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KCND3 encodes the transmembrane voltage-gated potassium channel, Kv4.3, involved in the transient outward K+ current. It is expressed in heart, smooth muscle, and brain. Mutations are reported in a wide array of neurologic abnormalities/phenotypes. Gain-of-function mutations in Kv4.3 have previously been described in Brugada Syndrome. Rarely,  Kv4.3 mutations have been associated with early-onset lone atrial fibrillation (AF). 

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Case report: An 8-year-old male with a history of PDA presented with SVT at 15 months of age, febrile seizures at 18 months, and developmental delays at 3.5 years. ADHD medications during school ensued. 

At age 8, nocturnal events of eye-rolling, limpness, and unresponsiveness, with concurrent atrial flutter progressing to self-terminating AF and multifocal sharp waves on EEG, prompted Levetiracetam treatment. Seizure progression with EEG worsening (multifocal epileptiform discharges occupying 80% of sleep) prompted treatment with valproic acid.  Brain MRI/PET showed left Sylvian fissure focal cortical dysplasia but diffuse cerebral glucose hypermetabolism. AF increased in frequency despite Sotalol treatment. Genetic testing revealed a de novo mutation in 916 G>A (G306S) KCND3.

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Discussion: KCND3 mutations present well-characterized but variable neurological phenotypes. The early-onset form displays neurodevelopmental disorders, ataxia, and ocular disturbances, while the late-onset form manifests with cerebellar ataxia. Epilepsy is exclusive to early presentation, with characteristic EEG findings comprising multifocal, frontally and temporally predominant spike/polyspike-wave. Focal right temporal slow waves are notable. Also seen are frontal/frontoparietal theta waves, and photic/hyperventilation induced bursts of high amplitude sharp waves. 

Several genetic studies described KCND3 mutations associated with AF. Most demonstrate a gain-of-function mutation contributing to cardiac repolarization. Shortening the atrial action potential hypothetically induces AF.

This unique presentation of a KCND3 mutation demonstrates that Kv4.3 mutations cause concomitant developmental delays, epilepsy, and cardiac arrhythmias. Investigating  the simultaneous occurrence of neurologic and cardiac disease in gain of function mutations of KCDN3 is worthwhile.