyon Civil Hospices, Lyon, France.
⁹ NeuroMyoGène Institute, National Center for Scientific Research, Mixed Unit of Research 5310, National Institute of Health and Medical Research U1217, University of Lyon, Claude Bernard Lyon 1 University, Villeurbanne, France.
¹⁰ National Institute of Health and Medical Research, U1127, National Center for Scientific Research Mixed Unit of Research 7225, Pierre and Marie Curie University Paris 6 Mixed Unit of Research S1127, Brain and Spine Institute, Sorbonne University, Paris, France.
¹¹ Department of Genetics, Rare Causes of Intellectual Disability Reference Center, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹² Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Florence, Italy.
¹³ Pediatric Neurologist, Medical Office, Lyon, France.
¹⁴ Department of Pediatrics, Nantes University Hospital Center, Nantes, France.
¹⁵ Department of Genetics and Medical Embryology, Reference Center for Malformations and Congenital Diseases of the Cerebellum and Rare Causes of Intellectual Disabilities, Sorbonne University, AP-HP, Trousseau Hospital, Paris, France.
¹⁶ Pediatric Neurosurgery Department, Rothschild Foundation Hospital, Paris, France.
¹⁷ Department of Pediatric Neurology, AP-HP, Armand Trousseau Hospital, Sorbonne University, Paris, France.
¹⁸ Department of Pediatrics and Child Health, University of Otago, Wellington, New Zealand.
¹⁹ Department of Pediatric Radiology, Necker-Enfants Malades Hospital, Paris, France.
²⁰ Laboratory of Developmental Brain Disorders, National Institute of Health and Medical Research Mixed Unit of Research 1163, Imagine Institute, Sorbonne University, Paris, France.
²¹ Epileptology Unit and Rehabilitation Unit, AP-HP, Pitie-Salpêtrière-Charles Foix Hospital, Paris, France.
²² Epilepsy and Clinical Neurophysiology Unit, Scientific Institute, IRCCS E. Medea, Treviso, Italy.
²³ Pediatric Neurology Unit, Luxembourg Hospital Center, Luxembourg City, Luxembourg.
²⁴ Department of Pediatric Neurology, Strasbourg University Hospital, Hautepierre Hospital, Strasbourg, France.
²⁵ Department of Medical Genetics, Strasbourg University Hospitals, Hautepierre Hospital, Strasbourg, France.
²⁶ GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, le Vinatier Hospital Center and EDR-Psy Team (National Center for Scientific Research and Lyon 1 Claude Bernard University), Villeurbanne, France.
²⁷ Reims University Hospital Center, Maison Blanche Hospital, Biology Department, Reims, France.
²⁸ Neurology Department, Center for Clinical Research (CIC 1414), Rennes University Hospital, Rennes, France.
²⁹ Laboratory of Signal Processing, National Institute of Health and Medical Research Mixed Unit of Research 1099, Rennes, France.
³⁰ Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.
³¹ National Center for Scientific Research Mixed Unit of Research 6290, Institute of Genetics and Development of Rennes (IGDR), University of Rennes, Rennes, France.
³² Department of Pediatric Neurology, C.H.I.R.E.C, Brussels, Belgium.
³³ Clinic for Child Neurology and Psychiatry, Belgrade, Serbia.
³⁴ Reference Center for Developmental Anomalies and Malformation Syndromes, Rouen University Hospital Center, Rouen, France.
³⁵ Reference Center for Refractory Epilepsy, Catholic University of Louvain, William Lennox Neurological Hospital, Ottignies, Belgium.
³⁶ Human Genetic Center, IPG, Gosselies, Belgium.
³⁷ Department of Pediatric Neurology, AP-HP, Bicêtre University Hospital, Kremlin Bicêtre, France.
³⁸ Department of Translational Medical Sciences, Section of Pediatrics, Child Neurology Unit, Federico II University, Naples, Italy.
³⁹ Translational Genetics, National Institute of Health and Medical Research Mixed Unit of Research 1163, Imagine Institute, University of Paris, Paris, France.
⁴⁰ Department of Pediatric Neurology, Amiens-Picardie University Hospital Center, University of Picardy Jules Verne, Amiens, France.
⁴¹ Department of Clinical Genetics, Nantes University Hospital Center, Nantes, France.
⁴² Departments of Neurology and Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
⁴³ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁴⁴ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, United States.
⁴⁵ Pediatric Neurology Unit, Department of Pediatric, Virgen Macarena Hospital, Seville, Spain.
⁴⁶ Department of Pediatrics, School of Medicine, University of Seville, Seville, Spain.
⁴⁷ Department of Pediatric Neurology, Montpellier University Hospital Center, Montpellier, France.
⁴⁸ PhyMedExp, National Institute of Health and Medical Research, U1046, National Center for Scientific Research Mixed Unit of Research 9214, University of Montpellier, Montpellier, France.
⁴⁹ Department of Medical Genetics, Rare Disease, and Personalized Medicine, IRMB, University of Montpellier, National Institute of Health and Medical Research, Montpellier University Hospital Center, Montpellier, France.
⁵⁰ Department of Pediatrics, Louis-Mourier Hospital, Colombes, France.
⁵¹ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵² Department of Pediatric Neurology and ENCORE Expertise Center, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.
⁵³ Clinical Genetics, Côte de Nacre University Hospital Center, Caen, France.
⁵⁴ Florey Institute of Neurosciences and Mental Health, Heidelberg, Victoria, Australia.

PMID: 32954514
DOI: 10.1111/epi.16679

Free article

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome

Claire Bar et al. Epilepsia. 2020 Nov.

Free article

. 2020 Nov;61(11):2461-2473.

doi: 10.1111/epi.16679. Epub 2020 Sep 21.

Authors

Affiliations

¹ Department of Pediatric Neurology, Reference Center for Rare Epilepsies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France.
² Imagine Institute, Mixed Unit of Research 1163, University of Paris, Sorbonne University, Paris, France.
³ Department of Clinical Genetics, AP-HP, Necker-Enfants Malades Hospital, Paris, France.
⁴ Department of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
⁵ Department of Pediatrics, American Memorial Hospital, Reims, France.
⁶ Department of Genetics, Poitiers University Hospital Center, Poitiers Cedex, France.
⁷ EA3808-NEUVACOD Neurovascular and Cognitive Disorders Unit, University of Poitiers, Poitiers, France.
⁸ Department of Genetics, Lyon Civil Hospices, Lyon, France.
⁹ NeuroMyoGène Institute, National Center for Scientific Research, Mixed Unit of Research 5310, National Institute of Health and Medical Research U1217, University of Lyon, Claude Bernard Lyon 1 University, Villeurbanne, France.
¹⁰ National Institute of Health and Medical Research, U1127, National Center for Scientific Research Mixed Unit of Research 7225, Pierre and Marie Curie University Paris 6 Mixed Unit of Research S1127, Brain and Spine Institute, Sorbonne University, Paris, France.
¹¹ Department of Genetics, Rare Causes of Intellectual Disability Reference Center, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
¹² Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Florence, Italy.
¹³ Pediatric Neurologist, Medical Office, Lyon, France.
¹⁴ Department of Pediatrics, Nantes University Hospital Center, Nantes, France.
¹⁵ Department of Genetics and Medical Embryology, Reference Center for Malformations and Congenital Diseases of the Cerebellum and Rare Causes of Intellectual Disabilities, Sorbonne University, AP-HP, Trousseau Hospital, Paris, France.
¹⁶ Pediatric Neurosurgery Department, Rothschild Foundation Hospital, Paris, France.
¹⁷ Department of Pediatric Neurology, AP-HP, Armand Trousseau Hospital, Sorbonne University, Paris, France.
¹⁸ Department of Pediatrics and Child Health, University of Otago, Wellington, New Zealand.
¹⁹ Department of Pediatric Radiology, Necker-Enfants Malades Hospital, Paris, France.
²⁰ Laboratory of Developmental Brain Disorders, National Institute of Health and Medical Research Mixed Unit of Research 1163, Imagine Institute, Sorbonne University, Paris, France.
²¹ Epileptology Unit and Rehabilitation Unit, AP-HP, Pitie-Salpêtrière-Charles Foix Hospital, Paris, France.
²² Epilepsy and Clinical Neurophysiology Unit, Scientific Institute, IRCCS E. Medea, Treviso, Italy.
²³ Pediatric Neurology Unit, Luxembourg Hospital Center, Luxembourg City, Luxembourg.
²⁴ Department of Pediatric Neurology, Strasbourg University Hospital, Hautepierre Hospital, Strasbourg, France.
²⁵ Department of Medical Genetics, Strasbourg University Hospitals, Hautepierre Hospital, Strasbourg, France.
²⁶ GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, le Vinatier Hospital Center and EDR-Psy Team (National Center for Scientific Research and Lyon 1 Claude Bernard University), Villeurbanne, France.
²⁷ Reims University Hospital Center, Maison Blanche Hospital, Biology Department, Reims, France.
²⁸ Neurology Department, Center for Clinical Research (CIC 1414), Rennes University Hospital, Rennes, France.
²⁹ Laboratory of Signal Processing, National Institute of Health and Medical Research Mixed Unit of Research 1099, Rennes, France.
³⁰ Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.
³¹ National Center for Scientific Research Mixed Unit of Research 6290, Institute of Genetics and Development of Rennes (IGDR), University of Rennes, Rennes, France.
³² Department of Pediatric Neurology, C.H.I.R.E.C, Brussels, Belgium.
³³ Clinic for Child Neurology and Psychiatry, Belgrade, Serbia.
³⁴ Reference Center for Developmental Anomalies and Malformation Syndromes, Rouen University Hospital Center, Rouen, France.
³⁵ Reference Center for Refractory Epilepsy, Catholic University of Louvain, William Lennox Neurological Hospital, Ottignies, Belgium.
³⁶ Human Genetic Center, IPG, Gosselies, Belgium.
³⁷ Department of Pediatric Neurology, AP-HP, Bicêtre University Hospital, Kremlin Bicêtre, France.
³⁸ Department of Translational Medical Sciences, Section of Pediatrics, Child Neurology Unit, Federico II University, Naples, Italy.
³⁹ Translational Genetics, National Institute of Health and Medical Research Mixed Unit of Research 1163, Imagine Institute, University of Paris, Paris, France.
⁴⁰ Department of Pediatric Neurology, Amiens-Picardie University Hospital Center, University of Picardy Jules Verne, Amiens, France.
⁴¹ Department of Clinical Genetics, Nantes University Hospital Center, Nantes, France.
⁴² Departments of Neurology and Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
⁴³ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁴⁴ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, United States.
⁴⁵ Pediatric Neurology Unit, Department of Pediatric, Virgen Macarena Hospital, Seville, Spain.
⁴⁶ Department of Pediatrics, School of Medicine, University of Seville, Seville, Spain.
⁴⁷ Department of Pediatric Neurology, Montpellier University Hospital Center, Montpellier, France.
⁴⁸ PhyMedExp, National Institute of Health and Medical Research, U1046, National Center for Scientific Research Mixed Unit of Research 9214, University of Montpellier, Montpellier, France.
⁴⁹ Department of Medical Genetics, Rare Disease, and Personalized Medicine, IRMB, University of Montpellier, National Institute of Health and Medical Research, Montpellier University Hospital Center, Montpellier, France.
⁵⁰ Department of Pediatrics, Louis-Mourier Hospital, Colombes, France.
⁵¹ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵² Department of Pediatric Neurology and ENCORE Expertise Center, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.
⁵³ Clinical Genetics, Côte de Nacre University Hospital Center, Caen, France.
⁵⁴ Florey Institute of Neurosciences and Mental Health, Heidelberg, Victoria, Australia.

PMID: 32954514
DOI: 10.1111/epi.16679

Abstract

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

Keywords: autism spectrum disorders; developmental and epileptic encephalopathy; developmental encephalopathy; drug-resistant epilepsy; potassium channels; sudden unexpected death in epilepsy.

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References

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Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome

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Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome

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Abstract

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