CDKL5

The CDKL5 gene provides instructions for making a protein that is essential for normal brain function. 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. One of the proteins targeted by the CDKL5 protein is MeCP2, which plays important roles in the function of nerve cells (neurons) and in the maintenance of connections (synapses) between neurons. Researchers have not determined which other proteins are targeted by the CDKL5 protein.

Rett syndrome - caused by mutations in the CDKL5 gene

More than 10 mutations in the CDKL5 gene have been identified in girls with an atypical form of Rett syndrome known as the early-onset seizure variant. This severe form of the 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 gene 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. Researchers are working to determine how these changes result in seizures and the characteristic features of Rett syndrome in affected children.

other disorders - caused by mutations in the CDKL5 gene

Mutations in the CDKL5 gene can also cause a disorder known as early infantile epileptic encephalopathy-2 (EIEE-2) or X-linked infantile spasm syndrome-2 (ISSX-2). Like the early-onset seizure variant of Rett syndrome, EIEE-2 is characterized by recurrent seizures that begin in infancy. Children with this condition also have severe to profound intellectual disability and may have other brain abnormalities. Unlike Rett syndrome, which occurs almost exclusively in females, EIEE-2 has also been reported in a few males.

Some cases of EIEE-2 are caused by a deletion involving part or all of the CDKL5 gene; others result from mutations that alter the function of the CDKL5 protein or prevent the production of any functional protein. It is unclear how defects in this protein cause seizures and intellectual disability.