The three stages of epilepsy in patients with CDKL5 mutations

Authors

  • Nadia Bahi-Buisson,

    1. Service de Neurologie Pédiatrique, Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Paris V, Paris, France
    2. Inserm, U663, Paris, France; Université René Descartes, Paris V, France
    Search for more papers by this author
  • Anna Kaminska,

    1. Inserm, U663, Paris, France; Université René Descartes, Paris V, France
    2. Centre de Reference pour les Epilepsies Rares de l'enfant, Hopital Necker Enfants Malades APHP, Paris, France
    3. Service de Neurophysiologie clinique, Hopital Necker Enfants Malades, AP-HP, Paris, France
    Search for more papers by this author
  • Nathalie Boddaert,

    1. Service de Radiologie Pédiatrique, Hopital Necker Enfants Malades, AP-HP, Paris V, Paris, France
    2. U797- INSERM-CEA, Service Hospitalier Frédéric Joliot, CEA, 4, place du General Leclerc, 91406, Orsay, France
    Search for more papers by this author
  • Marlène Rio,

    1. Service de Génétique, Hopital Necker Enfants Malades, AP-HP, Paris, France
    Search for more papers by this author
  • Alexandra Afenjar,

    1. Service de Neurologie Pédiatrique, Hopital Trousseau AP-HP, Paris, France
    Search for more papers by this author
  • Marion Gérard,

    1. Service de Génétique, Hopital Robert Debré AP-HP, Paris, France
    Search for more papers by this author
  • Fabienne Giuliano,

    1. Service de Génétique, Centre Hospitalo-Universitaire, Nice, France
    Search for more papers by this author
  • Jacques Motte,

    1. Centre de Reference pour les Epilepsies Rares de l'enfant, Hopital Necker Enfants Malades APHP, Paris, France
    2. Service de Neurologie Pédiatrique, Département de Pédiatrie, Hopital Américain de Reims, Reims, France
    Search for more papers by this author
  • Delphine Héron,

    1. Département de Génétique Groupe Hospitalier Pitié Salpêtrière Paris France
    Search for more papers by this author
  • Marie Ange N'Guyen Morel,

    1. Département de Pédiatrie, Centre du Langage et troubles des apprentissages, Centre Hospitalo-Universitaire, Grenoble, France
    Search for more papers by this author
  • Perrine Plouin,

    1. Inserm, U663, Paris, France; Université René Descartes, Paris V, France
    2. Centre de Reference pour les Epilepsies Rares de l'enfant, Hopital Necker Enfants Malades APHP, Paris, France
    3. Service de Neurophysiologie clinique, Hopital Necker Enfants Malades, AP-HP, Paris, France
    Search for more papers by this author
  • Christian Richelme,

    1. Service de Neurologie Pédiatrique, Centre Hospitalo-Universitaire, Nice, France
    Search for more papers by this author
  • Vincent Des Portes,

    1. Service de Neurologie Pédiatrique, Centre Hospitalo-Universitaire de Lyon, France
    Search for more papers by this author
  • Olivier Dulac,

    1. Service de Neurologie Pédiatrique, Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Paris V, Paris, France
    2. Inserm, U663, Paris, France; Université René Descartes, Paris V, France
    3. Centre de Reference pour les Epilepsies Rares de l'enfant, Hopital Necker Enfants Malades APHP, Paris, France
    Search for more papers by this author
  • Christophe Philippe,

    1. Laboratoire de Génétique Médicale, EA 4002, Centre Hospitalo-Universitaire Nancy-Brabois, Vandoeuvre les Nancy, France
    Search for more papers by this author
  • Catherine Chiron,

    1. Service de Neurologie Pédiatrique, Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Paris V, Paris, France
    2. Inserm, U663, Paris, France; Université René Descartes, Paris V, France
    3. Centre de Reference pour les Epilepsies Rares de l'enfant, Hopital Necker Enfants Malades APHP, Paris, France
    Search for more papers by this author
  • Rima Nabbout,

    1. Service de Neurologie Pédiatrique, Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Paris V, Paris, France
    2. Inserm, U663, Paris, France; Université René Descartes, Paris V, France
    3. Centre de Reference pour les Epilepsies Rares de l'enfant, Hopital Necker Enfants Malades APHP, Paris, France
    Search for more papers by this author
  • Thierry Bienvenu

    1. Service de Biochimie et Génétique Moléculaire Hopital Cochin, et Université René Descartes, Institut Cochin, Inserm U567, Paris, France
    Search for more papers by this author

Address correspondence to: Nadia Bahi-Buisson, M.D., Ph.D., Pediatric Neurology Hopital Necker Enfants Malades, 149 rue de Sevres, 75015 Paris. E-mail: nadia.bahi-buisson@nck.aphp.fr

Summary

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for a severe encephalopathy with early epilepsy. So far, the electroclinical phenotype remains largely unknown and no clear genotype–phenotype correlations have been established.

Purpose: To characterize the epilepsy associated with CDKL5 mutations and to look for a relationship between the genotype and the course of epilepsy.

Methods: We retrospectively analyzed the electroclinical phenotypes of 12 patients aged from 2.5 to 19 years diagnosed with pathogenic CDKL5 mutations and one patient with a novel intronic sequence variation of uncertain pathogenicity and examined whether the severity of the epilepsy was linked to the type and location of mutations.

Results: The epilepsy course reveals three successive stages: (Stage I) early epilepsy (onset 1–10 weeks) with normal interictal electroencephalogram (EEG) (10/13) despite frequent convulsive seizures; (Stage II) epileptic encephalopathy with infantile spasms (8/8) and hypsarrhythmia (8/8). At the age of evaluation, seven patients were seizure free and six had developed refractory epilepsy (stage III) with tonic seizures and myoclonia (5/6).

 Interestingly, the patients carrying a CDKL5 mutations causing a truncation of the catalytic domain tended to develop a more frequent refractory epilepsy than patients with mutations located downstream (4/6, 66.6% versus 1/6, 16%) although, these trends are not yet significant.

Discussion: Our data contribute to a better definition of the epileptic phenotype in CDKL5 mutations, and might give some clues to a potential relationship between the phenotype and the genotype in these patients.

Ancillary