Towbin Ja

X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus.

Background. X‐linked cardiomyopathy (XLCM) is a rapidly progressive primary myocardial disorder presenting in teenage males as congestive heart failure. Manifesting female carriers have later onset (fifth decade) and slower progression. The purpose of this study was to localize the XLCM gene locus in two families using molecular genetic techniques. Methods and Results. Linkage analysis using 60 X‐chromosome‐specific DNA markers was performed in a previously reported large XLCM pedigree and a smaller new pedigree. Two‐point and multipoint linkage was calculated using the LINKAGE computer program package. Deletion analysis included multiplex polymerase chain reaction (PCR). Dystrophin protein was evaluated by Western blotting with N‐terminal and C‐terminal dystrophin antibody. Linkage of XLCM to the centromeric portion of the dystrophin or Duchenne muscular dystrophy (DMD) locus at Xp21 was demonstrated with combined maximum logarithm of the scores of +4.33, &thgr;=0 with probe XJ1.1 (DXS206) using two‐point linkage and +4.81 at XJ1.1 with multipoint linkage analysis. LOD scores calculated using other proximal DMD genomic and cDNA probes and polymerase chain reaction polymorphisms supported linkage. No deletions were observed. Abnormalities of cardiac dystrophin were shown by Western blotting with N‐terminal dystrophin antibody, whereas skeletal muscle dystrophin was normal, suggesting primary involvement of the DMD gene with preferential involvement of cardiac muscle. Conclusions. XLCM is due to an abnormality within the centromeric half of the dystrophin genomic region in heart. This abnormality could be due to 1) a point mutation in the 5′ region of the DMD coding sequence preferentially affecting cardiac function, 2) a cardiac‐specific promoter mutation that alters expression in this tissue, 3) splicing abnormalities, resulting in an abnormal cardiac protein, or 4) deletion mutations undetectable by Southern and multiplex polymerase chain reaction analysis. (Circulation 1993;87:1854‐1865)

Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: a prospective clinical study

Objectives: To compare tissue Doppler (TD) velocities between patients with dilated cardiomyopathy (DCM) and normal controls and to determine whether TD velocities, Tei index, right ventricular fractional area change, and left ventricular ejection fraction (LVEF) predict adverse clinical outcomes in children with DCM. Methods: Prospective evaluation of children with DCM. Results: 54 children with DCM and 54 age and sex matched control group participants were studied. Mitral inflow velocities were similar for both groups except for decreased mitral deceleration time in patients with DCM. Systolic and diastolic TD velocities at the mitral annulus (septal and lateral sides) and tricuspid annulus were significantly reduced in children with DCM compared with controls (p < 0.001 for each). By multivariate analysis, after adjustment for Tei index and right ventricular fractional area change, decreased LVEF and tricuspid velocity during early diastole (Ea) were predictors of the primary end point (PEP), a composite end point consisting of need for hospitalisation or the outcome transplantation or death. Tricuspid Ea velocity < 8.5 cm/s had 87% specificity and 60% sensitivity for reaching the PEP. LVEF < 30% had 68% specificity and 74% sensitivity for the PEP. Combined LVEF < 30% and tricuspid Ea < 11.5 cm/s had 100% specificity and 44% sensitivity for the PEP. Conclusions: Children with DCM have significantly lower TD velocities than normal controls. In such cases, lower LVEF (< 30%) is more sensitive but less specific than lower tricuspid Ea velocities (< 8.5 cm/s) in predicting which patients are at risk of hospitalisation, transplantation, or death.

Evidence of genetic heterogeneity in Romano-Ward long QT syndrome. Analysis of 23 families.

BackgroundThe Romano-Ward long-QT Syndrome (LQTS) is an autosomal dominant inherited trait characterized by prolonged QT interval on ECG, life-threatening arrhythmias, syncope, and sudden death in affected individuals. A gene responsible for this disorder has been shown to be linked to the Harvey ras-1 locus (H-ras-1) DNA marker on the short arm of chromosome 11 (11p) in 7 families. The purpose of this study was to determine, by analyzing 23 families with LQTS for linkage to chromosome 11p, whether evidence exists for more than one gene causing LQTS (ie, locus heterogeneity). Methods and ResultsTwenty-three families (262 family members) were clinically evaluated using medical histories, ECGs, and Holter recordings. Each corrected QT interval (QTc) were determined using Bazetts formula. Blood for DNA extraction and cell line immortalization was obtained after informed consent. Southern blotting and polymerase chain reaction were performed, and linkage analysis carried out using the LINKAGE computer program (v 5.03). Genetic heterogeneity was determined using the HOMOG 2 (v 2.51) computer program. Twenty-three families were studied for evidence of linkage to chromosome 11p using the H-ras-1 locus probe pTBB-2 and multiple flanking markers, including tyrosine hydroxylase (TH). Two- point linkage analysis using pTBB-2 and TH markers was consistent with linkage in 15 of 23 families, with the maximum single-family LOD score of +3.038 occurring at Θ = 0. However, 8 of 23 families had negative LOD scores, with the values in 4 families being less than −2 at Θ = 0, consistent with exclusion of linkage. Analysis with the HOMOG program was consistent with genetic heterogeneity (P < .0001). Multipoint linkage data using pTBB-2 and TH were also examined for evidence of heterogeneity. HOMOG analysis of multipoint LOD scores from 100 cM surrounding the H-ras-1 locus also supported heterogeneity (P < .001). ConclusionsIn the 23 families with LQTS analyzed for linkage to the H-ras-1 locus on chromosome 11p15.5, 15 of 23 families had LOD scores consistent with linkage. The remaining 8 of 23 families had negative LOD scores, 4 of which were definitively excluded from linkage. Thus, genetic heterogeneity is definitively (P < .001) demonstrated for this disorder.

Localization of gene for familial hypertrophic cardiomyopathy to chromosome 14q1 in a diverse US population.

BackgroundFamilial hypertrophic cardiomyopathy, an inherited primary cardiac abnormality characterized by ventricular hypertrophy, is the leading cause of sudden death in the young. Recent application of restriction fragment length polymorphism markers has provided provocative results, with localization to chromosome 18 (Japanese studies), 16 (Italian studies), 14 (US and French-Canadian studies), and two (National Institutes of Health studies) indicating genetic heterogeneity. Interpretation remains speculative until at least one of these loci is confirmed in unrelated pedigrees by independent investigators. Methods and ResultsWe studied eight unrelated families of varied ethnic origins across the United States. DNA from each individual was digested with restriction enzymes TaqI or BamHI and analyzed by Southern blots followed by hybridization with probes T cell receptor a (TCRA), myosin heavy chain fi, D14S25, and D14S26. Multipoint linkage analysis showed a maximum lod score of 4.3, placing the locus 10 cM from D14S26 between D14S26 and TCRA, with an odds ratio of 20,000:1 and 90% confidence limits of 12 cM proximal to D14S25 to 4 cM distal to TCRA. The probability of linkage to 14ql was more than 99%. ConclusionsThese results indicate that the loci for familial hypertrophic cardiomyopathy in our families is primarily 14ql but does not exclude other loci in a small proportion of the families. Thus, 14ql appears to be the locus for familial hypertrophic cardiomyopathy in a significant proportion of the US population.

Current Concepts in Long QT Syndrome

Abstract. Sudden cardiac death occurs in the United States with an incidence of more than 300,000 persons per year. The underlying cause of death is commonly considered to be due to primary or secondary arrhythmias. In young persons in whom no structural heart disease can be identified, the long QT syndromes (LQTS) are commonly considered as likely causes. Multiple genes causing LQTS have been identified thus far, all of which encode cardiac ion channels. These include two potassium channel α subunits (KVLQT1 and HERG), two potassium channel β subunits (minK and MiRP1), and one sodium channel gene (SCN5A). The purpose of this review is to describe the current understanding of the molecular genetics of LQTS and the resultant phenotypes, particularly in young patients.

Left ventricular noncompaction cardiomyopathy in association with trisomy 13.

In recent years, left ventricular noncompaction (LVNC) has been recognized as a distinct form of cardiomyopathy with its own clinical presentation and natural history. More than 100 cases of LVNC have been described in children. Although LVNC has been described in association with metabolic disorders such as Fabrys disease or genetic disorders such as Roifmans syndrome, this case represents the first report of LVNC in a child with trisomy 13.

Overlapping Phenotypes: Left Ventricular Noncompaction and Hypertrophic Cardiomyopathy

Patient KM is a 26-year-old male in whom a systolic ejection murmur was recently identified on a routine physical examination. As part of his evaluation, he underwent 2-dimensional echocardiography, which revealed asymmetrical left ventricular (LV) hypertrophy with a maximum LV wall thickness of 22 mm in the basal anterior septum and extension of hypertrophy into the posterior septum. His LV ejection fraction was 55%, with a normal cavity size and no evidence of resting LV outflow tract obstruction. In addition, the myocardium was noted to be highly trabeculated from the apex to the midportion of the LV (Figure 1; online-only Data Supplement Movie I). The right ventricle was normal in size and function. He has never developed heart failure …

Long-term results of triple-drug-based immunosuppression in nonneonatal pediatric heart transplant recipients.

BACKGROUND Few reports document long-term results of pediatric cardiac transplantation in which triple therapy (cyclosporine, azathioprine, and corticosteroids) was the mainstay of immunosuppression. This report details a single centers pediatric transplant experience and analyzes the relative contributions of selected pre/posttransplant risk factors on long-term morbidity and mortality. METHODS Retrospective data were collected for all non-neonatal pediatric transplant recipients including: presenting diagnosis, cardiac hemodynamics (particularly pulmonary vascular resistance index), donor ischemic time, occurrence of postoperative infections, episodes of allograft rejection, incidence of posttransplant lymphoproliferative disease or coronary artery disease (CAD), and overall survival. Analysis of single variables and a Cox-proportional hazards model were utilized to determine the impact of pre/posttransplant risk factors on long-term survival. RESULTS From 1984 to 1995, 64 patients (mean age, 8.3 years), 46 of whom had cardiomyopathy and 18 who had inoperable complex congenital heart disease, underwent cardiac transplantation and received triple-drug immunosuppression. Orthotopic transplantation was performed unless the pulmonary vascular resistance index remained >6 um2 (despite use of pulmonary vasodilator). One patient required heterotopic transplantation. Average donor ischemic time was 217 min. An average of 1.2 rejection episodes/patient occurred (average follow-up period: 50 months). No patient developed posttransplant lymphoproliferative disease, but 22 patients (34%) developed CAD. Overall survival was 80%, 60%, and 57% at 1, 5, and 10 years, respectively. Of outcome variables analyzed, rejection frequency was significantly increased in patients who subsequently developed CAD, but the presence of CAD was not significantly correlated with mortality. CONCLUSION Triple-drug-based immunosuppressive maintenance therapy in pediatric heart transplant recipients results in good long-term graft survival.

Erratum: Left ventricular non-compaction cardiomyopathy in children: Characterisation of clinical status using tissue Doppler-derived indices of left ventricular diastolic relaxation (Heart (2007) 93 (676-681))

PHYSICS Correction for “Anomalous expansion of the copper-apicaloxygen distance in superconducting cuprate bilayers,” by Hua Zhou, Yizhak Yacoby, Vladimir Y. Butko, Gennady Logvenov, Ivan Božovi c, and Ron Pindak, which appeared in issue 18, May 4, 2010, of Proc Natl Acad Sci USA (107:8103–8107; first published April 19, 2010; 10.1073/pnas.0914702107). The authors note that due to a printer’s error, the figure legends for Figs. 5, 6, and 7 do not correspond to the proper figure. The figures and their corrected legends appear below.