Phenotypic variability and preserved cognition in a family with KCNA2-related developmental epileptic encephalopathy.

Developmental and epileptic encephalopathy type 32 (DEE32) is a severe neurological disorder caused by pathogenic variants in the KCNA2 gene, encoding the Kv1.2 voltage-gated potassium channel. DEE32 typically presents with early-onset seizures, ataxia, and intellectual impairment, though severity varies widely. We describe a family with a rare KCNA2 loss-of-function variant in two siblings, evaluating their clinical phenotype, neuroimaging, electroencephalography (EEG), developmental assessments, and treatment response. Cognitive function in patients 1 and 2 was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI), while cognitive function in patient 3 was inferred from his ability to maintain employment and function independently. The family included a father and two children, all with early-onset seizures in infancy and normal development. Patient 1, a male, exhibited delayed myelination at 15 months, with seizures initially controlled but later recurring after medication weaning. His WPPSI assessment indicated normal cognition with a standard score of 113, and his mild speech delay resolved. Patient 2, a female, had a normal brain MRI and normal WPPSI evaluation (standard score of 111), with well-controlled seizures on zonisamide. The father had childhood-onset epilepsy persisting into adulthood, ultimately leading to Sudden Unexpected Death in Epilepsy (SUDEP) at age 30. Genetic testing confirmed that both children carried the c.765_773del (p.Met255_Ile257del) KCNA2 variant, linking their seizures to the father's epilepsy. Patients 1 and 2 responded well to zonisamide, while patient 3's response remains unknown due to a lack of medical records. This study highlights the variability of KCNA2-related epilepsy, ranging from early-onset seizures to long-term epilepsy with developmental delays and episodic ataxia. Despite carrying a loss-of-function variant, both children demonstrated a favorable response to zonisamide without additional neurological manifestations. Our findings underscore the need for further research into genetic modifiers of KCNA2 phenotypes. The interpretation of any association between SUDEP and KCNA2-related epilepsy and the determination of cause of death is hampered by limited data, as it is based on a single case with normal cardiac evaluation.