CDKL5 alterations lead to early epileptic encephalopathy in both genders

Liang, Jao‐Shwann; Shimojima, Keiko; Takayama, Rumiko; Natsume, Jun; Shichiji, M.; Hirasawa, Kyoko; Imai, Kaoru S.; Okanishi, Tohru; Mizuno, Seiji; Okumura, Akihisa; Sugawara, Midori; Ito, Tsubasa; Ikeda, Hiroko; Takahashi, Yukitoshi; Oguni, Hirokazu; Imai, Katsumi; Ōsawa, Makiko; Yamamoto, Toshiyuki

doi:10.1111/j.1528-1167.2011.03174.x

Cited by 68 publications

(86 citation statements)

References 26 publications

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“…In a large study, CDKL5 mutations were estimated to occur in approximately 8% of females with early-onset seizures (before nine months of age) and up to 28% of females with early-onset seizures and ISS [19]. Mutations in males, on the other hand, appear less common, having been reported in ten boys to date with a more severe phenotype characterized by early-onset tonic and myoclonic seizures, intractable ISS, severe global developmental delay, cortical visual impairment, sleep disturbances, and hand stereotypies in some patients [13; 20–25]. …”

Section: Introductionmentioning

confidence: 99%

CDKL5 and ARX Mutations in Males With Early-Onset Epilepsy

Mirzaa

Paciorkowski

Marsh

et al. 2013

Pediatric Neurology

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Mutations in CDKL5 and ARX are known causes of early-onset epilepsy and severe developmental delay in males and females. While numerous males with ARX mutations associated with various phenotypes have been reported in the literature, the majority of CDKL5 mutations have been identified in females with a phenotype characterized by early-onset epilepsy, severe global developmental delay, absent speech, and stereotypic hand movements. To date, only ten males with CDKL5 mutations have been reported. Our retrospective study reports on the clinical, neuroimaging and molecular findings of 18 males with early-onset epilepsy caused by either CDKL5 or ARX mutations. The 18 patients include eight new males with CDKL5 mutations and ten with ARX mutations identified through sequence analysis of 266 and 346 males, respectively, at our molecular diagnostic laboratory. Our large data set therefore expands on the number of reported males with CDKL5 mutations and highlights that aberrations of CDKL5 and ARX combined are an important consideration in the genetic forms of early-onset epilepsy.

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Section: Introductionmentioning

confidence: 99%

CDKL5 and ARX Mutations in Males With Early-Onset Epilepsy

Mirzaa

Paciorkowski

Marsh

et al. 2013

Pediatric Neurology

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“…Mice. Given the clinical relevance of CDKL5-related disorders in males (14,15) and the confounding effects of mosaic CDKL5 expression in females from random X-chromosome inactivation, we characterized the behavioral profile of Cdkl5 knockouts in male (Cdkl5 -/y ) mice, compared with wild-type male littermates (WT, Cdkl5 +/y ). We found that Cdkl5 -/y mice exhibit motor and anxiety impairments similar to those observed in other ASD and RTT mouse models (2,(16)(17)(18)(19).…”

Section: Resultsmentioning

confidence: 99%

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Wang

Allen²,

Goffin³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

181

247

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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKTmammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.C yclin-dependent kinase-like 5 (CDKL5) is an X-linked gene associated with early infantile epileptic encephalopathy 2 (EIEE2) (1), atypical Rett syndrome (RTT) (2), and autism spectrum disorders (ASDs) (3, 4). Patients with CDKL5 mutations display a heterogenous array of clinical phenotypes, the most prominent of which include early-onset seizures, intellectual disability, and autistic features (5).CDKL5 is a serine/threonine (S/T) kinase that is highly expressed in the brain (6). In vitro studies have demonstrated that CDKL5 may mediate the phosphorylation of methyl-CpG binding protein 2 (MeCP2) (7), DNA methyltransferase 1 (DNMT1) (8), and netrin-G1 ligand (NGL-1) (9). RNAi-mediated knockdown studies show that CDKL5 can regulate neuronal outgrowth and synapse stability (9, 10). Despite these proposed functions, the exact role of CDKL5 in the phosphorylation of MeCP2 (7, 11) and in dendritic outgrowth (9, 10) remains unclear, and thus requires further investigation. The limited understanding of CDKL5 function and its associated signal transduction pathways has hindered the development of therapeutics for CDKL5-related disorders. Current treatments focus on managing symptoms and reducing seizure frequency, but have limited effectiveness (12).To investigate the function of CDKL5 in a disease model and identify potential avenues of therapeutic intervention, we developed a Cdkl5 knockout mouse. We found that mice lacking CDKL5 show autistic-like behavioral abnormalities, deficits in neural circuit communication, and alterations in multiple signal transduction pathways. We establish a causal link between Cdkl5 loss-of-function and disease-related phenotypes and identify the AKT-mammalian target of rapamycin (mTOR) pathway as a unique candidate for targeted therapeutic intervention of CDKL5-related disorders. ResultsGeneration of Cdkl5 Knockout Mice. To investigate the pathophysiology underlying CDKL5-related disorders, we generated ...

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“…There were no significant clinical differences between males and females. 46 Expansion in the first and second polyalanine tracts of ARX is associated with epileptic encephalopathy or mental retardation in males without brain malformations. Patients usually present with infantile spasms, tonic seizures, and often hypsarrhythmia.…”

Section: Dravet-like Conditionsmentioning

confidence: 99%