Abstracts

Rationale: Benign familial neonatal epilepsy most often arises from KCNQ2 alleles causing haploinsufficiency or partial loss-of-function (LOF) when tested in vitro. Initial studies of several KCNQ2 variants causing epileptic encephalopathy (EE) revealed more complete LOF, suggesting a potential direct relationship between LOF extent and clinical severity (Miceli, 2013; Orhan, 2014). Recently, however, KCNQ2 R201C and R201H variants identified in published EE patients were shown to produce a gain-of-function in vitro (Miceli, 2015). Given this novel molecular physiology, we sought to understand if these variants might be associated with distinctive clinical features.Methods: We established an IRB-approved KCNQ2 patient registry and database. Anonymized clinical data on EE patients harboring KCNQ2 R201C and R201H variants in KCNQ2 were reviewed and analyzed.Results: Nine patients (eight R201C, one R201H) were identified. To date, detailed clinical and EEG data regarding the neonatal presentation were reviewed for 3/9 cases. The infants were born severely encephalopathic and exhibited persistently exaggerated startle reactions, particularly to tactile stimuli, characterized by high-amplitude, repetitive myoclonic jerks involving the upper and the lower limbs. Prolonged video-EEG recording showed a burst-suppression pattern that persisted for several days and demonstrated that spontaneous or stimulus-evoked myoclonic jerks lacked ictal correlates. Serial EEG recordings in the first few months of life revealed evolution into multifocal epileptiform discharges with random attenuations (Figure 1 A at 2 days of age and B at 3 months of age in the same infant). In addition to the movement disorder, two patients had seizures with tonic component and apnea in the neonatal period that responded to carbamazepine, and one of them evolved to infantile spasms at 4 months which remained intractable. The neonatal course of the third patient was complicated by recurrent apneas and persistent hypoventilation requiring ventilator support. Polygraphic EEG failed to demonstrate any ictal correlate to the apneas. Trials of retigabine and clonazepam in two patients did not improve EEG background or myoclonus. Interestingly, in both patients, vigabatrin induced a marked reduction of the exaggerated startle response and myoclonic jerking. All three infants had profound developmental delay. Two of them developed diabetes insipidus and one died at 7 months of life of multi-organ failure. Brain MRI in early infancy in all 3 cases revealed diffuse atrophy and delayed myelination that in one case was associated to subependymal heterotopias.Conclusions: Our initial analysis suggests that KCNQ2 R201C results in a distinctive, severe phenotype characterized by encephalopathy with and without seizures, excessive startle response, and diffuse MRI abnormalities. Continuing broad collaboration enabling sharing of such rare cases and the increasing use of video-EEG in the Neonatal Intensive Care Unit will allow for a better definition of the electroclinical phenotype.