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We report 2 patients with drug-resistant epilepsy caused by KCNT1 mutations who were treated with quinidine. Both mutations manifested gain of function in vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency as recorded in seizure diaries, and partially validated by objective seizure evaluation on EEG. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. Although quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies.

Radiofrequency catheter ablation can be effectively and safely performed for certain supraventricular tachycardia types in addition to intraatrial reentry. A novel catheter course is required for slow pathway modification. High-grade AV block is a potential risk of lesions placed in the systemic venous medial isthmus.

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na + channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (∆K1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and ∆K1500 mutant channel. The mutation shifted the potential for half inactivation (V 1/2 h ∞ ) to more negative values and reduced its voltage dependence consistent with a reduction of inactivation valence of 1. The shift in inactivation was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). The potential for half activation (V 1/2 m) was shifted to more positive potentials, and its voltage dependence reduced by 50% in the ∆K1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (∆ charge, -1, -2). For both mutations, V 1/2 h ∞ was shifted back toward control; however, V 1/2 m shifted progressively to more positive potentials. The late component of Na + current was increased in the ∆K1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.

Clinical trials often rely on echocardiographic measures of left ventricular (LV) size and function as surrogate end-points. However, the quantitative impact of factors that affect reproducibility of these measures is unknown. To address this issue, the NHLBI-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy (DCM) aged 0–22 years from 8 pediatric clinical centers. Methods Clinical data were collected together with 150 echocardiographic indices of LV size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intra and interobserver variability. We studied the impact of beat averaging (BA), observer type (local vs. core) and variable type (areas, calculations, dimensions, slopes, time intervals and velocities) on measurement reproducibility. The outcome measure was %error (100 × difference/mean) Results Of 173 enrolled subjects, 131 met criteria for DCM. BA, variable type and observer type all impacted %error (p<0.0001). Core inter-observer %error (median 11.4, 10.2 and 9.3% for 1-, 2- and 3-BA, respectively) was approximately twice the intra-observer %error (median 6.3, 4.9 and 4.2% for 1-, 2- and 3-BA, respectively). Slopes and calculated variables exhibited high %error despite BA. Chamber dimensions, areas, velocities and time intervals exhibited low %error. Conclusions This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for design of future pediatric studies. BA and a single core lab observer improve reproducibility of echo measurements in children with DCM. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.

Barth syndrome is an X-linked disorder characterized by dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, abnormal mitochondria, and growth deficiency. The primary defect is a mutation in the TAZ gene on the X chromosome at Xq28, resulting in abnormal phospholipid biosynthesis and cardiolipin deficiency. To date, there has been no systematic evaluation of the cardiac phenotype. We report five cases of cardiac arrest and/or placement of an internal cardiac defibrillator with documented ventricular arrhythmia. We suggest that ventricular arrhythmia is part of the primary phenotype of the disorder and that patients should be screened accordingly.

IMPORTANCE Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release—the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT—but has never been assessed prospectively. OBJECTIVE To determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. DESIGN, SETTING, AND PARTICIPANTS This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. INTERVENTIONS Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. MAIN OUTCOMES AND MEASURES The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). RESULTS Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0–22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0–4), with no difference noted between the baseline and placebo (median, 2.5; range, 0–4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0–2] vs 2.5 [range, 0–4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01117454