Abstract
Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were “rescued” after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.
Highlights
Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE)
The phenotype determined by in vitro functional current changes is consistent with Miceli et al.[36], who reported the differences between R213Q and R213W, which showed that R213Q leads to a significantly greater functional change than does R213W, and that it yields distinct phenotypical outcomes and neurodevelopmental outcomes: R213W caused BFNC and R213Q caused neonatal-onset EE
Neurodevelopmental outcome was more favourable in the patient carrying the S247X mutation, who presented with BFNC, than in those carrying the S247L, S247W, and P285T mutations, who presented with neonatal-onset EE identified based on burst suppression in EEG recordings (Table 1)
Summary
Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes. Mutations in KCNQ2, a voltage-gated potassium channel gene at 20q13, are usually inherited in an autosomal-dominant manner in benign epileptic s yndromes[1,2]. The phenotype determined by in vitro functional current changes is consistent with Miceli et al.[36], who reported the differences between R213Q and R213W, which showed that R213Q leads to a significantly greater functional change than does R213W, and that it yields distinct phenotypical outcomes and neurodevelopmental outcomes: R213W caused BFNC and R213Q caused neonatal-onset EE
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