A Novel CDKL5 Mutation in a 47,XXY Boy With the Early-Onset Seizure Variant of Rett Syndrome

Mutations of the cyclin-dependent kinase-like 5 gene (CDKL5), reported almost exclusively in female subjects, have been recent- ly found to be the cause of a phenotype overlapping Rett syndrome with early-onset epileptic encephalopathy. We de- scribe the first CDKL5 mutation detected in a male individual with 47,XXY karyotype. This previously unreported, de novo, mutation truncates the large CDKL5 COOH-terminal region, thought to be crucial for the proper sub-cellular localization of the CDKL5 protein. The resulting phenotype is characterized by a severe early-onset epileptic encephalopathy, global develop- mental delay, and profound intellectual and motor impairment with features reminiscent of Rett syndrome. In light of the data presented we discuss the possible phenotypicmodulatory effects of the supernumerary wild type X allele and pattern of X chromosome inactivation and stress the importance of consid- ering the causal involvement of CDKL5 in developmentally delayed males with early-onset seizures.