Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

Authors

Wolff M1, Johannesen KM2,3, Hedrich UBS4, Masnada S5, Rubboli G2,6, Gardella E2,3, Lesca G7,8,9, Ville D10, Milh M11,12, Villard L12, Afenjar A13, Chantot-Bastaraud S13, Mignot C14, Lardennois C15, Nava C16,17, Schwarz N4, Gérard M18, Perrin L19, Doummar D20, Auvin S21,22, Miranda MJ23, Hempel M24, Brilstra E25, Knoers N25, Verbeek N25, van Kempen M25, Braun KP26, Mancini G27, Biskup S28, Hörtnagel K28, Döcker M28, Bast T29, Loddenkemper T30, Wong-Kisiel L31, Baumeister FM32, Fazeli W33, Striano P34, Dilena R35, Fontana E36, Zara F37, Kurlemann G38, Klepper J39, Thoene JG40, Arndt DH41, Deconinck N42, Schmitt-Mechelke T43, Maier O44, Muhle H45, Wical B46, Finetti C47, Brückner R48, Pietz J49, Golla G50, Jillella D51, Linnet KM52, Charles P53, Moog U54, Õiglane-Shlik E55, Mantovani JF56, Park K57, Deprez M58, Lederer D58, Mary S58, Scalais E59, Selim L60, Van Coster R61, Lagae L62, Nikanorova M2, Hjalgrim H2,3, Korenke GC63, Trivisano M64, Specchio N64, Ceulemans B65, Dorn T66, Helbig KL67, Hardies K68,69, Stamberger H68,69,70, de Jonghe P68,69,70, Weckhuysen S68,69,70, Lemke JR71, Krägeloh-Mann I1, Helbig I45,72, Kluger G73,74, Lerche H4, Møller RS2,3.
  1. Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany.
  2. The Danish Epilepsy Centre, Dianalund, Denmark.
  3. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
  4. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
  5. Department of Brain and Behavior, University of Pavia, Italy.
  6. University of Copenhagen, Copenhagen, Denmark.
  7. Department of Genetics, Lyon University Hospital, Lyon, France.
  8. Claude Bernard Lyon I University, Lyon, France.
  9. Lyon Neuroscience Research Centre, CNRS UMRS5292, INSERM U1028, Lyon, France.
  10. Department of Pediatric Neurology and Reference Center for Rare Children Epilepsy and Tuberous Sclerosis, Hôpital Femme Mere Enfant, Centre Hospitalier Universitaire de Lyon, HCL, France.
  11. APHM Service de neurologie pédiatrique, Marseille, France.
  12. Aix Marseille Univ, Inserm, GMGF, UMR-S 910, Marseille, France.
  13. AP-HP, Unité de Gènètique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire de l’Est Parisien, Paris, France.
  14. AP-HP, Département de Génétique; Centre de Référence Défiences Intellectuelles de Causes Rares; Groupe de Recherche Clinique UPMC „Déficiences Intellectuelles et Autisme“ GH Pitié-Salpêtrère, Paris, France.
  15. Service de Pediatrie neonatale et Réanimation – Neuropediatrie, 76000 Rouen, France.
  16. Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, France.
  17. Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, F-75013 Paris, France.
  18. Service de Génétique Clinique, CHU Caen, France.
  19. Department of Genetics, Robert Debré Hospital, AP-HP, Paris, France.
  20. AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, Paris, France.
  21. Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France.
  22. AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Paris, France.
  23. Department of Pediatrics, Herlev University Hospital, Herlev, Denmark.
  24. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  25. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  26. Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
  27. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  28. CeGaT – Center for Genomics and Transcriptomics, Tübingen, Germany.
  29. Epilepsy Center Kork, Kehl, Germany.
  30. Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Harvard Medical School, Boston MA, USA.
  31. Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester MN, USA.
  32. Children’s Hospital, RoMed Klinikum, Rosenheim, Germany.
  33. Pediatric Neurology, University Hospital Cologne, Germany.
  34. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa ‚G. Gaslini‘ Institute, Genova, Italy.
  35. Servizio di Epilettologia e Neurofisiopatologia Pediatrica, UO Neurofisiopatologia, Fondazione IRCCS Ca‘ Granda Ospedale Maggiore Policlinico, Milano, Italy.
  36. Centro di Diagnosi e Cura delle Epilessie Infantili, Azienda Ospedaliera -Policlinico Gianbattista Rossi, Verona, Italy.
  37. Laboratory of Neurogenetics and Neuroscience, Department of Neuroscience, „G. Gaslini“ Institute, Genova, Italy.
  38. Department of Pediatric Neurology, University Children’s Hospital, Münster, Germany.
  39. Children’s Hospital, Klinikum Aschaffenburg, Germany.
  40. University of Michigan, Pediatric Genetics, Ann Arbor, MI USA.
  41. Division of Pediatric Neurology and Epilepsy – Beaumont Children’s Hospital, William Beaumont Oakland University School of Medicine, Royal Oak, Michigan, USA.
  42. Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
  43. Children’s Hospital Lucerne, Luzerner Kantonsspital, Kinderspital Luzern, CH-6000 Luzern 16, Switzerland.
  44. Department of child neurology, Children’s Hospital, St. Gallen, Switzerland.
  45. Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany.
  46. Gillette Children’s Specialty Healthcare, Saint Paul, MN, USA.
  47. Klinik für Kinder- und Jugendmedizin, Elisabeth-Krankenhaus, Essen, Germany.
  48. Wangen, Germany.
  49. Pediatric Practice University Medical Center for Children and Adolescents, Angelika Lautenschläger Children’s Hospital, Heidelberg, Germany.
  50. Klinik für Kinder- und Jugendmedizin, Klinikum Lippe GmbH, Detmold, Germany.
  51. Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Boston, MA, USA.
  52. Department of Pediatrics, Aarhus University hospital, Aarhus, Denmark.
  53. Department of Genetics and Cytogenetics, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France.
  54. Institute of Genetics, University Hospital, Heidelberg, Germany.
  55. Children’s Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
  56. Department of Pediatrics and Mercy Kids Autism Center, Mercy Children’s Hospital, St. Louis, Missouri, USA.
  57. Department of Pediatrics and Neurology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
  58. Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium.
  59. Pediatric Neurology Unit, Pediatric Department, Centre Hospitalier de Luxembourg, Luxembourg.
  60. Department of Pediatrics, Pediatric Neurology and Neurometabolic Unit, Cairo University Children Hospital, Cairo, Egypt.
  61. Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium.
  62. Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven, Leuven, Belgium.
  63. Zentrum für Kinder- und Jugendmedizin (Elisabeth Kinderkrankenhaus), Klinik für Neuropädiatrie u. Angeborene, Stoffwechselerkrankungen, Oldenburg, Germany.
  64. Neurology Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.
  65. Paediatric Neurology University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium.
  66. Swiss Epilepsy Center, Zurich, Switzerland.
  67. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA.
  68. Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
  69. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  70. Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium.
  71. Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
  72. Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, USA.
  73. Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen Klinik, Vogtareuth, Germany.
  74. PMU Salzburg, Austria.

Abstract

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.