Mohammad A. Ebrahim

Background: Infantile‐onset cardiomyopathy due to mitochondrial dysfunction is a severe condition frequently associated with poor prognosis. Biallelic pathogenic variants in ELAC2 , an essential mitochondrial tRNA processing gene, have been implicated in this phenotype. This study investigates the clinical and genetic spectrum of ELAC2 ‐related disease in a national cohort from Kuwait. Methods: We conducted a retrospective cohort study using data from the Kuwait Medical Genetics Center registry, including individuals with genetically confirmed or clinically suspected ELAC2 ‐related cardiomyopathy. Clinical, metabolic, and molecular data were reviewed. Exome sequencing or targeted mutation testing was performed in affected individuals and at‐risk family members. Results: A total of 34 individuals from 23 consanguineous families were identified, of whom 30 were genetically confirmed to harbor the homozygous ELAC2 founder variant c.460T>C; p.(Phe154Leu). All individuals presented in infancy with severe cardiomyopathy and refractory lactic acidosis. Neurological involvement was observed in 39% of cases. The majority exhibited hypertrophic cardiomyopathy, with variable dilated features and pericardial effusion. The disease course was fatal in all, with most patients dying in infancy. Conclusion: This is the largest single‐country cohort reported to date with ELAC2 ‐related mitochondrial cardiomyopathy, raising the global case total to over 70. The uniform presence of the Phe154Leu variant across unrelated Bedouin families highlights a strong founder effect. Given the rapid disease progression and high mortality, we recommend targeted ELAC2 screening in infants with idiopathic cardiomyopathy and persistent lactic acidosis, particularly in consanguineous populations. Premarital carrier testing and early family counseling should be prioritized to support preventive strategies.

Background: We describe the youngest (2.8 years, 9 kg) successful cavotricuspid isthmus (CTI) cryoablation whose medical management was complicated with severe sinus node dysfunction and recurrent atrial flutter despite medical therapy (sotalol). Case summary: Two-catheter, zero fluoroscopy electrophysiology study was performed using EnSite PrecisionTM mapping system. Cavotricuspid isthmus proved to be ‘in’ circuit with entrainment. Point-by-point 2 min cryolesions resulted in termination of atrial flutter, and later bidirectional block (>120 ms) was confirmed. There was no recurrence post-ablation (>1.5-year follow-up). Conclusion: Ablation offers a less invasive approach (vs. pacemaker implantation) to toddlers with tachyarrhythmia and coexisting conduction disease, limiting medical management option.

BACKGROUND: Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2 -related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype. METHODS: Retrospective combined review of patients with RYR2 -related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury. RESULTS: Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%–17.1%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P =0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%, P P P =0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%, P P =0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants. CONCLUSIONS: This study demonstrates a wider spectrum of RYR2 -related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.

BACKGROUND: Nonischemic cardiomyopathies are frequently caused by genetic mutations in about 100 different genes. The cardiomyopathy-associated gene DES encodes the intermediate filament protein desmin, which is important for the structural integrity of the cardiomyocytes. METHODS: Using a next-generation sequencing approach, we performed cascade screening of a previously identified heterozygous DES missense mutation (c.380G>C, p.R127P) segregating in a large 6-generation Kuwaiti family, where several members died from sudden cardiac death or developed different cardiomyopathies, partially in combination with conduction disease and atrial fibrillation. DES -p.R127P affects a highly conserved position and is absent or super rare in different genetic human population databases. In silico predictions support the pathogenicity of DES -p.R127P. To investigate the detrimental impact of desmin-p.R127P, we performed cell transfection experiments using different cell lines and cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy. RESULTS: These experiments demonstrated a severe desmin filament assembly defect leading to aberrant cytoplasmic desmin aggregates, even when co-expressed with wild-type desmin. Atomic force microscopy analysis supported the filament assembly defect of mutant recombinant desmin-p.R127P. To investigate the physicochemical impact of the amino acid at this position, we generated a set of 20 different variants and analyzed their filament formation in cell culture. Most of these variants disturbed the filament assembly comparable to p.R127P. CONCLUSIONS: In summary, we present and characterize a likely pathogenic missense mutation DES -p.R127P, which causes high cardiac mortality and morbidity in the described family. Our study has relevance for the interpretation and classification of further DES variants and might be helpful for the genetic counseling of patients and their relatives in future cases.

Objectives: The goal of this study is to document outcomes of ablation for high-risk accessory pathways in paediatrics using 3D mapping systems with minimal to zero fluoroscopy. Methods: It is a cross-sectional, multicentre study, conducted between 2013 and 2023, and involving four different centres in Hungary, Croatia, Kuwait, and Slovenia. Results: A total of 128 procedures were performed on 111 patients. The cohort included 57.8% anteroseptal (AS) pathways and 42.2% midseptal (MS) pathways. The mean follow-up time was 2.0 ± 2.1 years. Cryoablation was used in 72.7% of the cases, and radiofrequency ablation was used in 27.3%. The EnSite Precision™ Cardiac Mapping System was the predominant system used. The overall acute success rate was 89.1%, with recurrence rates at 17.2% with similar results regardless of the type of energy used. The success rate was not significantly different between AS and MS substrates. The age and weight of the patient had no bearing on the outcomes (median age and weight were 13 years and 52 kg, respectively). The complications rate was at 4.69% and included transient AV block (three patients), hematoma (one patient), right bundle branch block (one patient), and possible permanent complete AV block (one patient). Fluoroscopy was utilized in 18 cases, with a fluoroscopy time mean of 3 min and 45 s. Conclusions: MS and AS AP in paediatric patients can be treated effectively with either RF or cryoablation and with a low dose of radiation using 3D mapping systems, with excellent acute success rates and low complication rates.

Introduction: We describe a unique case of TECRL‐CPVT presented with cardiac arrest.Methods: Post resuscitation, the patient developed regular ventricular tachycardia featuring a left purkinje system morphology.Results: There was clear suppression of arrhythmia with the addition of flecainide and isolated ventricular ectopy causing secondary T‐wave changes.Conclusion: A high index of suspicion was required to eventually make the diagnosis through whole exome sequencing.

To document outcomes of cardiac surgical repair in Down syndrome (DS) patients with specific focus on the associated electrical conduction morbidities, ultimately leading to a higher incidence of pacemaker implantation (PMI). A retrospective study conducted between 2011 and 2020. A total of 167 DS patients undergoing 204 surgeries were included. The mean gestational age (GA) and mean weight were 37.3 weeks and 5.5 kg, respectively. Complete atrioventricular septal defect (AVSD) was the most common diagnosis. Pre-operative ECG revealed superior axis deviation (SAD) in 92 and 32% of patients with AVSD and isolated perimembranous ventricular septal defect (VSD), respectively (p < 0.01). Postoperative right bundle branch block (RBBB) was observed in 83 and 55% of patients with AVSD and following perimembranous VSD repair, respectively (p = 0.04). Ten patients underwent post-operative pacemaker implantation (PMI). Reintervention rate was around 8.9%. Three mortalities were encountered throughout the study period, 2 of which were in-hospital deaths. Low mortality was observed, however, a higher rate of PMI requirements noted with risk factors including lower age and weight.

This was a retrospective study documenting all pacemaker implantations (PMIs) secondary to postoperative atrioventricular block. A total of 26 patients were included between 2011 and 2020. The incidence rate was 1.8%, with a median follow-up time of 4.5 years. At the time of the initial PMI, the median weight was 5 kg, and the median generator longevity was 45 months. Mean cardiopulmonary bypass and aortic clamp times were significantly longer among surgeries complicated with PMI (P≤ 0.05). Trisomy 21 patients were 4 times more likely to need a PMI (95% CI 1.8–9, P < 0.001). The mean Risk Adjustment in Congenital Heart Surgery and Society of Thoracic Surgery scores were higher in patients with PMI. All initial PMIs were epicardial (18 single chamber). Most patients underwent ventricular septal defect closure (isolated or complex), except for 5 patients who underwent left-sided surgery. Pacing-induced dilated cardiomyopathy occurred in 3 patients. All implanted leads were functional except for 2 leads with high thresholds and another biventricular system infection. There was a 31% rate of pacing reintervention. Conclusion: PMI resulted in significant morbidity but without mortality. The highest risk for PMI was left ventricular outflow tract repair, trisomy 21, prolonged cardiopulmonary bypass, and aortic cross times. What is Known: •Incidence rate for postoperative atrioventricular block requiring pacemaker was at 1.8%, similar to previously published reports. •Longer cardiopulmonary bypass and aortic cross-clamp times were associated with higher risk for developing postoperative persistent atrioventricular block. What is New: •Incidence for persistent atrioventricular block requiring pacemaker was highest among left ventricular outflow tract surgery at 8.6%. •Following all intracardiac repair, Down syndrome patients were 4 times more likely to need a pacemaker implantation compared to the non-syndromic group.