KCNA2 Variants in Epilepsy: Focusing on Spike-and-Wave Activation in Sleep

The clinical manifestations and genotype-phenotype correlations of KCNA2 variants in epilepsy patients, particularly those with spike-and-wave activation in sleep (SWAS), remain poorly characterized.

We analyzed clinical data from our 18 patients with KCNA2 variants and conducted a comprehensive literature review of cases with complete clinical data, resulting in a total of 77 patients. For genotype-phenotype correlation analysis, patients were categorized based on variant localization. Additionally, we summarized and analyzed the clinical characteristics and treatment of 14 patients with SWAS.

All our 18 patients presented with epilepsy, with a median seizure onset age of 6 months. Intellectual disability was observed in 83.3% of patients, and developmental delay in 77.8%. Abnormal electroencephalography findings were present in 94.4% of patients, with 44.4% exhibiting SWAS. Genotype-phenotype analysis of total 77 patients revealed that variants in the pore domain were significantly associated with higher rates of motor disorders (P = 0.007) and SWAS (P < 0.001), while S1-S4 segment variants showed a higher incidence of magnetic resonance imaging abnormalities (P = 0.049). Among 18.2% (14/77) patients with SWAS (12 with p. Pro405Leu, one with p. Val369Phe and one with p. Ile409Phe/Leu), only 42.9% responded effectively to treatment, with 28.6% developing drug-resistant epilepsy. Valproic acid was the most commonly prescribed medication, and combination therapies showed promising results in some cases.

Our findings provide strong evidence supporting the association between KCNA2 pathogenic variants and SWAS. The high prevalence of SWAS in our cohort and literature review highlights the importance of considering KCNA2 variants in diagnosing patients with SWAS.