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CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development. Mutations in the gene can cause deficiencies in the protein. The gene regulates neuronal morphology through cytoplasmic signaling and controlling gene expression.[5] The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.[6]
The CDKL5 protein acts as a kinase, which is an enzyme that modulates the activity of other proteins by adding a phosphate group to specific positions. The CDKL5 protein regulates neuronal morphology through cytoplasmic signaling and by controlling gene expression, playing a crucial role in the development and maintenance of the nervous system.
Studies have shown that the CDKL5 protein interacts with various signaling pathways and plays a role in controlling neurotransmitter release, synaptic plasticity, and cell survival. The CDKL5 protein has also been shown to regulate the activity of genes involved in neuronal development and the formation of synaptic connections.
Researchers are actively working to better understand the role of the CDKL5 protein in brain development and the underlying mechanisms of CDKL5 disorders. Further studies are needed to determine which proteins are targeted by the CDKL5 protein, as well as to develop effective treatments for individuals affected by CDKL5 disorders.
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Mutations in the CDKL5 gene cause CDKL5 deficiency disorder.[7] CDKL5 deficiency disorder had, earlier, been thought of as a variant of Rett syndrome, due to some similarities in the clinical presentation.[8] CDKL5 deficiency syndrome is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and is considered separate from Rett Syndrome, rather than a variant of it.[9] While CDKL5 is primarily found in girls, it has been seen in boys as well.[10] This disorder includes many of the features of classic Rett syndrome, including developmental problems, loss of language skills, and repeated hand-wringing or "hand-washing" movements), but also causes recurrent seizures, beginning in infancy. Some CDKL5 mutations alter a single amino acid in a region of the CDKL5 protein that is critical for its kinase function. Other mutations lead to the production of an abnormally short, nonfunctioning version of the protein. At least 50 disease-causing mutations in this gene have been discovered.[11]
Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by a 2016 study which concluded that the clinical presentations of the two disorders were not identical.[12] At one time, mutations in the CDKL5 gene were thought to cause a disorder called X-linked infantile spasm syndrome (ISSX),[13][14] or West syndrome.[15][16] Studies have established CDKL5 disorder as a distinct clinical entity.
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GSK3β inhibitors in CDKL5 knockout (CDKL5 -/Y) mice permit normal hippocampal development and learning.[17]
IGF-1 treatment in CDKL5 knockout mice restores synaptic function.[further explanation needed][18]
 | This section needs to be updated. The reason given is: Ganaxolone is a recently-approved neurosteroid indicated for seizures associated with CDKL5 deficiency disorder.. (March 2022) |
Anticonvulsants were the mainstay of treatment for most affected people. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients.[19] Some treatments might show efficacy in a relevant proportion of patients, such as valproic acid, vigabatrin, clobazam or sodium channel blockers, as well as a ketogenic diet[20][21]
Ganaxolone (brand name Ztalmy) was approved for medical use in the United States in March 2022[22][23] and considered by the US Food and Drug Administration (FDA) to be a first-in-class medication.[24] Ganaxolone, a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator, treats seizures in those with CDKL5 deficiency disorder.[22]
A CDKL5 protein replacement therapy is in development.[25]
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The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22.[26] More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome.[6]
G40.42
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