. 2022 Sep 14;145(9):2991-3009.

doi: 10.1093/brain/awab321.

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Katrine M Johannesen^{1

2}, Yuanyuan Liu³, Mahmoud Koko³, Cathrine E Gjerulfsen¹, Lukas Sonnenberg^{3

4}, Julian Schubert³, Christina D Fenger¹, Ahmed Eltokhi³, Maert Rannap³, Nils A Koch⁴, Stephan Lauxmann^{3

4}, Johanna Krüger³, Josua Kegele³, Laura Canafoglia⁵, Silvana Franceschetti⁵, Thomas Mayer⁶, Johannes Rebstock⁶, Pia Zacher⁶, Susanne Ruf⁷, Michael Alber⁷, Katalin Sterbova⁸, Petra Lassuthová⁸, Marketa Vlckova⁸, Johannes R Lemke⁹, Konrad Platzer⁹, Ilona Krey⁹, Constanze Heine⁹, Dagmar Wieczorek¹⁰, Judith Kroell-Seger¹¹, Caroline Lund¹², Karl Martin Klein¹³, P Y Billie Au¹⁴, Jong M Rho¹⁵, Alice W Ho¹⁵, Silvia Masnada¹⁶, Pierangelo Veggiotti^{16

17}, Lucio Giordano¹⁸, Patrizia Accorsi¹⁸, Christina E Hoei-Hansen^{19

20}, Pasquale Striano^{21

22}, Federico Zara²², Helene Verhelst²³, Judith S Verhoeven²⁴, Hilde M H Braakman²⁵, Bert van der Zwaag²⁶, Aster V E Harder²⁶, Eva Brilstra²⁶, Manuela Pendziwiat²⁷, Sebastian Lebon^{28

29}, Maria Vaccarezza³⁰, Ngoc Minh Le³¹, Jakob Christensen³², Sabine Grønborg³³, Stephen W Scherer^{34

35}, Jennifer Howe³⁶, Walid Fazeli^{37

38}, Katherine B Howell^{38

39

40}, Richard Leventer^{38

39

40}, Chloe Stutterd^{39

40}, Sonja Walsh⁴¹, Marion Gerard⁴², Bénédicte Gerard⁴³, Sara Matricardi⁴⁴, Claudia M Bonardi⁴⁵, Stefano Sartori⁴⁶, Andrea Berger⁴⁷, Dorota Hoffman-Zacharska⁴⁸, Massimo Mastrangelo⁴⁹, Francesca Darra⁵⁰, Arve Vøllo⁵¹, M Mahdi Motazacker⁵², Phillis Lakeman⁵³, Mathilde Nizon⁵⁴, Cornelia Betzler^{55

56}, Cecilia Altuzarra⁵⁷, Roseline Caume⁵⁸, Agathe Roubertie⁵⁹, Philippe Gélisse⁵⁹, Carla Marini⁶⁰, Renzo Guerrini⁶¹, Frederic Bilan⁶², Daniel Tibussek⁶³, Margarete Koch-Hogrebe⁶⁴, M Scott Perry⁶⁵, Shoji Ichikawa⁶⁶, Elena Dadali^{67

68}, Artem Sharkov^{68

69}, Irina Mishina⁶⁷, Mikhail Abramov⁶⁸, Ilya Kanivets^{70

71}, Sergey Korostelev^{70

72}, Sergey Kutsev⁶⁷, Karen E Wain⁷³, Nancy Eisenhauer⁷³, Monisa Wagner⁷³, Juliann M Savatt⁷³, Karen Müller-Schlüter⁷⁴, Haim Bassan^{75

76}, Artem Borovikov⁶⁷, Marie Cecile Nassogne⁷⁷, Anne Destrée⁷⁸, An Sofie Schoonjans⁷⁹, Marije Meuwissen⁸⁰, Marga Buzatu⁸⁰, Anna Jansen⁸¹, Emmanuel Scalais⁸², Siddharth Srivastava⁸³, Wen Hann Tan⁸⁴, Heather E Olson^{83

85}, Tobias Loddenkemper⁸³, Annapurna Poduri^{83

85}, Katherine L Helbig^{86

87}, Ingo Helbig^{86

87

88

89

90

91}, Mark P Fitzgerald^{86

87

88

90}, Ethan M Goldberg^{86

87}, Timo Roser⁹², Ingo Borggraefe^{92

93}, Tobias Brünger⁹⁴, Patrick May⁹⁵, Dennis Lal^{94

96

97

98}, Damien Lederer⁷⁸, Guido Rubboli^{1

99}, Henrike O Heyne^{9

100

101

102}, Gaetan Lesca^{103

104}, Ulrike B S Hedrich³, Jan Benda⁴, Elena Gardella^{1

2}, Holger Lerche³, Rikke S Møller^{1

2}

Affiliations

¹ Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark.
² Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark.
³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany.
⁴ Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany.
⁵ Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo Besta, 20125 Milan, Italy.
⁶ Epilepsy Center Kleinwachau, 01454 Dresden-Radeberg, Germany.
⁷ Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tuebingen, Germany.
⁸ Department of Child Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 10000 Prague, Czech Republic.
⁹ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany.
¹⁰ Institute of Human Genetics, University Clinic, Heinrich-Heine-University, 40210 Düsseldorf, Germany.
¹¹ Children's Department, Swiss Epilepsy Centre, Clinic Lengg, 8001 Zurich, Switzerland.
¹² National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, 0001 Oslo, Norway.
¹³ Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada.
¹⁴ Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, AB T6G 2T4, Canada.
¹⁵ Section of Pediatric Neurology, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada.
¹⁶ Department of Child Neurology, V. Buzzi Children's Hospital, 20125 Milan, Italy.
¹⁷ 'L. Sacco' Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy.
¹⁸ Child Neuropsychiatric Unit, Civilian Hospital, 25100 Brescia, Italy.
¹⁹ Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark.
²⁰ Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
²¹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16121 Genova, Italy.
²² IRCCS 'G. Gaslini' Institute, 16121 Genoa, Italy.
²³ Department of Pediatrics, Division of Pediatric Neurology, Gent University Hospital, 9042 Gent, Belgium.
²⁴ Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, 5591 Heeze, The Netherlands.
²⁵ Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands.
²⁶ Department of Genetics, University Medical Center Utrecht, Utrecht University, 3553 Utrecht, The Netherlands.
²⁷ Department of Neuropediatrics, Universitätsklinikum Schleswig Holstein Campus Kiel, 24106 Kiel, Germany.
²⁸ Pediatric Neurology and Neurorehabilitation Unit, Woman Mother Child Department, Lausanne University Hospital (CHUV), 1000 Lausanne, Switzerland.
²⁹ University of Lausanne, 1000 Lausanne, Switzerland.
³⁰ Department of Pediatric Neurology, Hospital Italiano de Buenos Aires, C1428 Buenos Aires, Argentina.
³¹ Center for Pediatric Neurology, Cleveland Clinic, Cleveland, OH 44102, USA.
³² Department of Neurology, Aarhus University Hospital, 8000 Aarhus, Denmark.
³³ Center for Rare Diseases, Department of Pediatrics and Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark.
³⁴ McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON 66777, Canada.
³⁵ The Centre for Applied Genomics and Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON 66777, Canada.
³⁶ Department of Neuropediatrics, University Hospital Bonn, 53229 Bonn, Germany.
³⁷ Institute for Molecular and Behavioral Neuroscience, University of Cologne, 50667 Cologne, Germany.
³⁸ Neurology Department, The Royal Children's Hospital Melbourne, 3002 Melbourne, Australia.
³⁹ Murdoch Children's Research Institute, 3052 Parkville, Australia.
⁴⁰ Department of Pediatrics, University of Melbourne, Royal Children's Hospital, 3052 Parkville, Australia.
⁴¹ Department of Neuropediatrics, Children's Hospital, University Hospital Carl Gustav Carus, Technical University, 1099 Dresden, Germany.
⁴² Genetics Department, CHU Côte de Nacre, 14118 Caen, France.
⁴³ Genetics Department, CHRU Strasbourg, 67000 Strasbourg, France.
⁴⁴ Child Neurology and Psychiatry Unit, Children's Hospital G. Salesi, 60121 Ancona, Italy.
⁴⁵ Department of Woman's and Child's Health, Padova University Hospital, 35100 Padova, Italy.
⁴⁶ Child Neurology and Clinical Neurophysiology Unit, Padova University Hospital, 35100 Padova, Italy.
⁴⁷ Department of Neuropediatrics, Klinikum Weiden, Kliniken Nordoberpfalz AG, 92637 Weiden, Germany.
⁴⁸ Department of Medical Genetics, Institute of Mother and Child, 00-034 Warsaw, Poland.
⁴⁹ Pediatric Neurology Unit, Vittore Buzzi Hospital, ASST Fatebenefratelli Sacco, 20100 Milan, Italy.
⁵⁰ Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37121 Verona, Italy.
⁵¹ Department of Pediatrics, Oestfold Hospital, 1712 Graalum, Norway.
⁵² Laboratory of Genome Diagnostics, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands.
⁵³ Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands.
⁵⁴ Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France.
⁵⁵ Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik, 83569 Vogtareuth, Germany.
⁵⁶ Research Institute 'Rehabilitation, Transition, Palliation', PMU Salzburg, 5020 Salzburg, Austria.
⁵⁷ Department of Pediatrics, St. Jacques Hospital, 25000 Besançon, France.
⁵⁸ Clinique de Génétique Guy Fontaine, CHU Lille, 59000, Lille, France.
⁵⁹ Département de Neuropédiatrie, INSERM, CHU Montpellier, 34000 Montpellier, France.
⁶⁰ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50131 Florence, Italy.
⁶¹ IRCCS Stella Maris, 56121 Pisa, Italy.
⁶² Service de Génétique, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers, France.
⁶³ Child Neurology, Center for Pediatric and Teenage Health Care, 53757 Sankt Augustin, Germany.
⁶⁴ Vestische Kinder- und Jugendklinik, 45711 Datteln, Germany.
⁶⁵ Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX 76101, USA.
⁶⁶ Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA 92637, USA.
⁶⁷ Research Centre for Medical Genetics, 115522 Moscow, Russia.
⁶⁸ Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia.
⁶⁹ Genomed Ltd., 100000 Moscow, Russia.
⁷⁰ Svt. Luka's Institute of Child Neurology & Epilepsy, 100000 Moscow, Russia.
⁷¹ Russian Medical Academy of Continuous Professional Education, 100000 Moscow, Russia.
⁷² I.M. Sechenov First Moscow State Medical University, 100000 Moscow, Russia.
⁷³ Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA.
⁷⁴ Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, 16816 Neuruppin, Germany.
⁷⁵ Pediatric Neurology & Development Center, Shamir Medical Center (Assaf Harofe), Be'er Ya'akov, Israel.
⁷⁶ Sackler Faculty of Medicine, Tel Aviv University, 5296001 Tel Aviv, Israel.
⁷⁷ Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1000 Brussels, Belgium.
⁷⁸ Institute for Pathology and Genetics, 6040 Gosselies, Belgium.
⁷⁹ Department of Pediatrics and Pediatric Neurology, Antwerp University Hospital, University of Antwerp, 2650 Edegem, Belgium.
⁸⁰ Pediatric Neurology, Marie Curie Hospital-CHU Charleroi, 6032 Charleroi, Belgium.
⁸¹ Pediatric Neurology Unit, Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
⁸² Pediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de Luxembourg, 1313 Luxembourg, Luxembourg.
⁸³ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA.
⁸⁴ Department of Genetics, Boston Children's Hospital, Boston, MA 02108, USA.
⁸⁵ Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA 02108, USA.
⁸⁶ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸⁷ The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸⁸ Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104USA.
⁸⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104USA.
⁹⁰ Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.
⁹¹ Department of Neuropediatrics, Kiel University, 24105 Kiel, Germany.
⁹² Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children's Hospital, Ludwig-Maximilian-University of Munich, 80331 Munich, Germany.
⁹³ Comprehensive Epilepsy Center, Ludwig-Maximilian- University of Munich, 80331 Munich, Germany.
⁹⁴ Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243 Esch-sur-Alzette, Luxembourg.
⁹⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44102, USA.
⁹⁶ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44102, USA.
⁹⁷ Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T ., Cambridge, MA 02138, USA.
⁹⁸ Cologne Center for Genomics (CCG), University of Cologne, 50667 Cologne, Germany.
⁹⁹ University of Copenhagen, 2200 Copenhagen, Denmark.
¹⁰⁰ Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, 320 Helsinki, Finland.
¹⁰¹ Program for Medical and Population Genetics/Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
¹⁰² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02108, USA.
¹⁰³ Department of Medical Genetics, Groupement Hospitalier Est and ERN EpiCARE, University Hospitals of Lyon (HCL), 69001 Lyon, France.
¹⁰⁴ Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, 69001 Lyon, France.

PMID: 34431999
PMCID: PMC10147326
DOI: 10.1093/brain/awab321

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Katrine M Johannesen et al. Brain. 2022.

. 2022 Sep 14;145(9):2991-3009.

doi: 10.1093/brain/awab321.

Authors

Affiliations

¹ Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark.
² Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark.
³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany.
⁴ Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany.
⁵ Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo Besta, 20125 Milan, Italy.
⁶ Epilepsy Center Kleinwachau, 01454 Dresden-Radeberg, Germany.
⁷ Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tuebingen, Germany.
⁸ Department of Child Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 10000 Prague, Czech Republic.
⁹ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany.
¹⁰ Institute of Human Genetics, University Clinic, Heinrich-Heine-University, 40210 Düsseldorf, Germany.
¹¹ Children's Department, Swiss Epilepsy Centre, Clinic Lengg, 8001 Zurich, Switzerland.
¹² National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, 0001 Oslo, Norway.
¹³ Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada.
¹⁴ Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, AB T6G 2T4, Canada.
¹⁵ Section of Pediatric Neurology, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada.
¹⁶ Department of Child Neurology, V. Buzzi Children's Hospital, 20125 Milan, Italy.
¹⁷ 'L. Sacco' Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy.
¹⁸ Child Neuropsychiatric Unit, Civilian Hospital, 25100 Brescia, Italy.
¹⁹ Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark.
²⁰ Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
²¹ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16121 Genova, Italy.
²² IRCCS 'G. Gaslini' Institute, 16121 Genoa, Italy.
²³ Department of Pediatrics, Division of Pediatric Neurology, Gent University Hospital, 9042 Gent, Belgium.
²⁴ Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, 5591 Heeze, The Netherlands.
²⁵ Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands.
²⁶ Department of Genetics, University Medical Center Utrecht, Utrecht University, 3553 Utrecht, The Netherlands.
²⁷ Department of Neuropediatrics, Universitätsklinikum Schleswig Holstein Campus Kiel, 24106 Kiel, Germany.
²⁸ Pediatric Neurology and Neurorehabilitation Unit, Woman Mother Child Department, Lausanne University Hospital (CHUV), 1000 Lausanne, Switzerland.
²⁹ University of Lausanne, 1000 Lausanne, Switzerland.
³⁰ Department of Pediatric Neurology, Hospital Italiano de Buenos Aires, C1428 Buenos Aires, Argentina.
³¹ Center for Pediatric Neurology, Cleveland Clinic, Cleveland, OH 44102, USA.
³² Department of Neurology, Aarhus University Hospital, 8000 Aarhus, Denmark.
³³ Center for Rare Diseases, Department of Pediatrics and Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark.
³⁴ McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON 66777, Canada.
³⁵ The Centre for Applied Genomics and Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON 66777, Canada.
³⁶ Department of Neuropediatrics, University Hospital Bonn, 53229 Bonn, Germany.
³⁷ Institute for Molecular and Behavioral Neuroscience, University of Cologne, 50667 Cologne, Germany.
³⁸ Neurology Department, The Royal Children's Hospital Melbourne, 3002 Melbourne, Australia.
³⁹ Murdoch Children's Research Institute, 3052 Parkville, Australia.
⁴⁰ Department of Pediatrics, University of Melbourne, Royal Children's Hospital, 3052 Parkville, Australia.
⁴¹ Department of Neuropediatrics, Children's Hospital, University Hospital Carl Gustav Carus, Technical University, 1099 Dresden, Germany.
⁴² Genetics Department, CHU Côte de Nacre, 14118 Caen, France.
⁴³ Genetics Department, CHRU Strasbourg, 67000 Strasbourg, France.
⁴⁴ Child Neurology and Psychiatry Unit, Children's Hospital G. Salesi, 60121 Ancona, Italy.
⁴⁵ Department of Woman's and Child's Health, Padova University Hospital, 35100 Padova, Italy.
⁴⁶ Child Neurology and Clinical Neurophysiology Unit, Padova University Hospital, 35100 Padova, Italy.
⁴⁷ Department of Neuropediatrics, Klinikum Weiden, Kliniken Nordoberpfalz AG, 92637 Weiden, Germany.
⁴⁸ Department of Medical Genetics, Institute of Mother and Child, 00-034 Warsaw, Poland.
⁴⁹ Pediatric Neurology Unit, Vittore Buzzi Hospital, ASST Fatebenefratelli Sacco, 20100 Milan, Italy.
⁵⁰ Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37121 Verona, Italy.
⁵¹ Department of Pediatrics, Oestfold Hospital, 1712 Graalum, Norway.
⁵² Laboratory of Genome Diagnostics, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands.
⁵³ Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands.
⁵⁴ Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France.
⁵⁵ Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik, 83569 Vogtareuth, Germany.
⁵⁶ Research Institute 'Rehabilitation, Transition, Palliation', PMU Salzburg, 5020 Salzburg, Austria.
⁵⁷ Department of Pediatrics, St. Jacques Hospital, 25000 Besançon, France.
⁵⁸ Clinique de Génétique Guy Fontaine, CHU Lille, 59000, Lille, France.
⁵⁹ Département de Neuropédiatrie, INSERM, CHU Montpellier, 34000 Montpellier, France.
⁶⁰ Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50131 Florence, Italy.
⁶¹ IRCCS Stella Maris, 56121 Pisa, Italy.
⁶² Service de Génétique, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers, France.
⁶³ Child Neurology, Center for Pediatric and Teenage Health Care, 53757 Sankt Augustin, Germany.
⁶⁴ Vestische Kinder- und Jugendklinik, 45711 Datteln, Germany.
⁶⁵ Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX 76101, USA.
⁶⁶ Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA 92637, USA.
⁶⁷ Research Centre for Medical Genetics, 115522 Moscow, Russia.
⁶⁸ Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia.
⁶⁹ Genomed Ltd., 100000 Moscow, Russia.
⁷⁰ Svt. Luka's Institute of Child Neurology & Epilepsy, 100000 Moscow, Russia.
⁷¹ Russian Medical Academy of Continuous Professional Education, 100000 Moscow, Russia.
⁷² I.M. Sechenov First Moscow State Medical University, 100000 Moscow, Russia.
⁷³ Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA.
⁷⁴ Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, 16816 Neuruppin, Germany.
⁷⁵ Pediatric Neurology & Development Center, Shamir Medical Center (Assaf Harofe), Be'er Ya'akov, Israel.
⁷⁶ Sackler Faculty of Medicine, Tel Aviv University, 5296001 Tel Aviv, Israel.
⁷⁷ Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1000 Brussels, Belgium.
⁷⁸ Institute for Pathology and Genetics, 6040 Gosselies, Belgium.
⁷⁹ Department of Pediatrics and Pediatric Neurology, Antwerp University Hospital, University of Antwerp, 2650 Edegem, Belgium.
⁸⁰ Pediatric Neurology, Marie Curie Hospital-CHU Charleroi, 6032 Charleroi, Belgium.
⁸¹ Pediatric Neurology Unit, Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
⁸² Pediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de Luxembourg, 1313 Luxembourg, Luxembourg.
⁸³ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA.
⁸⁴ Department of Genetics, Boston Children's Hospital, Boston, MA 02108, USA.
⁸⁵ Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA 02108, USA.
⁸⁶ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸⁷ The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸⁸ Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104USA.
⁸⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104USA.
⁹⁰ Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.
⁹¹ Department of Neuropediatrics, Kiel University, 24105 Kiel, Germany.
⁹² Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children's Hospital, Ludwig-Maximilian-University of Munich, 80331 Munich, Germany.
⁹³ Comprehensive Epilepsy Center, Ludwig-Maximilian- University of Munich, 80331 Munich, Germany.
⁹⁴ Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243 Esch-sur-Alzette, Luxembourg.
⁹⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44102, USA.
⁹⁶ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44102, USA.
⁹⁷ Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T ., Cambridge, MA 02138, USA.
⁹⁸ Cologne Center for Genomics (CCG), University of Cologne, 50667 Cologne, Germany.
⁹⁹ University of Copenhagen, 2200 Copenhagen, Denmark.
¹⁰⁰ Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, 320 Helsinki, Finland.
¹⁰¹ Program for Medical and Population Genetics/Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
¹⁰² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02108, USA.
¹⁰³ Department of Medical Genetics, Groupement Hospitalier Est and ERN EpiCARE, University Hospitals of Lyon (HCL), 69001 Lyon, France.
¹⁰⁴ Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, 69001 Lyon, France.

PMID: 34431999
PMCID: PMC10147326
DOI: 10.1093/brain/awab321

Abstract

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Keywords: SCN8A; epilepsy; genetics; personalized medicine.

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Conflict of interest statement

The authors report no competing interests.

Figures

**Figure 1**
**Functional characterizations of *SCN8A* variants in the neuroblastoma cell line ND7/23.** Wild-type or mutant Na_v1.6 channels were transfected into ND7/23 cells and recorded in the presence of tetrodotoxin to block endogenous Na⁺ channels. (A) Representative Na⁺ current traces for transfected Na_v1.6 wild-type (WT, black) or mutant channels (colour code in the *bottom right*). (B) Peak Na⁺ currents normalized by cell capacitance were plotted versus voltage. Both the p.(Phe846Ser) and p.(Leu840Pro) variants caused a hyperpolarizing shift of the current-voltage relationship, whereas the p.(Val1758Ala) and p.(Thr1787Pro) variants caused a depolarizing shift compared with the wild-type channels. The p.(Ile1654Asn), p.(Val1758Ala) and p.(Thr1787Pro) variants significantly decreased the current density in comparison with the wild-type. Wild-type: n = 30; mutants: n = 14–19. (C) Voltage-dependent steady-state activation curves. Lines represent Boltzmann functions fit to the data-points. (D) Voltage-dependent steady-state inactivation curves. Lines represent Boltzmann functions fit to the data-points. (E) Time course of recovery from fast inactivation at −100 mV. The p.(Val1758Ala), p.(Thr1787Pro) and p.(Asn374Lys) variants accelerated the recovery from fast inactivation compared with the wild-type. (F) Voltage-dependence of the major time constant of fast inactivation τ_h. Shown are means ± SEM (B–F). Numbers of recorded cells and statistical analysis for all experiments are provided in Supplementary Table 2.

**Figure 2**
**Effects of *SCN8A* variants in primary cultured hippocampal mouse neurons in the absence of tetrodotoxin.** Neurons were transfected with wild-type or mutant Na_v1.6 channels and recorded in the absence of tetrodotoxin. (A) Representative voltage traces of evoked action potentials (APs) in the absence of tetrodotoxin from neurons transfected with wild-type (WT, black) or mutant neurons (colour code indicated in B). (B) Numbers of evoked action potentials plotted versus injected current in the absence of tetrodotoxin. Shown are means ± SEM. (C) Area under the curve for the input-output relationships. The p.(Thr1787Pro) variant shows a significantly decreased area under the curve compared with the wild-type channels. Rheobase (D) and threshold (E) of action potentials were decreased for neurons transfected with the p.(Phe846Ser) variant but increased for neurons transfected with the p.(Thr1787Pro) variant compared with the wild-type channels. Box-and-whisker plots (C–E) show means (plus sign), the 25th, 50th and 75th percentiles, minima and maxima; *P < 0.05; **P < 0.01; ***P < 0.001; one-way ANOVA with Dunnett’s *post hoc* test or ANOVA on ranks with Dunn’s *post hoc* test were performed. Numbers of recorded cells and statistical analysis are provided in Supplementary Table 3.

**Figure 3**
**Neuronal properties carried only by transfected wild-type or mutant Na_v1.6 channels**. Hippocampal neurons transfected with wild-type or mutant Na_v1.6 channels were recorded in the presence of tetrodotoxin to block endogenous Na⁺ channels. (A) Representative voltage traces of evoked action potentials (APs) from neurons transfected with wild-type (black) or mutant channels (colour code in the *bottom left*). (B) Numbers of evoked action potentials plotted versus injected current in the presence of tetrodotoxin. Shown are means ± SEM. (C) Area under the curve for the input-output relationships. (D) Peak Na⁺ current amplitudes of neurons transfected with wild-type or mutant Na_v1.6 channels in the presence of tetrodotoxin. Rheobase (E) and threshold (F) were significantly decreased in neurons transfected with p.(Phe846Ser) or p.(Leu840Pro) variants compared with the wild-type channels. The p.(Asn1877Ser) variant also significantly decreased the rheobase. The rheobase or threshold could not be obtained in neurons transfected with p.(Asn374Lys), p.(Val1758Ala), p.(Thr1787Pro) and p.(Ile 1654Asn) mutant channels due to very few evoked action potentials. Box-and-whisker plots (C–F) show means (plus symbol), the 25th, 50th and 75th percentiles, minima and maxima; *P < 0.05; **P < 0.01; ***P < 0.001; one-way ANOVA with Dunnett’s *post hoc* test or ANOVA on ranks with Dunn’s *post hoc* test were performed. The numbers of recorded cells and statistical analysis are provided in Supplementary Table 4.

**Figure 4**
**Distribution of affected individuals carrying *SCN8A* variants according to phenotype and age of seizure onset.** Phenotypic subgroups of the total cohort (A) and individuals carrying LOF (B) or GOF (C) variants. (A) In the total cohort, 225 affected individuals (57.4%) had BFIE, intermediate epilepsy or DEE; 20 individuals (5.1%) had generalized epilepsy; and 20 individuals (5.1%) had a NDDwoE. (B) Twenty-five affected individuals had generalized epilepsy or an NDDwoE, accounting for 73.5% of LOF variant carriers, whereas 71.6% of GOF variant carriers had BFIE, intermediate epilepsy or DEE (C). Histogram of the age at seizure onset in affected individuals with BFIE (D), intermediate epilepsy (E), DEE (F) and generalized epilepsy (G). (H) Stacked histogram of age at seizure onset in affected individuals with focal epilepsy (FE) carrying GOF (FE+GOF), LOF (FE+LOF) or *SCN8A* variants which are not functionally characterized. (I) Stacked histogram of age at seizure onset in affected individuals with generalized epilepsy (GE) carrying LOF (GE+LOF) or *SCN8A* variants which are not functionally characterized. (J) Stacked histogram of age at seizure onset in affected individuals carrying GOF variants with FE (FE+GOF) or unclassifiable epilepsy (UE+GOF). (K) Stacked histogram of age at seizure onset in affected individuals carrying LOF variants with generalized epilepsy (GE+LOF), FE (FE+LOF) or unclassifiable epilepsy (UE+GOF). Affected individuals with BNIE, intermediate epilepsy or DEE exhibited a significant earlier age at seizure onset than individuals with generalized epilepsy (Kruskal-Wallis test, P < 0.001), which is also observed for GOF versus LOF variant carriers (Mann-Whitney test, P < 0.001). Histogram bin size = 1 month. Seizure type distributions of affected individuals with FE versus generalized epilepsy (L) and GOF versus LOF variant carriers (M).

**Figure 5**
**Correlation of a computed electrophysiological score with the clinical severity of *SCN8A* GOF variants.** Electrophysiological scores of *SCN8A* GOF variants were obtained according to the effect of variants on action potential firing simulated by a single-compartment conductance-based model. (A–F) The contrast of the simulated area under the input-output curve (AUC, Equation 1) as a function of the changes in single Na⁺ current gating parameters, such as: (A) the V_1/2 of the activation curve; (B) the slope factor k of the activation curve; (C) the V_1/2 of the fast inactivation curve; (D) the slope factor k of the fast inactivation curve; (E) the persistent Na⁺ current; and (F) the Na⁺ conductivity (or current density). Changes in the V_1/2 and the slope of the activation curve had a much stronger effect on the AUC than other parameters. (G) Correlation (dashed grey line) of the simulation-based score (Equation 9) with the severity of each *SCN8A* GOF variant averaged over affected individuals (blue dots with the respective one-amino acid code). (H) Distributions of simulation-based scores of each patient (blue dots) for each of the four categories of clinical severities. *P < 0.05; ***P < 0.001 (ANOVA on ranks with Dunn’s *post hoc* test).

**Figure 6**
**Location of *SCN8A* variants associated with neurodevelopmental disorders.** Schematic 2D representation of the Na_v1.6 channel displaying the location of pathogenic variants. A comparison of the location of missense variants with proven GOF or a BFIE/intermediate epilepsy/DEE phenotype (without functional analysis) on one hand, and variants with proven LOF or generalized epilepsy/NDDwoE phenotypes (without functional analysis) on the other, revealed a significant difference in the distribution of variants (see main text and Supplementary material). Recurring variants are indicated with larger symbol size relative to the number of patients and in frame indels or deletions are indicated showing the whole affected regions [p.(Ile888_Val892delinsMet), p.(Glu1774_Ala1777del) and p.(Pro1428_Lys1473del)].

**Figure 7**
**Treatment responses to anti-seizure medications in affected individuals carrying *SCN8A* variants.** Treatment effects of ASMs on seizures in affected individuals with BFIE, intermediate epilepsy or DEE versus those with generalized epilepsy (A) and those carrying *SCN8A* GOF versus LOF variants (B). Phenytoin, carbamazepine, lamotrigine, oxcarbazepine, zonisamide and lacosamide are SCBs. (C and D) Individuals with BFIE, intermediate epilepsy or DEE and those carrying *SCN8A* GOF variants responded significantly better to SCBs than non-SCBs, whereas treatment with SCBs or non-SCBs did not cause a different effect in individuals with generalized epilepsy and those carrying *SCN8A* LOF variants (please consider the very small numbers in these latter categories). P values derived from Fisher’s exact test are provided in the figure. Responders were defined as those who became seizure-free or experienced a seizure reduction while staying on the drug; non-responders were defined as those experiencing no effect or seizure worsening. CBZ = carbamazepine; CLB = clobazam; CLZ = clonazepam; ESM = ethosuximide; KD = ketogenic diet; LCM = lacosamide; LEV = levetiracetam; LTG = lamotrigine; OXC= oxcarbazepine; PB = phenobarbital; PHT = phenytoin; TPM = topiramate; VGB = vigabatrin; VPA = valproate; ZNS = zonisamide.

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Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

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Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

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