The three stages of epilepsy in patients with CDKL5 mutations.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Bahi-Buisson
Nadia
N
Département de Pédiatrie, Service de Neurologie Pédiatrique, Hopital Necker Enfants Malades, AP-HP, Paris V, Paris, France. nadia.bahi-buisson@nck.aphp.fr
Kaminska
Anna
A
Boddaert
Nathalie
N
Rio
Marlène
M
Afenjar
Alexandra
A
Gérard
Marion
M
Giuliano
Fabienne
F
Motte
Jacques
J
Héron
Delphine
D
Morel
Marie Ange N'guyen
MA
Plouin
Perrine
P
Richelme
Christian
C
des Portes
Vincent
V
Dulac
Olivier
O
Philippe
Christophe
C
Chiron
Catherine
C
Nabbout
Rima
R
Bienvenu
Thierry
T
D000293:Adolescent; D020134:Catalytic Domain / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D002908:Chronic Disease; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000175:diagnosis / Q000235:genetics; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D012729:Sex Chromosome Aberrations; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics*
D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human