The three stages of epilepsy in patients with <i>CDKL5</i> mutations

Bahi‐Buisson, Nadia; Kamińska, Anna; Boddaert, Nathalie; Rio, Marlène; Afenjar, Alexandra; Gérard, Marion; Giuliano, Fabienne; Motté, Jacques; Héron, Delphine; Morel, Marie Ange N'Guyen; Plouin, Perrine; Richelme, Christian; Portes, Vincent Des; Dulac, Olivier; Philippe, Christophe; Chiron, Catherine; Nabbout, Rima; Bienvenu, Thierry

doi:10.1111/j.1528-1167.2007.01520.x

Cited by 172 publications

(193 citation statements)

References 24 publications

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“…Brain imaging in patients with CDKL5 mutations demonstrated cortical atrophy and white-matter hyperintensities. 53 In patients 3 and 5, MRI studies were normal and patient 6 had right tonsillar ectopia. Interestingly, patient 6 has also exotropia, which is frequently seen in patients with CDKL5 deficiency.…”

Section: Discussionmentioning

confidence: 93%

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Szafrański

Golla²,

Jin

et al. 2014

Eur J Hum Genet

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Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667 kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.

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Section: Discussionmentioning

confidence: 93%

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Szafrański

Golla²,

Jin

et al. 2014

Eur J Hum Genet

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“…Three stages for the course of the epilepsy in girls with CDKL5 mutations have been described and include an unusual, distinctive seizure type called hypermotor-tonic-spasms sequence (25,26).…”

Section: Other Genes For Epileptic Encephalopathies (Ee)mentioning

confidence: 99%

Genetic Testing in Epilepsy: What Should you be Doing?

Scheffer

2011

Epilepsy Curr

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With the burgeoning array of molecular tests available in the epilepsies, the clinician needs to know which tests to order for each patient. Epileptic encephalopathies are the most important clinical group for genetic testing with an increasing number of distinctive epilepsy syndromes being recognized. Identification of the causative mutation affects treatment as well as prognostic and genetic counseling.

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“…On the basis of this clinical presentation, the CDKL5-positive group has been assimilated to the Hanefeld early seizure variant of RTT [2]. Bahi-Buisson [7] has recently identified an epilepsy phenotype whose three-stage pattern begins with "early epilepsy", moves on to epileptic encephalopathy and ends with late multifocal and myoclonic epilepsy.…”

Section: Introductionmentioning

confidence: 99%

“…Given the small number of patients, genotype-phenotype correlation studies have been limited, but it has been suggested that mutations affecting the aminoterminal catalytic domain are associated with a more severe phenotype consisting of an earlier onset and intractable infantile spasms followed by late-onset multifocal and myoclonic epilepsy [7]. A more extensive knowledge of the currently restricted CDKL5 mutational repertoire might provide new clues concerning genotype-phenotype correlations, and analysing synthetic derivatives of particular mutants in functional assays might highlight new protein domains.…”

Section: Introductionmentioning

confidence: 99%

“…Thirty-eight CDKL5 mutations have so far been described [2,6,7,13,14], and recently, various missense mutations have been found in three unrelated boys affected by profound mental retardation and intractable seizures, thus suggesting that amino acid changes in the CDKL5 protein can be tolerated despite the hemizygous condition [15]. Given the small number of patients, genotype-phenotype correlation studies have been limited, but it has been suggested that mutations affecting the aminoterminal catalytic domain are associated with a more severe phenotype consisting of an earlier onset and intractable infantile spasms followed by late-onset multifocal and myoclonic epilepsy [7].…”

Section: Introductionmentioning

confidence: 99%

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Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

et al. 2009

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It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/ atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T>C p.Ile72Thr and c.380A>G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145+2 T>C and c.2376 + 5G > A, the c.1648C > T p.Arg550X and the MPLA-identified c.162_99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162_99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.

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The three stages of epilepsy in patients with CDKL5 mutations

Abstract: SUMMARYInterestingly, 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.

Cited by 172 publications

References 24 publications

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Genetic Testing in Epilepsy: What Should you be Doing?

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

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