|, EIEE2, ISSX, STK9, CFAP247, cyclin dependent kinase like 5, DEE2|
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. 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.
Mutations in the CDKL5 gene cause CDKL5 deficiency disorder. CDKL5 Deficiency had been thought of as a variant of Rett's Syndrome due to some similarities in the clinical presentation, but it 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. While CDKL5 is primarily associated with girls, it has been seen in boys as well. 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 change a single protein building block (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, nonfunctional version of the protein. At least 50 disease-causing mutations in this gene have been discovered.
Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by this study, published in April 2016, which concluded 'There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics'. At one time, mutations in the CDKL5 gene were said to cause a disorder called X-linked infantile spasm syndrome (ISSX) or West syndrome. but this research established CDKL5 disorder as a distinct clinical entity.
GSK3β inhibitors in Cdkl5 knockout (Cdkl5 -/Y) mice rescues hippocampal development and learning. Likewise, IGF-1 treatment in CDKL5 null mice restores synaptic deficits.
Aside from novel therapies with limited availability, anticonvulsants are the mainstay of treatment for most affected people. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients. Some treatments might show efficacy in a relevant proportion of patients, such as valproic acid, vigabatrin, clobazam or sodium channel blockers, as well as ketogenic diet
A clinical trial of Ataluren for nonsense mutations in CDKL5 and Dravet Syndrome has been announced. This same drug was approved by the UK's National Institute for Health and Care Excellence (NICE) for use in treating nonsense mutations in Duchenne muscular dystrophy. This drug did not show any efficacy in patients with CDKL5 mutations. Finally a CDKL5 protein replacement therapy is in development.
The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22. More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome.