KCNT1-Related Epilepsy: International Cohort Rare inheritance patterns, phenotypic variability and response to treatment
2The Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology
3Pediatric Neurology Unit, Ruth Rappaport Children's Hospital, Rambam Health Care Campus
Introduction: KCNT1 related epilepsy is emerging as an important form of severe monogenic epilepsy with a possible treatment option. Here we report on KCNT1 variants identified in pedigrees followed at the Rambam Genetics Institute as part of an international cohort and discuss response to treatment.
Material and Methods: Molecular diagnosis using next generation sequencing was performed on two pedigrees referred to our clinic with a proband presenting with severe early onset refractory epilepsy and profound developmental delay. Subsequently information on natural history, genotype and treatment response of our patients was compared to 27 patients collected as part of an international cohort.
Results: A known pathogenic variant p.Gly288Ser was detected in both patients. Unexpectedly in one patient, the p.Gly288Ser variant was inherited from the healthy mother detected in blood and buccal sample as well as a subsequent pregnancy.
As compared to the cohort our patients had a similarly severe clinical course. Only our patient had a variant inherited form a healthy parent. Quininde was administered in half of the patients with a 25-50% seizure reduction while our patients experienced up to 50% reduction.
Conclusion: KCNT1-related epilepsy generally includes severe refractory epileptic syndromes. The vast majority of previously reported pathogenic variants are de-novo mutations, while cases of inherited mutation from a healthy or mildly affected parents are exceedingly rare. Our findings raise the possibility of incomplete penetrance, even in seemingly severe genotypes. Additionally, this series hints at the benefit of quinidine treatment for the p.Gly288Ser genotype however large scale studies are necessary.