Background-A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. Methods and Results-The study population included 233 patients. Beginning in 2002, data were collected prospectively.Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516Ϯ65 milliseconds; mean age at implantation was 30Ϯ17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow-up, 4.6Ϯ3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age Ͻ20 years at implantation, a QTc Ͼ500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. Conclusions-Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary. (Circulation. 2010;122:1272-1282.)
Objective: Cardiomyopathy (CMP) in children is a clinically and genetically heterogeneous group of disorders. Disease-associated mutations have been identified in more than 50 genes. Recently, mutations in the mitochondrial tRNA processing gene, ELAC2, were reported to be associated with the recessively inherited form of hypertrophic CMP (HCM). This study is aimed at describing the cardiac phenotype and outcome of ELAC2 mutation. Methods: We performed whole exome sequencing followed by targeted mutation screening to identify the genetic etiology of severe infantile-onset CMP in 64 consanguineous Saudi families. Results: A previously reported mutation (p.Phe154Leu) in ELAC2 gene was detected in 16 families. The index cases presented between 2 and 7 months of age with HCM in 13 infants and dilated CMP (DCM) in 3. Pericardial effusion was observed in 7 infants (44%). All infants died with a median age of death of 4 months. Almost 1/3 of them died during the initial presentation. Conclusion: Our study suggests screening the ELAC2 gene in severe infantile-onset HCM or DCM of unknown etiology, especially in the presence of pericardial effusion. Our work demonstrates a universally poor outcome of the (p.Phe154Leu) variant in ELAC2 gene; a correlation that helps in counseling parents and in planning appropriate medical intervention.
Ivabradine is a new antiarrhythmic agent with direct inhibition of the pacemaker (If) current. It has been used extensively to decrease sinus rate in the treatment of cardiac failure, and also in a single case of atrial ectopic tachycardia in a child. Here we report the case of a 3-year-old girl with congenital junctional ectopic tachycardia (JET), resistant to conventional antiarrhythmic medications, who was successfully treated with ivabradine. We suggest that ivabradine can be an effective treatment for junctional automatic tachycardias and can be considered as a new line of therapy for this incessant form of tachycardia.
Background - Childhood-onset cardiomyopathy (CMP) is a heterogenous group of conditions the etiology of which is largely unknown. The influence of consanguinity on the genetics of CMP has not been addressed at a large scale. Methods - To unravel the genetic etiology of childhood-onset CMP in a consanguineous population a categorized approach was adopted. Cases with childhood-onset CMP were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either: (i) Targeted Genetic Test (TGT) with: targeted mutation test, single gene test, or multi-gene panel for Noonan syndrome, or (ii) Untargeted genetic test with whole exome sequencing (WES) or whole genome sequencing (WGS). Several bioinformatics tools were used to filter the variants. Results - 205 unrelated probands with various forms of CMP were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), TGT had a yield of 82.7% compared to 33.6% for WES/WGS (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB , AASDH , CASZ1 , FLII , RHBDF1 , RPL3L , ULK1 ). Conclusions - Our work demonstrates the impact of consanguinity on the genetics of childhood-onset CMP, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting WES/WGS as a first-line test should be considered.
DKS can be safely performed in conjunction with CPC without added mortality risk. It is very effective in mitigating SVOTO risk, with sustainable good semilunar valves function. Our data support an aggressive approach to performing DKS concurrent with CPC in children with single ventricle pathologies at risk of developing SVOTO.
BackgroundFamilial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM.MethodsIn a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect.ResultsA region of homozygosity (ROH) on chromosome 8q24.13–24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32-knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES variants in 48 genes known to be implicated in hypertrophic and dilated cardiomyopathy was negative.ConclusionsOur data suggest that FBXO32 is a candidate gene for recessive DCM. Acting as a cardiac ubiquitin ligase, mutated FBXO32 could perturb the degradation of target proteins in the UPS, the impairment of which has been observed in cardiomyopathy. Our work proposes that genes encoding other ubiquitin ligases could also be implicated in familial cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0267-5) contains supplementary material, which is available to authorized users.
Clostridium difficile, the most common cause of hospital-associated diarrhoea in developed countries, presents major public health challenges. The high clinical and economic burden fromC. difficileinfection (CDI) relates to the high frequency of recurrent infections caused by either the same or different strains ofC. difficile. An interval of 8 weeks after index infection is commonly used to classify recurrent CDI episodes. We assessed strains ofC. difficilein a sample of patients with recurrent CDI in Western Australia from October 2011 to July 2017. The performance of different intervals between initial and subsequent episodes of CDI was investigated. Of 4612 patients with CDI, 1471 (32%) were identified with recurrence. PCR ribotyping data were available for initial and recurrent episodes for 551 patients. Relapse (recurrence with same ribotype (RT) as index episode) was found in 350 (64%) patients and reinfection (recurrence with new RT) in 201 (36%) patients. Our analysis indicates that 8- and 20-week intervals failed to adequately distinguish reinfection from relapse. In addition, living in a non-metropolitan area modified the effect of age on the risk of relapse. Where molecular epidemiological data are not available, we suggest that applying an 8-week interval to define recurrent CDI requires more consideration.
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