A novel de Novo KCNC1 mutation (c.1147 C > T) presenting with epilepsy and ADHD: a case report and literature review

Abstract Background Pathogenic KCNC1 mutations (encoding Kv3.1 potassium channels) drive heterogeneous neurological disorders, ranging from progressive myoclonus epilepsy-ataxia (MEAK) to developmental/epileptic encephalopathies (DEE) and global developmental delay. Transmembrane-domain variants predominantly cause MEAK-like phenotypes, whereas cytoplasmic mutations associate with severe DEE characterized by refractory seizures and cognitive impairment. The genotype-phenotype correlation in the currently reported 54 cases remains unclear, particularly for non-transmembrane mutations. This paper describes a novel KCNC1 variant (c.1147 C > T, p.His383Tyr) and utilizes protein modeling to elucidate its structural impact, aiming to advance precision therapy for KCNC1-related channelopathies. Case presentation An 11-year-old male with normal early development developed febrile convulsions at 19 months, progressing to generalized tonic-clonic seizures and drop attacks by 20 months. Initiated on valproate at age 2 after EEG confirmation of epilepsy, he achieved sustained seizure freedom (> 3 years) with dose optimization. Current assessment shows age-appropriate motor/social function and superior cognition (Raven’s 75-80th percentile) alongside idiopathic short stature (-2.08 SDS height), persistent EEG abnormalities, mega cisterna magna on MRI, and Attention-Deficit/Hyperactivity Disorder-related academic impairment. The whole exome sequencing identified a de novo KCNC1 mutation (c.1147 C > T). Three-dimensional protein modeling demonstrated structural disruption in voltage-sensing domains. Comparative analysis of 54 published cases revealed that transmembrane domain mutations predominantly cause epilepsy-ataxia syndrome, whereas non-transmembrane variants are correlated with developmental encephalopathies. Conclusions The present study is the first to report a c.1147 C > T KCNC1 mutation and highlights the importance of transmembrane domain integrity for neurological function. The dissociation between seizure control and persistent neurodevelopmental deficits suggests distinct pathomechanisms for epileptic versus cognitive manifestations. These findings emphasize the prognostic value of mutation localization as well as support early genetic testing in neurological disorder patients with subclinical EEG abnormalities.