Mutational spectrum of CDKL5 in early‐onset encephalopathies: a study of a large collection of French patients and review of the literature

@article{Nmos2009MutationalSO,
  title={Mutational spectrum of CDKL5 in early‐onset encephalopathies: a study of a large collection of French patients and review of the literature},
  author={C. N{\'e}mos and L. Lambert and F. Giuliano and B. Doray and A. Roubertie and A. Goldenberg and B. Delobel and V. Layet and M. N’Guyen and A. Saunier and F. Verneau and P. Jonveaux and C. Philippe},
  journal={Clinical Genetics},
  year={2009},
  volume={76}
}
The CDKL5 gene has been implicated in the molecular etiology of early‐onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early‐onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as… Expand

Paper Mentions

Observational Clinical Trial
The overarching purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), RTT-related disorders including… Expand
ConditionsCDKL5, FOXG1 Disorders, MECP2 Duplication, (+1 more)
Observational Clinical Trial
The purpose of this study is to advance understanding of the natural history of Rett syndrome (RTT), MECP2-duplication disorder (MECP2 Dup), CDKL5, FOXG1, and individuals with MECP2… Expand
ConditionsCDKL5 Disorder, FOXG1 Syndrome, MECP2 Duplication dIsorder, (+1 more)
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TLDR
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Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Expand
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TLDR
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TLDR
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References

SHOWING 1-10 OF 39 REFERENCES
Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy
TLDR
Interestingly these missense mutations that result in a mislocalisation of the CDKL5 protein are associated with severe developmental delay which was apparent within the first months of life characterised by early and generalised hypotonia, and autistic features, and as well as early infantile spasms. Expand
CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.
TLDR
It is shown here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis, and that it is indeed a kinase, which is able to phosphorylate itself and to mediate Me CP2 phosphorylation, suggesting that they belong to the same molecular pathway. Expand
Key clinical features to identify girls with CDKL5 mutations.
TLDR
It is shown that search for mutations in CDKL5 is indicated in girls with early onset of a severe intractable seizure disorder or infantile spasms with severe hypotonia, and inGirls with RTT-like phenotype and early onset seizures, though, in this cohort, mutations in CDsL5 account for about 10% of the girls affected by these disorders. Expand
Early onset seizures and Rett-like features associated with mutations in CDKL5
TLDR
Novel pathogenic CDKL5 mutations were identified in three girls, two of whom had initially been diagnosed with the early onset seizure variant of RTT and the other with early onset seizures and some features ofRTT. Expand
CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms
TLDR
CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type, based on the clinical overlap between the Hanefeld variant and West syndrome. Expand
CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients
TLDR
The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported, irrespective of whether they have suspected Rett syndrome. Expand
Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.
TLDR
CDKL5 is confirmed as another locus associated with epilepsy and X-linked mental retardation and suggested that mutations in CDKL 5 can lead to a clinical phenotype that overlaps RTT, however, it remains to be determined whether CDkL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations. Expand
Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes
TLDR
This is the first description of a male patient with a deletion of these genes, showing the involvement of CDKL5 in severe epileptic encephalopathy in males, and illustrates the added value of high resolution array‐CGH in molecular diagnosis of mental retardation‐multiple congenital anomaly cases. Expand
Functional Consequences of Mutations in CDKL5, an X-linked Gene Involved in Infantile Spasms and Mental Retardation*
TLDR
A model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions is proposed. Expand
Seizures and electroencephalographic findings in CDKL5 mutations: Case report and review
TLDR
The observation and review of the literature suggest that a broader polymorphic electroclinical pattern with both generalized and focal seizures may occur in patients with CDKL5 mutations. Expand
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