Seizure Progression and Management in 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 fifth episode of this NeurologyLive® Insights video program, Raj Rajaraman, MD, MS, the director of the UCLA CDKL5 Center of Excellence, he explained that seizure progression in CDD can fluctuate over time, with initial presentations often including focal tonic, focal tonic-clonic, or generalized tonic seizures. He noted that infantile spasms may also occur independently or following early-onset seizures. Approximately 50% of patients may experience a “honeymoon period,” during which seizures temporarily improve without medication, though the underlying mechanisms remain unclear. As children age, he noted, seizures may persist in multiple forms, including tonic, generalized tonic-clonic, and spasms.

Raj also highlighted that EEG monitoring is critical for accurately identifying seizure types, particularly when movements may mimic seizures or when spasms are subtle. Early-onset seizures, including infantile spasms, are often refractory to first-line treatments, though some patients may respond to ketogenic diet. He said that broader-spectrum antiseizure medications, including those used for Lennox-Gastaut syndrome, may be considered. In addition, Raj talked about how regular EEGs support treatment evaluation and eligibility for clinical trials by ensuring alignment between families and providers regarding seizure identification.

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