Differentiating CDKL5 Deficiency Disorder From Rett and Lennox-Gastaut Syndrome

CDKL5 deficiency disorder (CDD) is a rare, X-linked developmental and epileptic encephalopathy caused by pathogenic variants in the CDKL5 gene.¹ The condition is estimated to occur in approximately 1 in 40,000 to 60,000 live births and is more commonly observed in girls.² Clinically, CDD is characterized by early-onset, often treatment-resistant seizures, severe developmental impairment, and a range of associated neurologic and systemic features.³ Given its early presentation and phenotypic overlap with other infantile-onset epilepsies, timely recognition and appropriate use of genetic testing may be critical for accurate diagnosis and management.

In the second episode of this NeurologyLive® Insights video program, Raj Rajaraman, MD, MS, the director of the UCLA CDKL5 Center of Excellence, described CDD as a distinct developmental epileptic encephalopathy that has historically overlapped with Rett syndrome and Lennox-Gastaut syndrome (LGS) but can now be differentiated based on genetic and clinical features. He noted that prior to identification of the CDKL5 gene, CDD was often classified as an atypical form of Rett syndrome because of overlapping early developmental delays and seizures. However, CDD is characterized by earlier onset of both developmental impairment and seizure compared with Rett syndrome, where regression and seizure onset typically occur later in the first year.

He also highlighted differences between CDD and LGS, describing LGS as a broader electroclinical syndrome with multiple etiologies, including genetic and acquired causes. Although some patients with CDD may exhibit features similar to LGS, such as multiple seizure types, they may not meet full diagnostic criteria. Additionally, Raj emphasized that CDD is an ultra-rare condition with distinct seizure presentations, including early-onset epileptic spasms and characteristic seizure sequencing patterns. He further noted that hypsarrhythmia may not be present early in the disease course, which can complicate diagnosis and underscores the importance of considering genetic testing in suspected cases.