KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine.

OBJECTIVE: Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels. METHODS: Here we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300 µM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined. RESULTS: We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there is a significant group difference in gain of function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain of function for all mutations studied. INTERPRETATION: These results establish direction for a targeted therapy and potentially exemplify a translational paradigm for in vitro studies informing novel therapies in a neuropsychiatric disease.

Longitudinal changes in brain magnetic resonance imaging findings in children with sickle cell disease.

Children with sickle cell anemia (HbSS) are at high risk for neurologically overt cerebral infarcts associated with stroke and neurologically silent cerebral infarcts correlated with neuropsychometric deficit. We used complete magnetic resonance imaging (MRI) histories from 266 HbSS children, aged 6 through 19 years, who were enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) to examine silent infarct prevalence, localization, recurrence, and progression. We report a baseline prevalence of 21.8%, marginally higher than previously reported due to improved imaging technologies. Although we observed no overall sex difference in prevalence, most lesions in girls occurred before age 6, whereas boys remained at risk until age 10. Silent infarcts were significantly smaller and less likely to be found in the frontal or parietal cortex than were infarcts associated with stroke. Children with silent infarct had an increased incidence of new stroke (1.03/100 patient-years) and new or more extensive silent infarct (7.06/100 patient-years) relative to stroke incidence among all children in our cohort (0.54/100 patient-years). Both events were substantially less frequent than the risk of stroke recurrence among children not provided chronic transfusion therapy. Although chronic transfusion is known to decrease occurrence of new silent infarcts and strokes in children with elevated cerebral arterial blood flow velocity, further study is required to determine its risk-benefit ratio in children with silent infarct and normal velocities. Until safe and effective preventive strategies against infarct recurrence are discovered, MRI studies are best reserved for children with neurologic symptoms, neuropsychometric deficits, or elevated cerebral artery velocities.

Diagnosis and treatment of ischemic pediatric stroke.

Tremendous progress has been made in the diagnosis, prevention, and treatment of pediatric stroke. With a complete investigation, stroke etiology can be determined in most children, and multiple factors are commonly identified. Stroke can be prevented in some children and treated in others. Children at risk for recurrent strokes can be treated effectively. The prognosis after pediatric stroke is usually good, but today we can identify and initiate treatment in selected patients at risk for long-term problems. This article reviews recent advances in the identification, prevention, treatment, and outcome in pediatric ischemic stroke.