Mutations
CDKL5 is associated with Rett syndrome (though much less frequently than MECP2). At least 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 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.
Mutations in the CDKL5 gene also cause a disorder called X-linked infantile spasm syndrome (ISSX) or West syndrome. Like the early-onset seizure variant of Rett syndrome, X-linked infantile spasm syndrome 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. The CDKL5 mutations responsible for X-linked infantile spasm syndrome lead to the production of an abnormally short, nonfunctional version of the CDKL5 protein. It remains uncertain how these defects cause seizures and intellectual disability.
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