CDKL5 deficiency disorder (CDD) is an infantile, epileptic encephalopathy presenting with early-onset seizures, intellectual disability, motor impairment, and autistic features. The disorder has been linked to mutations in the X-linked CDKL5, and mouse models of the disease recapitulate several aspects of CDD symptomology, including learning and memory impairments, motor deficits, and autistic-like features. Although early-onset epilepsy is one of the hallmark features of CDD, evidence of spontaneous seizure activity has only recently been described in Cdkl5-deficient heterozygous female mice, but the etiology, prevalence, and sex-specificity of this phenotype remain unknown. Here, we report the first observation of disturbance-associated seizure-like events in heterozygous female mice across two independent mouse models of CDD: Cdkl5 knockout mice and CDKL5 R59X knock-in mice. We find that both the prevalence and severity of this phenotype increase with aging, with a median onset around 28 weeks of age. Similar seizure-like events are not observed in hemizygous knockout male or homozygous knockout female littermates, suggesting that X-linked cellular mosaicism is a driving factor underlying these seizure-like events. Together, these findings not only contribute to our understanding of the effects of CDKL5 loss on seizure susceptibility, but also document a novel, pre-clinical phenotype for future therapeutic investigation.