Current and Emerging Treatment Options for CDKL5 Deficiency Disorder

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 sixth and final episode of this NeurologyLive® Insights video program, Raj Rajaraman, MD, MS, the director of the UCLA CDKL5 Center of Excellence, explained that CDD is associated with frequent, often daily seizures, and most patients have failed multiple antiseizure medications. He highlighted first-line treatments for infantile spasms and noted that the ketogenic diet could also provide additional benefit. He noted that ganaxolone (Ztalmy; Marinus Pharmaceutical) is currently the only FDA-approved medication for CDKL5-associated seizures. Other therapeutic options include medications used for Lennox-Gastaut syndrome, neuromodulation devices, as well as palliative surgical approaches.

Raj also talked about emerging therapies for CDKL5 that focus on gene-targeted approaches, including antisense oligonucleotides and gene therapy delivered via viral vectors, which are expected to enter clinical trials in the coming years. Raj emphasized the importance of validated clinical outcome measures, such as the CDKL5 Clinical Severity Assessment, to capture treatment effects across seizure activity, motor function, communication, and other domains. He empathized that collaboration with patient advocacy groups has been key in defining meaningful outcomes to ensure future therapies address the full spectrum of disease impact.

REFERENCES
1. Dell'Isola GB, Fattorusso A, Pisani F, et al. Correction to: CDKL5 deficiency-related neurodevelopmental disorders: a multi-center cohort study in Italy. J Neurol. 2024;271(12):7648-7649. doi:10.1007/s00415-024-12653-1
2. Paul SK, Panday SK, Boccuto L, Alexov E. CDKL5 Deficiency Disorder: Revealing the Molecular Mechanism of Pathogenic Variants. Int J Mol Sci. 2025;26(17):8399. Published 2025 Aug 29. doi:10.3390/ijms26178399
3. Daniels C, Greene C, Smith L, et al. CDKL5 deficiency disorder and other infantile-onset genetic epilepsies. Dev Med Child Neurol. 2024;66(4):456-468. doi:10.1111/dmcn.15747