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

Author:

Johannesen Katrine M12,Liu Yuanyuan3,Koko Mahmoud3,Gjerulfsen Cathrine E1,Sonnenberg Lukas34,Schubert Julian3,Fenger Christina D1,Eltokhi Ahmed3,Rannap Maert3,Koch Nils A4,Lauxmann Stephan34,Krüger Johanna3,Kegele Josua3,Canafoglia Laura5,Franceschetti Silvana5,Mayer Thomas6,Rebstock Johannes6,Zacher Pia6,Ruf Susanne7,Alber Michael7,Sterbova Katalin8,Lassuthová Petra8,Vlckova Marketa8,Lemke Johannes R9,Platzer Konrad9,Krey Ilona9,Heine Constanze9,Wieczorek Dagmar10,Kroell-Seger Judith11,Lund Caroline12,Klein Karl Martin13,Billie Au P Y14,Rho Jong M15,Ho Alice W15,Masnada Silvia16,Veggiotti Pierangelo1617,Giordano Lucio18,Accorsi Patrizia18,Hoei-Hansen Christina E1920,Striano Pasquale2122,Zara Federico22,Verhelst Helene23,Verhoeven Judith S24,van der Zwaag Bert25,Harder Aster V E25,Brilstra Eva25,Pendziwiat Manuela26,Lebon Sebastian2728,Vaccarezza Maria29,Minh Le Ngoc30,Christensen Jakob31,Grønborg Sabine32,Scherer Stephen W3334,Howe Jennifer34,Fazeli Walid3536,Howell Katherine B373839,Leventer Richard373839,Stutterd Chloe3839,Walsh Sonja40,Gerard Marion41,Gerard Bénédicte42,Matricardi Sara43,Bonardi Claudia M44,Sartori Stefano45,Berger Andrea46,Hoffman-Zacharska Dorota47,Mastrangelo Massimo48,Darra Francesca49,Vøllo Arve50,Motazacker M Mahdi51,Lakeman Phillis52,Nizon Mathilde53,Betzler Cornelia5455,Altuzarra Cecilia56,Caume Roseline57,Roubertie Agathe58,Gélisse Philippe58,Marini Carla59,Guerrini Renzo60,Bilan Frederic61,Tibussek Daniel62,Koch-Hogrebe Margarete63,Perry M Scott64,Ichikawa Shoji65,Dadali Elena6667,Sharkov Artem6768,Mishina Irina66,Abramov Mikhail67,Kanivets Ilya6970,Korostelev Sergey6971,Kutsev Sergey66,Wain Karen E72,Eisenhauer Nancy72,Wagner Monisa72,Savatt Juliann M72,Müller-Schlüter Karen73,Bassan Haim7475,Borovikov Artem66,Nassogne Marie-Cecile76,Destrée Anne77,Schoonjans An-Sofie78,Meuwissen Marije78,Buzatu Marga79,Jansen Anna80,Scalais Emmanuel81,Srivastava Siddharth82,Tan Wen-Hann83,Olson Heather E8284,Loddenkemper Tobias82,Poduri Annapurna8284,Helbig Katherine L8586,Helbig Ingo8586878889,Fitzgerald Mark P85868789,Goldberg Ethan M8586,Roser Timo90,Borggraefe Ingo9091,Brünger Tobias92,May Patrick93,Lal Dennis92949596,Lederer Damien77,Rubboli Guido197,Heyne Henrike O99899100,Lesca Gaetan101102,Hedrich Ulrike B S3,Benda Jan4,Gardella Elena12,Lerche Holger3,Møller Rikke S12

Affiliation:

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, Charles University, 2nd Faculty of Medicine 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 & Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, T2P 0A1 Calgary, Canada

14. Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, T6G 2T4 Alberta, Canada

15. Section of Pediatric Neurology, Alberta Children’s Hospital, Cumming School of Medicine, University of Calgary, T2P 0A1 Calgary, Canada

16. Department of Child Neurology, V. Buzzi Children’s Hospital, 20125 Milan, Italy

17. Department of Biomedical and Clinical Sciences, L. Sacco, University of Milan, 20125 Milan, 25100 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, Divisuion 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 Genetics, University Medical Center Utrecht, Utrecht University, 3553 Utrecht, The Netherlands

26. Department of Neuropediatrics, Universitätsklinikum Schleswig Holstein Campus Kiel, 24106 Kiel, Germany

27. Pediatric Neurology and Neurorehabilitation Unit, Woman Mother Child Department, Lausanne University Hospital (CHUV), 1000 Lausanne, Switzerland1

28. University of Lausanne, 1000 Lausanne, Switzerland

29. Department of Pediatric Neurology, Hospital Italiano de Buenos Aires, C1428 Buenos Aires, Argentina

30. Center for Pediatric Neurology, Cleveland Clinic, 44102 Cleveland, Ohio, USA

31. Department of Neurology, Aarhus University Hospital, 8000 Aarhus, Denmark

32. Center for Rare Diseases, Department of Pediatrics and Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark

33. McLaughlin Centre and Dept. of Molecular Genetics, University of Toronto, 66777 Toronto, Ontario, Canada

34. The Centre for Applied Genomics and Dept. of Genetics and Genome Biology, The Hospital for Sick Children, 66777 Toronto, Ontario, Canada

35. Department of Neuropediatrics, University Hospital Bonn, 53229 Bonn, Germany

36. Institute for Molecular and Behavioral Neuroscience, University of Cologne, 50667 Cologne, Germany

37. Neurology Department, The Royal Children’s Hospital Melbourne, 3002 Melbourne, Australia

38. Murdoch Children’s Research Institute, 3052 Parkville, Australia

39. Department of Pediatrics, University of Melbourne, Royal Children’s Hospital, 3052 Parkville, Australia

40. Department of Neuropediatrics, Children’s hospital, University Hospital Carl Gustav Carus, Technical University, 1099 Dresden, Germany

41. Genetic Department, CHU Côte de Nacre, 14118 Caen, France

42. Genetic Department, CHRU Strasbourg, 67000 Strasbourg, France

43. Child Neurology and Psychiatry Unit, Children’s Hospital G. Salesi, 60121 Ancona, Italy

44. Department of Woman’s and Child’s Health, Padova University Hospital, 35100 Padova, Italy

45. Child Neurology and Clinical Neurophysiology Unit, Padova University Hospital, 35100 Padova, Italy

46. Department of Neuropediatrics, Klinikum Weiden, Kliniken Nordoberpfalz AG, 92637 Weiden, Germany

47. Department of Medical Genetics, Institute of Mother and Child, 00-034 Warsaw, Poland

48. Pediatric Neurology Unit, Vittore Buzzi Hospital, ASST Fatebenefratelli Sacco, 20100 Milan, Italy

49. Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of 37121 Verona, Italy

50. Department of Pediatrics, Oestfold Hospital, 1712 Graalum, Norway

51. Laboratory of Genome Diagnostics, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands

52. Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, 1019 Amsterdam, Netherlands

53. CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France

54. Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik, 83569 Vogtareuth, Germany

55. Research Institute “Rehabilitation, Transition, Palliation”, PMU Salzburg, 5020 Salzburg, Austria

56. Department of Pediatrics, St. Jacques Hospital, 25000 Besançon, France

57. CHU Lille, Clinique de Génétique, Guy Fontaine, 59000, Lille, France

58. NM, Univ Montpellier, INSERM, CHU Montpellier, Département de Neuropédiatrie, 34000 Montpellier, France

59. Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children’s Hospital, University of Florence, 50131 Florence, Italy

60. IRCCS Stella Maris, 56121 Pisa, Italy

61. Centre Hospitalier Universitaire de Poitiers, Service de Génétique, BP577, 86021 Poitiers, France

62. Center for Pediatric and Teenage Health Care, Child Neurology, 53757 Sankt Augustin, Germany

63. Vestische Kinder- und Jugendklinik, 45711 Datteln, Germany

64. Justin Neurosciences Center, Cook Children’s Medical Center, 76101 Fort Worth, Texas, USA

65. Department of Clinical Diagnostics, Ambry Genetics, 92637 Aliso Viejo, California, USA

66. Research Centre for Medical Genetics, 100000 Moscow, Russian Federation

67. Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, 100000 Moscow, Russian Federation

68. Genomed ltd, 100000 Moscow, Russian Federation

69. Svt. Luka’s Institute of Child Neurology & Epilepsy, 100000 Moscow, Russian Federation

70. Russian Medical Academy Continuous Professional Education, 100000 Moscow, Russian Federation

71. I.M. Sechenov First Moscow State Medical University, 100000 Moscow, Russian Federation

72. Autism & Developmental Medicine Institute, Geisinger, 17837 Lewisburg, PA, USA

73. Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, 16816 Neuruppin, Germany

74. Pediatric Neurology & Development Center Shamir Medical Center (Assaf Harofe) Be’er Ya’akov, Tel Aviv, Israel

75. Tel Aviv University, Sackler faculty of Medicine, 5296001 Tel Aviv, Israel

76. Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1000 Brussels, Belgium

77. Institute for Pathology and Genetics, 6040 Gosselies, Belgium

78. Department of Pediatrics and Pediatric Neurology, Antwerp University Hospital, University of Antwerp, 2650 Edegem, Belgium

79. Pediatric neurology, Marie Curie Hospital—CHU Charleroi, 6032 Charleroi, Belgium

80. Vrije Universiteit Brussel, UZ Brussel, Department of Pediatrics, Pediatric Neurology Unit, 1000 Brussels, Belgium

81. Pediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de Luxembourg, 1313 Luxembourg, Luxembourg

82. Department of Neurology, Boston Children’s Hospital and Harvard Medical School, 02108 Boston, USA

83. Department of Genetics, Boston Children’s Hospital, 02108 Boston, USA

84. Epilepsy Genetics Program, Boston Children’s Hospital, 02108 Boston, USA

85. Division of Neurology, Children’s Hospital of Philadelphia, 19104 Philadelphia, PA, USA

86. The Epilepsy Neurogenetics Initiative (ENGIN), Children’s Hospital of Philadelphia, 19104 Philadelphia, PA, USA

87. Department of Biomedical and Health Informatics (DBHi), Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USA

88. Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104 USA

89. Institute of Clinical Molecular Biology, Kiel University, Rosalind-Franklin-Strasse 12, 24105 Kiel, Germany

90. 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

91. Comprehensive Epilepsy Center, Ludwig-Maximilian- University of Munich, 80331 Munich, Germany

92. Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243, Esch-sur-Alzette, Luxembourg

93. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 44102 Cleveland, OH, USA

94. Epilepsy Center, Neurological Institute, Cleveland Clinic, 44102 Cleveland, OH, USA

95. Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T., 02138 Cambridge, MA, USA

96. Cologne Center for Genomics (CCG), University of Cologne, 50667 Cologne, Germany

97. University of Copenhagen, 2200 Copenhagen, Denmark

98. Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, 320 Helsinki, Finland

99. Program for Medical and Population Genetics/Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 02138 Cambridge, MA, USA

100. Analytic and Translational Genetics Unit, Massachusetts General Hospital, 02108 Boston, MA, USA

101. Department of Medical Genetics, Groupement Hospitalier Est, and ERN EpiCARE, University Hospitals of Lyon (HCL), 69001 Lyon, France

102. Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, 69001 Lyon, France

Abstract

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 could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 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 DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of 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 LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Publisher

Oxford University Press (OUP)

Subject

Clinical Neurology

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