A Mutational Hotspot in The LAMP2 Gene: Unravelling Intrafamilial Phenotypic Variation and Global Distribution of The c.877C>T Variant: A Descriptive Study.

OBJECTIVE: Danon disease is defined by a clinical trio of cardiomyopathy, skeletal myopathy, and cognitive impairment. It results from the lysosomal-associated membrane protein-2 (LAMP2) gene variants. The aim of study is determination of genotype and phenotype of a newly diagnosed Iranian family with a unique phenotype due to a pathogenic variant of the LAMP2 gene along with a phenotypic comparison of all reported patients. MATERIALS AND METHODS: In this descriptive study, we evaluated the demographic data, clinical features, management procedures, as well as genetic analysis of both patients in this newly diagnosed family. Whole genome sequencing (WGS) and in silico structural and functional predictions were applied. A comprehensive search of the c.877C>T variant in LAMP2 was conducted using the PubMed, Google Scholar, VarSome, ClinVar, Human Gene Mutation Database (HGMD), and Franklin databases to identify any genotype-phenotype correlations. RESULTS: Nine patients were carriers of the c.877C>T variant. All patients were male, and displayed variable degrees of left ventricular hypertrophy (LVH) that ranged from mild to severe. All patients exhibited typical cardiac conduction abnormalities consistent with Danon disease. Four underwent heart transplants and survived. Skeletal muscle involvement and cognitive impairment were observed in four patients each. The mean age of onset was 14 years. The proband in this study exhibited an earlier onset of cardiac symptoms. CONCLUSION: Genetic analysis is the preferred diagnosis approach for Danon disease and can assist families in managing affected patients, identify carriers, and assist with future family planning. This study highlights the intrafamilial phenotypic variability of Danon disease. It is possible that variants of this gene may be frequent in Iran.

Catheter ablation for an incessant arrhythmia in a preterm low-weight neonate.

A 15-day-old neonate weighing 1800 g presented with incessant long-RP tachycardia. Temporary cessation of the arrhythmia with adenosine confirmed the diagnosis of permanent junctional reciprocating tachycardia (PJRT). The arrhythmia was refractory to multiple drugs. An electrophysiological study confirmed diagnosis. The arrhythmia was successfully treated with radiofrequency. Learning objective: Transcatheter radiofrequency ablation can be done safely in infants who are unresponsive to medical therapy, regardless of age and body weight.

Percutaneous extraction of a protruding atrial pacing lead in an 8-year-old child.

An 8-year-old girl with a history of single-chamber epicardial pacemaker during infancy and cardiac resynchronization therapy with a His bundle pacing lead implantation six months earlier, presented with congenital complete heart block. At the follow-up visit, we found atrial pacing lead protrusion with probable insulation in the computed tomography scan. We have shown late pacemaker lead perforation management under fluoroscopic guidance in a pediatric patient. Learning objective: A serious complication associated with cardiac implantable electronic devices is lead perforation. In the pediatric age group, limited data exist on this complication and its challenging management.We present a case of atrial pacing lead protrusion in an 8-year-old girl. The lead was extracted under fluoroscopic guidance without any complications.

Ventricular tachycardia ablation in children.

INTRODUCTION: The ablation of ventricular tachycardia, including premature ventricular contractions, is an approved, albeit infrequent procedure in pediatric patients. Data are scarce regarding the outcomes of this procedure. The purpose of this study was to share a high-volume center experience and patient outcomes for catheter ablation of ventricular ectopy and ventricular tachycardia in pediatric population. METHODS: Data were retrieved from the institutional data bank. Outcomes over time were evaluated, and procedural details were compared. RESULTS: A total of 116 procedures were performed on 102 pediatric patients between July 2009 and May 2021 at the Rajaie Cardiovascular Medical and Research Center in Tehran, Iran. Ablation was not performed in 4 procedures (3.4%) due to high-risk substrates. Of the remaining 112 ablations performed, 99 (88.4%) were successful. However, one patient died due to a coronary complication. There were no significant differences observed in early ablation results based on patients' age, sex, cardiac anatomy, or ablation substrates (P > 0.05). Follow-up records were available for 80 procedures, and 13 (16.3%) of those experienced recurrence. During long-term follow-up, none of the variables mentioned above were statistically different between patients with or without arrhythmia recurrence. CONCLUSION: The overall success rate of pediatric ventricular arrhythmia ablation is favorable. We found no significant predictor for the procedural success rate concerning acute and late outcomes. Larger multicenter studies are needed to elucidate the predictors and outcomes of the procedure.

Clinical outcomes of subcutaneous implantable cardiac defibrillator implantation - Iran SICD registry.

BACKGROUND: The subcutaneous implantable-defibrillator (S-ICD) is a relatively new alternative to the transvenous ICD system to minimize intravascular lead-related complications. This paper presents outcome of SICD implantation in patients enrolled in Iran S-ICD registry. METHODS: Between October 2015 and June 2022, this prospective multicenter national registry included 223 patients with a standard indication for an ICD, who neither required bradycardia pacing nor needed cardiac resynchronization to evaluate the early post-implant complications and long-term follow-up results of the S-ICD system. RESULTS: The mean age of the patients was 45 ± 17 years. The majority (79.4%) were male. Ischemic cardiomyopathy (39.5%) was the most common underlying disorder among patients selected for S-ICD implant. Most study patients (68.6%) had ICD for primary prevention of sudden cardiac death. Seven patients (3.1%) were found to have suboptimal lead positions. Six patients (2.7%) developed a pocket hematoma; all were managed medically. During a mean follow-up of 2 years, the appropriate therapy was recorded in 13% of the patients and inappropriate ICD intervention mainly due to supraventricular tachycardia in 8.9%. Pocket infection was observed in four patients (1.8%) and five patients (2.2%) died mainly due to heart failure. CONCLUSION: S-ICDs were effective at detecting and treating both induced and spontaneous ventricular arrhythmias. Major clinical complications were rare.

A novel stop-gain pathogenic variant in the KCNQ1 gene causing long QT syndrome 1.

BACKGROUND: Inherited primary arrhythmias, such as long QT (LQT) syndromes, are electrical abnormalities of the heart mainly due to variants in 3 genes. We herein describe a novel stop-gain pathogenic variant in the KCNQ1 gene in an Iranian child with LQT syndrome 1. METHODS: The patient and his family underwent clinical evaluation, electrocardiographic Holter monitoring, and whole-exome sequencing. Sanger sequencing and segregation analysis were used to confirm the variant in the patient and his family, respectively. The pathogenicity of the variant was checked via an in silico analysis. RESULTS: The proband suffered from bradycardia and had experienced syncope without stress. The corrected QT interval was 470 ms (the Schwartz score ≥ 3.5), and the Holter monitoring showed sinus rhythm, infrequent premature atrial contractions, and a prolonged QT interval in some leads. Whole-exome and Sanger sequencing showed c.968G > A in 3 affected family members. According to the American College of Medical Genetics and Genomics criteria, c.968G > A was classified as a pathogenic variant. CONCLUSIONS: The KCNQ1 gene is the main cause of LQT syndromes in our population. The common genes of LQT syndromes should be studied in our country's different ethnicities to determine the exact role of these genes in these subpopulations.

Implantation of a cardioverter-defibrillator in an 8-kg infant: a case report and literature review.

The use of an implantable cardioverter-defibrillator to prevent sudden cardiac death is an approved method. Experience is limited regarding implantation techniques in infants and low-weight children. We herein describe the implantation of an epicardial implantable cardioverter-defibrillator in a 15-month-old infant weighing 8 kg. We also briefly discuss implantable cardioverter-defibrillator implantation in paediatrics, particularly infants, hoping that our experience will be drawn upon in further such attempts.

Pubertal status of children with congenital heart disease.

BACKGROUND: CHD influences many aspects of life in affected individuals. Puberty, a major aspect of development, is a concern for patients and families. OBJECTIVES: We investigated pubertal status in children and adolescents with CHD. METHODS: Patients with CHD aged 6-18 were enrolled. Cardiac diagnoses were confirmed using history, examination, and paraclinical tools including echocardiography. An endocrinologist determined pubertal stages, and the second Tanner stages for pubarche (P2), thelarche (B2), and gonadarche (G2) were considered as the pubertal onset. A study with a large sample size on pubertal onset in a normal population was used for comparison. RESULTS: Totally, 451 patients (228 girls and 223 boys) at a median (10th-90th percentile) age of 10.79 (8.02-14.28) years for the girls and 10.72 (8.05-14.03) years for the boys were enrolled. The median (10th-90th percentile) ages at B2 and P2 in the girls with CHD were 10.77 (9.55-12.68) and 10.53 (9.39-12.28) years, respectively, which were higher than the median ages of 9.74 (8.23-11.94) and 10.49 (8.86-12.17) years in the normal girls.The median (10th-90th percentile) ages at G2 and P2 in the boys with CHD were 11.04 (8.85-13.23) and 11.88 (9.78-13.46) years, correspondingly, which were higher than the median ages of 9.01 (6.00-11.84) and 10.34 (6.84-13.10) years in the normal boys. CONCLUSIONS: Pubertal onset could be delayed in children with CHD when compared with the normal population.

Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome.

TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice-site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN-related patients, including 27 patients from 21 families. The average age-onset was 30 months (range 1-10) for all cases. Adrenergic-mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss-of-function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic-mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations.

Successful Ablation of an Epicardial Accessory Pathway via the Subxiphoid Approach in a Child.

Data is scarce regarding epicardial ablation in children. I herewith present a case of successful epicardial ablation in a child with previous unsuccessful attempts at endocardial ablation. This report could be used to guide further such attempts.

Ductal closure with radiofrequency energy; outcomes of the first series.

Using radiofrequency energy for closure of the patent ductus arteriosus (PDA) has been reported by us previously. In this article we report the early and late outcome of the first group in whom patent ductus arteriosus has been occluded with radiofrequency. Six children with PDA were enrolled. The procedure was successful in five cases and transient hoarseness was observed in 2 cases as the only complication.

Genetic homozygosity in a diverse population: An experience of long QT syndrome.

BACKGROUND: Genomic variations have shown an ethnic-specific pattern within various cohorts. Genetic variants of KCNQ1, KCNH2, SCN5A and KCNE1 causing LQT syndrome have been described in many populations. In this article the spectrum of variants of these genes is presented in Iranian patients. METHODS: 102 unrelated individuals diagnosed with LQT were enrolled in this study. Clinical and electrocardiogram (ECG) data of 95 patients were documented, and analyzed by expert pediatric cardiologists. Coding regions and exon-intron boundaries were amplified and sequenced. Segregation analysis was done for novel variants as well as in silico analyses. RESULTS: Sixty nine of 95 cases (73%) had Schwartz score of ≥3.5. The causal variants were found in 31 cases (9 novel variants). 21 patients had KCNQ1 (LQTS1) of which15 patients were homozygous for KCNQ1 variants, 9 of these patients (29%) had a Jervell and Lange-Nielsen phenotype. 4 patients had KCNH2 (LQTS2) variants, 7 cases had SCN5A had heterozygous variants, and 2 cases had heterozygous variants in KCNE1 (LQTS5). 19 variants were missense, 3 were nonsense, and 3 were frameshifts. There was one large deletion and 3 intronic variants. CONCLUSION: The yield of genetic testing and the genotype profile of LQTS patients in Iran is different from reports elsewhere, with lower overall yield and with 48% having homozygous states.

Identification of a Novel KCNQ1 Frameshift Mutation and Review of the Literature among Iranian Long QT Families

Background: Long QT syndrome (LQTS) is characterized by the prolongation of QT interval, which results in syncope and sudden cardiac death in young people. KCNQ1 is the most common gene responsible for this syndrome. Methods: Molecular investigation was performed by DNA Sanger sequencing in Iranian families with a history of syncope. In silico examinations were performed for predicting the pathogenicity of the novel variant. Results: A novel homozygous KCNQ1 frameshift mutation, c.1426_1429delATGC (M476Pfs*4), was identified, and then the current literatures of five patients were reviewed regarding the LQTS. Conclusion: The novel frameshift mutation has been reported for the first time among the Iranian population. Our finding along with the case series study of LQTS patients illustrates the importance of genetic and case series in precise detection of the frequency of LQTS carriers.

Detection of a new KCNQ1 frameshift mutation associated with Jervell and Lange-Nielsen syndrome in 2 Iranian families.

Jervell-Lange Nielsen syndrome (JLNS) with autosomal recessive inheritance is a congenital cardiovascular disorder characterized by prolongation of QT interval on the ECG and deafness. We have performed molecular investigation by haplotype analysis and DNA Sanger sequencing in 2 unrelated Iranian families with a history of syncope. Mutational screening of KCNQ1 gene revealed the novel homozygous frameshift mutation c.733-734delGG (p.G245Rfs*39) in 2 obviously unrelated cases of JLNS which is probably a founder mutation in Iran. The novel mutation detected in this study is the first time reported among Iranian population and will be beneficial in the tribe and region-specific cascade screening of LQTS in Iran.

Identification and characterization of a novel recessive KCNQ1 mutation associated with Romano-Ward Long-QT syndrome in two Iranian families.

BACKGROUND: One of the foremost causes of sudden cardiac death in the young is an inherent cardiac arrhythmia known as Long-QT syndrome (LQTS). Whereas heterozygous mutations typically lead to the Romano-Ward type of LQTS, We have provided a further evidence for the recessive transmission of a novel KCNQ1 gene mutation in two consanguineous families for the first time in Iran. METHODS: Next generation sequencing, DNA Sanger sequencing and haplotype analysis were performed for genotype determination. Twelve different in silico tools were used for predicting the variant pathogenecity along with the family and population study. RESULTS: A novel recessive KCNQ1 variant (p.D564G) was revealed in none of the unrelated healthy individuals but four patients in two apparently unrelated families. The variant was classified as a likely pathogenic mutation by combining the resulted criteria for the changed amino acid. CONCLUSIONS: Identification of the novel mutation not only supports the genetic testing as a definitive diagnostic tool for detection of at risk family members, but also emphasizes its screening in Iranian LQTS patients as this mutation is very likely a founder mutation in Iran.

Enzyme Polymorphism in Warfarin Dose Management After Pediatric Cardiac Surgery.

BACKGROUND: Warfarin is an anticoagulant and is widely used for the prevention of thromboembolic events. Genetic variants of the enzymes that metabolize warfarin, i.e. cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to various warfarin doses. There is, however, a dearth of data on the role of these variants during initial anticoagulation in pediatric patients. OBJECTIVES: We aimed to evaluate the role of genetic variants of warfarin metabolizing enzymes in anticoagulation in a pediatric population. PATIENTS AND METHODS: In this prospective cohort study, 200 pediatric patients, who required warfarin therapy after cardiac surgery, were enrolled and divided into two groups. For 50 cases, warfarin was prescribed based on their genotyping (group 1) and for the remaining 150 cases, warfarin was prescribed based on our institute routine warfarin dosing (group 2). The study endpoints were comprised of time to reach the first therapeutic international normalization ratio (INR), time to reach a stable warfarin maintenance dose, time with over-anticoagulation, bleeding episodes, hospital stay days and stable warfarin maintenance dose. RESULTS: There was no significant difference concerning the demographic data between the two groups. The time to stable warfarin maintenance dose and hospital stay days were significantly lower in group 1 (P <0.001). However, there was no statistically significant difference in time to reach the first therapeutic INR, time with over-anticoagulation and bleeding episodes, between the two groups. CONCLUSIONS: The determination of warfarin dose, based on genotyping, might reduce the time to achieve stable anticoagulation of warfarin dose and length of hospital stay.

Single Dose Corticosteroid Therapy After Surgical Repair of Fallot's Tetralogy; A Randomized Controlled Clinical Trial.

BACKGROUND: Inflammatory reaction can produce several complications after cardiac surgery. Many attempts have been made to reduce these complications; perioperative corticosteroid therapy is one of the simplest methods. OBJECTIVES: We conducted a randomized study to evaluate the efficacy of single dose methylprednisolone, prescribed after surgery, for reducing the complications. Repair of Tetralogy of Fallot was chosen as a homogenous large group for the study. PATIENTS AND METHODS: One hundred children who underwent total repair of Tetralogy of Fallot were enrolled in this study. After the surgery, all patients were transferred to pediatric ICU and were randomized (in a double-blind fashion) in 2 groups (A and B); a single dose of methylprednisolone (30 mg/kg of body weight) was injected to participants of group "A" just at the time of ICU entrance. Group "B" received no drug. Then, clinical outcomes and laboratory data were compared between the two groups. RESULTS: The only significant differences were lower incidence of bacteremia and higher incidence of hyperglycemia in the group who were used methylprednisolone. CONCLUSIONS: Using a single postsurgical dose of methylprednisolone does not significantly alter the clinical outcome after repairing Tetralogy of Fallot.

Ductal closure with radiofrequency energy: the first in-human report.

BACKGROUND: Vascular obstruction is one of the complications of radiofrequency ablation. Following our previous report on the use of radiofrequency energy for vascular closure in an animal model in this journal, we herein present the first ever in-human report. Patient and method The patient was a 3-year-old boy, who received a permanent endocardial pacemaker for congenital complete heart block. He also had a conical patent ductus arteriosus. The ductus was occluded with radiofrequency energy on the arterial side with no complications. CONCLUSION: Closure of patent ductus arteriosus and probably other problematic small vessels could be achieved with radiofrequency energy. Further experience will elucidate the future scope of this novel technique.

Radiofrequency energy for vascular closure: a novel technique with multiple applications.

Vascular stricture is a known complication of radiofrequency ablation. We used this potential of radiofrequency for voluntary restriction and closure of a pulmonary artery branch in a sheep.