The three stages of epilepsy in patients with CDKL5 mutations

Authors: Bahi-Buisson, Nadia; Kaminska, Anna; Boddaert, Nathalie; Rio, Marlène¹; Afenjar, Alexandra²; Gérard, Marion³; Giuliano, Fabienne⁴; Motte, Jacques; Héron, Delphine⁵; Morel, Marie Ange N'Guyen⁶; Plouin, Perrine; Richelme, Christian⁷; des Portes, Vincent⁸; Dulac, Olivier; Philippe, Christophe⁹; Chiron, Catherine; Nabbout, Rima; Bienvenu, Thierry¹⁰

Source: Epilepsia, Volume 49, Number 6, June 2008 , pp. 1027-1037(11)

Publisher: Wiley-Blackwell

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Abstract:

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.

Keywords: Epileptic encephalopathy; Atypical Rett syndrome; CDKL5 mutations; Infantile spasms

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1528-1167.2007.01520.x

Affiliations: 1: Service de Génétique, Hopital Necker Enfants Malades, AP-HP, Paris, France 2: Service de Neurologie Pédiatrique, Hopital Trousseau AP-HP, Paris, France 3: Service de Génétique, Hopital Robert Debré AP-HP, Paris, France 4: Service de Génétique, Centre Hospitalo-Universitaire, Nice, France 5: Département de Génétique Groupe Hospitalier Pitié Salpêtrière Paris France 6: Département de Pédiatrie, Centre du Langage et troubles des apprentissages, Centre Hospitalo-Universitaire, Grenoble, France 7: Service de Neurologie Pédiatrique, Centre Hospitalo-Universitaire, Nice, France 8: Service de Neurologie Pédiatrique, Centre Hospitalo-Universitaire de Lyon, France 9: Laboratoire de Génétique Médicale, EA 4002, Centre Hospitalo-Universitaire Nancy-Brabois, Vandoeuvre les Nancy, France 10: Service de Biochimie et Génétique Moléculaire Hopital Cochin, et Université René Descartes, Institut Cochin, Inserm U567, Paris, France

Publication date: 2008-06-01

The three stages of epilepsy in patients with CDKL5 mutations

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