Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the CDKL5 gene (also known as STK9) have recently been shown to cause early onset epilepsy and severe mental retardation (ISSX or West syndrome). Patients with CDKL5 mutations sometimes also show features similar to those seen in Rett Syndrome (RTT). We have screened the CDKL5 gene in 94 patients with RTT or a RTT-like phenotype who had tested negative for MECP2 mutations (13 classical RTT female subjects, 25 atypical RTT female subjects, 40 RTT-like female and 16 RTT-like male subjects; 33 of the patients had early onset seizures). 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 of RTT. In addition, the 33 patients with early seizures were screened for the most common mutations in the ARX gene but none were found. Combining our three new cases with the previously published cases, 13/14 patients with CDKL5 mutations presented with seizures before the age of 3 months.
 ...
PMID:Early onset seizures and Rett-like features associated with mutations in CDKL5. 1601 84

X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills and infantile spasms and seizures in predominantly females. Besides CDKL5, these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.
 ...
PMID:CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. 1633 Apr 82

Studying infantile spasms is challenging because there are so many aspects of variation that introduce potential bias. These might relate to the many underlying etiologies, and variations in clinical semiology and electroencephalographic features that relate more to age or timing of investigation than to the underlying epilepsy or seizures type. New gene defects associated with the CDKL5/STK9 and ARX genes are associated with infantile spasms, but these illustrate that, when studying neurodevelopmental outcomes, it is necessary to deal also with heterogeneity at the level of genotype-phenotype correlation. We discuss these design issues with consideration of data from the United Kingdom infantile spasms study (UKISS)--in which neurodevelopmental outcomes show evidence of an interaction between underlying etiologic classification and randomised treatment--and with consideration to proposals on study design from the recent consensus statement of the West Delphi group. In the continual debate about whether we should "lump" or "split" when studying epilepsy syndromes, we propose the adoption of study designs using valid and consistent methods that permit both lumping and splitting.
 ...
PMID:The influence of etiology upon ictal semiology, treatment decisions and long-term outcomes in infantile spasms and West syndrome. 1682 60

CDKL5 deficiency disorder (CDD) is a complex of clinical symptoms resulting from the presence of non-functional CDKL5 protein, i.e., serine-threonine kinase (previously referred to as STK9), or its complete absence. The clinical picture is characterized by epileptic seizures (that start within the first three months of life and most often do not respond to pharmacological treatment), epileptic encephalopathy secondary to seizures, and retardation of psychomotor development, which are often observed already in the first months of life. Due to the fact that CDKL5 is located on the X chromosome, the prevalence of CDD among women is four times higher than in men. However, the course is usually more severe among male patients. Recently, many clinical centers have analyzed this condition and provided knowledge on the function of CDKL5 protein, the natural history of the disease, therapeutic options, and their effectiveness and prognosis. The International CDKL5 Disorder Database was established in 2012, which focuses its activity on expanding knowledge related to this condition and disseminating such knowledge to the families of patients.
 ...
PMID:CDKL5 Deficiency Disorder-A Complex Epileptic Encephalopathy. 3207 29