An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multi-center collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients

Common Childhood Epilepsy Mimics

Unusual movements in children frequently generate concern of underlying seizures from parents and lead to professional review. Stigma associated with epilepsy heightens anxiety and a wish to confirm or exclude the diagnosis as soon as possible. These considerations could lead to a wrong diagnosis of epilepsy being given with unwarranted exposure to medications with potential side effects and cost burden to families. This chapter seeks to provide practitioners in pediatric epilepsy with an exploration of practical differential diagnoses for epilepsy in children, particularly for convulsive seizures. Evaluation of all epilepsy mimics requires a precise and relevant history to help arrive at a diagnosis. Epilepsy mimics across various ages will be reviewed, with the most common differential diagnoses presented first. Examples of common potential epilepsy mimics include benign sleep myoclonus, which is frequently observed in infants and may be a challenge to differentiate from myoclonic seizures in infants. It is a very common phenomenon in pre-term infants with an incidence of 57–132 per 1000 live births. Breath-holding spells among toddlers are common and may be mistaken for epilepsy, as can reflex anoxic seizures. Self-gratification phenomena have been observed from infancy onward and may resemble clonic seizures. Inattention in school-going children is a differential diagnosis for absence seizures and both conditions may co-exist. Stressed or traumatized children may present with non-epileptic psychogenic seizures, as can children with established seizures. Lack of concurrent electrophysiological correlates and absence of stereotypic presentation help differentiate inattention and non-epileptic seizures from childhood epilepsy. Sleep-related activity such as hallucinations, parasomnias, and hypnagogic jerks could also be mistaken for epilepsy in children. Video electroencephalogram (video-EEG) telemetry evaluation is invaluable in such cases. Lack of video-EEG services, simple videos, or EEG studies in resource-poor settings makes diagnosis of epilepsy imitators challenging. The differences between epilepsy and common differential diagnoses for practitioners in resource-limited settings who may lack access to requisite investigative tools will be addressed in the following text. The outcome for most epilepsy mimics is excellent with minimal morbidity and mortality. The potential danger posed by unnecessary medical interventions caused by misdiagnosis of epilepsy makes it imperative that this possibility is minimized