Early Genetic Testing Key in Suspected CDKL5 Without Definitive EEG Pattern

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 third episode of this NeurologyLive® Insights video program, Raj Rajaraman, MD, MS, the director of the UCLA CDKL5 Center of Excellence, explained that EEG findings in suspected CDD may be nonspecific early in the disease course, often showing multifocal spikes or slowing without the classic hypsarrhythmia pattern. Although some patients may later develop hypsarrhythmia or slow spike-wave patterns seen in Lennox-Gastaut syndrome, these features are not universal. He noted that the presence of multiple seizure types, particularly in early-onset epilepsy, should raise suspicion for CDD, even in the absence of a defining EEG pattern.

He further highlighted that genetic testing remains the primary method for diagnosis, with EEG serving a supportive role in treatment selection rather than confirmation. Brain MRI findings are typically normal in CDD and are primarily used to exclude alternative etiologies, such as structural injury or hypoxic-ischemic encephalopathy. Raj also underscored the importance of considering other genetic epilepsies, particularly in cases with seizures occurring within the first days of life, and recommended early use of epilepsy gene panels or whole-exome sequencing to guide diagnosis.

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