Aviva Levitas

Familial neonatal isolated cardiomyopathy caused by a mutation in the flavoprotein subunit of succinate dehydrogenase

Cardiomyopathies are common disorders resulting in heart failure; the most frequent form is dilated cardiomyopathy (DCM), which is characterized by dilatation of the left or both ventricles and impaired systolic function. DCM causes considerable morbidity and mortality, and is one of the major causes of sudden cardiac death. Although about one-third of patients are reported to have a genetic form of DCM, reported mutations explain only a minority of familial DCM. Moreover, the recessive neonatal isolated form of DCM has rarely been associated with a mutation. In this study, we present the association of a mutation in the SDHA gene with recessive neonatal isolated DCM in 15 patients of two large consanguineous Bedouin families. The cardiomyopathy is presumably caused by the significant tissue-specific reduction in SDH enzymatic activity in the heart muscle, whereas substantial activity is retained in the skeletal muscle and lymphoblastoid cells. Notably, the same mutation was previously reported to cause a multisystemic failure leading to neonatal death and Leighs syndrome. This study contributes to the molecular characterization of a severe form of neonatal cardiomyopathy and highlights extreme phenotypic variability resulting from a specific missense mutation in a nuclear gene encoding a protein of the mitochondrial respiratory chain.

The Mutations Associated with Dilated Cardiomyopathy

Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children and adults. This paper describes the state of the genetic knowledge of dilated cardiomyopathy (DCM). The identification of the causing mutation is important since presymptomatic interventions of DCM have proven value in preventing morbidity and mortality. Additionally, as in general in genetic studies, the identification of the mutated genes has a direct clinical impact for the families and population involved. Identifying causative mutations immediately amplifies the possibilities for disease prevention through carrier screening and prenatal testing. This often lifts a burden of social isolation from affected families, since healthy family members can be assured of having healthy children. Identification of the mutated genes holds the potential to lead to the understanding of disease etiology, pathophysiology, and therefore potential therapy. This paper presents the genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM, and tries to relate these to the functions of the mutated genes.

Successful treatment of infective endocarditis with recombinant tissue plasminogen activator

OBJECTIVES In a prospective study, we examined the effect of treatment with recombinant tissue plasminogen activator (r-TPA) on survival and morbidity in a series of high-risk children with infectious endocarditis (IE) after prolonged treatment with indwelling catheters. We hypothesized that r-TPA is an adjunctive therapy for dissolution of infected thrombi in drug-resistant IE. STUDY DESIGN In the prospective 3-year study (1998-2001), we identified high-risk children with chronic illness and prolonged treatment with indwelling catheters who developed IE and overwhelming sepsis. Patients were allocated to receive r-TPA after persistent and enlarging intracardiac vegetations and failure to respond to conventional medical management. Complications associated with treatment, survival, and cardiac morbidity were observed. RESULTS Seven infants were treated prospectively with r-TPA. All infants responded promptly to treatment, with resolution of the intracardiac vegetations within 3 to 4 days of commencement and without any adverse complications. All patients survived without long-term cardiac morbidity. CONCLUSION Recombinant tissue plasminogen activator may offer a safe alternative to surgical intervention in the high-risk infant with IE.

Successful Non-Surgical Treatment of Candida tropicalis Endocarditis with Liposomal Amphotericin-B (AmBisome)

Fungal endocarditis in children is most commonly a complication of palliative or curative surgery for congenital heart disease, rheumatic valvulitis and prolonged indwelling central venous and umbilical catheters. We describe here the case of a 3-y-old patient with chronic diarrhoea and prolonged total parenteral alimentation who developed severe C. tropicalis endocarditis and was treated successfully using a liposomal preparation of amphotericin-B (AmBisome) without surgical intervention.Fungal endocarditis in children is most commonly a complication of palliative or curative surgery for congenital heart disease, rheumatic valvulitis and prolonged indwelling central venous and umbilical catheters. We describe here the case of a 3-y-old patient with chronic diarrhoea and prolonged total parenteral alimentation who developed severe C. tropicalis endocarditis and was treated successfully using a liposomal preparation of amphotericin-B (AmBisome) without surgical intervention.

Prenatal diagnosis of Shone's syndrome: parental counseling and clinical outcome.

To describe a series of fetuses diagnosed as having Shones syndrome, which includes four cardiac defects and for which there is a wide variety of clinical presentations, surgical treatments and outcomes, and to discuss the counseling strategy.

Methotrexate in recurrent postpericardiotomy syndrome.

The postpericardiotomy syndrome occurs in up to one-third of children undergoing cardiac surgery. Its treatment includes anti-inflammatory agents, diuresis, and drainage of effusions. Administration of steroids can have a dramatic effect, but is limited by adverse effects. Usually the syndrome lasts weeks only, and persistence beyond six months is exceptional. We describe a rare case of chronic postpericardiotomy syndrome, with recurrent pericardial effusions and steroid dependency, that was treated successfully with a low weekly dose of methotrexate.

Cardiac manifestations following electrocution in children

BACKGROUND Electrical injury can result in a variety of cardiac abnormalities. We evaluate the cardiac effects in patients injured by electric shock and treated in our medical centre. METHODS We reviewed retrospectively the findings in 52 children, aged from 7 months to 17 years, with a mean age of 10.1 +/- 5.1 years, all evaluated and treated for accidental electric shock from January, 1992, through July, 2004. Relevant data regarding clinical presentation, electrocardiogram recording and cardiac enzymes was compiled. We also evaluated the echocardiographic findings, clinical course, treatment, and outcome. RESULTS Syncope had been the presenting symptom in 17 children (33%), asystole in 1 patient, and ventricular fibrillation or tachycardia in 2 patients. Characteristic changes of acute ischaemia of the anterior wall on the basis of changes in the ST segments were noted in 2 patients. Total creatine phosphokinase was measured in 33 children (63%), and was elevated in 20. Creatine phosphokinase-MB was measured in 11 patients, and was abnormal in six (54%). Troponin was measured in three children, and was significantly high in one (33%). Cardiopulmonary resuscitation and mechanical ventilation for a significant period was necessary in 5 patients, of whom 4 (80%) survived. None of the survivors was left with any cardiac disability following the acute event. CONCLUSIONS Significant cardiac damage and complications are rare in children and young adults who survive incidental electrocution. Most of the cardiac events are observed during the acute phase and immediately subsequent to electrocution. No delayed complications are anticipated.

D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias.

Dilated cardiomyopathy (DCM) and malignant ventricular arrhythmias are important causes of congestive heart failure, heart transplantation, and sudden cardiac death in young patients. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line that has a pivotal role in maintaining adult cardiac structure and function. The putative mutation p.(D117N) in Cypher/ZASP has been suggested to cause systolic dysfunction, dilated left ventricle with hypertrabeculated myocardium, and intraventricular conduction disturbance, based on two reported sporadic cases. In two unrelated Bedouin families, one with pediatric DCM and the other with DCM and ventricular arrhythmias at young adulthood searching for the causative mutation by exome sequencing we identified the p.(D117N) variant in Cypher/ZASP. However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations. Furthermore, the carrier frequency in the Bedouin population of origin is estimated to be 5.2%, which is much higher than the incidence of idiopathic DCM in this population. Thus, our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation in the families tested by us. The results also indicates that at least in some cases, the p.(D117N) in Cypher/ZASP is not a causative mutation and the role of D117N in Cypher/ZASP in cardiac pathologies should be further clarified and re-evaluated.

Morbidity and mortality of adult patients with congenital dyserythropoietic anemia type I

Congenital dyserythropoietic anemia type I (CDAI) is a rare autosomal recessive disease characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. To better define the natural history of the disease among adult patients, we studied 32 Bedouin patients (median age 34 yr; range 21–60) all carrying the same CDAN1 founder mutation. Follow‐up studies included complete blood count, blood chemistry, abdominal ultrasound, echocardiography, and T2*MRI. Main complications were due to anemia and ineffective erythropoiesis [osteoporosis (8/9, 89%), cholelithiasis (21/30, 70%), pulmonary arterial hypertension (PAH) (6/25, 24%)] and iron overload [hypothyroidism (9/24, 38%), and diabetes mellitus (6/32, 19%)]. T2* MRI revealed increased liver iron but no cardiac iron (13/13). Anemia improved in the majority of patients who underwent splenectomy (5/6). Three patients died (9%) at the age of 46–56 due to PAH (1) and sepsis (2). All previously underwent splenectomy. Analyzing both our patients and the 21 patients previously described by Heimpel et al. (Blood 107:334, 2006), we conclude that adults with CDA I suffer significant morbidity and mortality. Careful monitoring of iron overload and prompt iron chelation therapy is mandatory. Due to possible complications and inconsistent response to splenectomy α‐interferon, transfusion therapy or stem cell transplantation should be considered as alternatives to this procedure in severely affected patients.

Recombinant tissue plasminogen activator as a novel treatment option for infective endocarditis: a retrospective clinical study in 32 children.

Infective endocarditis is a life-threatening infectious syndrome, with high morbidity and mortality. Current treatments for infective endocarditis include intravenous antibiotics, surgery, and involve a lengthy hospital stay. We hypothesised that adjunctive recombinant tissue plasminogen activator treatment for infective endocarditis may facilitate faster resolution of vegetations and clearance of positive blood cultures, and therefore decrease morbidity and mortality. This retrospective study included follow-up of patients, from 1997 through 2014, including clinical presentation, causative organism, length of treatment, morbidity, and mortality. We identified 32 patients, all of whom were diagnosed with endocarditis and were treated by recombinant tissue plasminogen activator. Among all, 27 patients (93%) had positive blood cultures, with the most frequent organisms being Staphylococcus epidermis (nine patients), Staphylococcus aureus (six patients), and Candida (nine patients). Upon treatment, in 31 patients (97%), resolution of vegetations and clearance of blood cultures occurred within hours to few days. Out of 32 patients, one patient (3%) died and three patients (9%) suffered embolic or haemorrhagic events, possibly related to the recombinant tissue plasminogen activator. None of the patients required surgical intervention to assist vegetation resolution. In conclusion, it appears that recombinant tissue plasminogen activator may become an adjunctive treatment for infective endocarditis and may decrease morbidity as compared with current guidelines. Prospective multi-centre studies are required to validate our findings.