Nico A. Blom

GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.

Rhizomelic chondrodysplasia punctata and cardiac pathology

Background Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive peroxisomal disorder characterised by rhizomelia, contractures, congenital cataracts, facial dysmorphia, severe psychomotor defects and growth retardation. Biochemically, the levels of plasmalogens (major constituents of cellular membranes) are low due to a genetic defect in their biosynthesis. Cardiac muscle contains high concentrations of plasmalogens. Recently cardiac dysfunction was found in a mouse model for RCDP with undetectable plasmalogen levels in all tissues including the heart. This suggests the importance of plasmalogens in normal cardiac development and function. Congenital heart disease (CHD), however, has not been recognised as a major characteristic of RCDP. Aims We aimed to determine the prevalence of CHD found in RCDP patients as well as to describe genetic, biochemical and cardiac correlations. Methods We included 23 patients with genetically proven RCDP. The genetic, biochemical and physical data were evaluated. Echocardiograms were reviewed. Results Cardiac data were available for 18 patients. 12 (52%) had CHD. All twelve had type 1 RCDP and 11 (92%) had the PEX 7:c.875T>A mutation, of whom seven were homozygous (58%). Plasmalogen levels were significantly lower in the patients with CHD. Cardiac lesions included: septal defects (80% atrial), patent ductus arteriosus, pulmonary artery hypoplasia, tetralogy of Fallot and mitral valve prolapse (mostly older patients). Conclusions The CHD prevalence among RCDP patients was at least 52%, significantly higher than among the normal population. Plasmalogen levels were significantly lower in patients with CHD. Routine cardiac evaluation should be included in the clinical management of RCDP patients.

Prenatal diagnosis of congenital heart defects: accuracy and discrepancies in a multicenter cohort

To examine the accuracy of fetal echocardiography in diagnosing congenital heart disease (CHD) at the fetal medicine units of three tertiary care centers.

Mid-term results of bidirectional cavopulmonary anastomosis and hemi-Mustard procedure in anatomical correction of congenitally corrected transposition of the great arteries †

OBJECTIVESnThe Senning or Mustard procedure combined with the arterial switch operation (ASO) (± VSD and no left ventricular (LV) outflow tract obstruction) or the Rastelli operation (VSD and LV outflow tract obstruction) has become the preferred strategy over conventional repair as it is thought to prevent long-term dysfunction of the right ventricle (RV). More recently, hemi-Mustard rerouting of blood from the inferior vena cava to the RV in combination with bidirectional cavopulmonary anastomosis (BCPA) has been adopted by some centres for potential benefits over the classic atrial switch procedure. The aim of this study was to analyse our experience with hemi-Mustard and BCPA as part of an anatomical repair of congenitally corrected transposition of the great arteries (CCTGA) in selected patients.nnnMETHODSnBetween 2004 and 2011, eight patients underwent hemi-Mustard/BCPA with the Rastelli operation (n = 6) or ASO (n = 2). The median age was 2.9 (range: 1.2-9.1) years. Positional anomalies were present in 75% of the patients. Both patients with ASO had dysplastic and insufficient tricuspid valves. In the Rastelli group, four patients had previously received shunts followed by BCPA in one patient. In the ASO group, both patients underwent pulmonary artery banding initially.nnnRESULTSnThere was one in-hospital death and no late mortality. Two patients received a pacemaker. One patient from the Rastelli group required conduit change 6 years later. At the mean follow-up of 4.5 years, six and one patients are in NYHA classes I and II, respectively; six patients showed good biventricular function, while one had LV dysfunction. Systemic venous obstruction and sinus node dysfunction were not observed, and BCPA was functioning well in all patients.nnnCONCLUSIONSnHemi-Mustard/BCPA is useful in anatomical repair of CCTGA in selected patients. When compared with the classic atrial switch operation, it is technically easier which makes it especially helpful in atrio-apical discordance; it unloads an RV with limited size or function, and avoids complications related to the upper limb of the classic atrial switch procedure. Mid-term results of this approach are favourable. Further follow-up is needed to prove long-term benefits.

Systematic review and meta-analysis of the performance of second-trimester screening for prenatal detection of congenital heart defects

The prenatal detection rate of congenital heart defects (CHDs) is increasing, but reported rates vary.

Diastolic dysfunction measured by tissue Doppler imaging in children with end-stage renal disease: a report of the RICH-Q study

INTRODUCTIONnEarly detection of cardiovascular disease in children with end-stage renal disease is essential in order to prevent cardiovascular morbidity and mortality in early adulthood. Tissue Doppler imaging has shown to be a promising method to detect and quantify subtle abnormalities in diastolic function. We therefore compared assessment of diastolic function by conventional echocardiography and tissue Doppler imaging.nnnMETHODSnWe performed conventional echocardiography and tissue Doppler imaging in 38 children with end-stage renal disease and 76 healthy controls. We compared outcomes on parameters related to diastolic function (E/a ratio for conventional echocardiography and E/E ratio for tissue Doppler imaging) for both groups using multiple linear regression analysis. Diastolic dysfunction was defined as E/a ratio <1 or E/E ratio > 95th percentile for age. To assess the intra-observer reproducibility, the coefficient of variation was calculated.nnnRESULTSnChildren with end-stage renal disease had on average a lower E/a ratio (p = 0.004) and a higher mitral and septal E/E ratio (both p < 0.001) compared with controls. In all, two children with end-stage renal disease (5%) had diastolic dysfunction according to the E/a ratio, 11 according to the mitral E/E ratio (29%), and 16 according to the septal E/E ratio (42%) compared with none of the controls (p = 0.109, p < 0.001, and p < 0.001, respectively). The coefficients of variation of the mitral (7%) and septal E/E ratio (4%) were smaller than the coefficient of variation of the E/a ratio (11%).nnnCONCLUSIONSnTissue Doppler imaging is a more sensitive and reliable method to detect diastolic dysfunction than conventional E/a ratio in children with end-stage renal disease.

Effect of age and gender on the QTc-interval in healthy individuals and patients with long-QT syndrome

Age- and gender-related differences in QTc-interval are most likely the result of changes in sex-specific hormones. Although the exact mechanisms and pathophysiology of sex hormones on the QTc-interval are not known, testosterone appears to shorten the QTc-interval. In females, however, there is a more complex interaction between progesterone and estrogen. In patients with an impaired repolarization, such as long-QT syndrome (LQTS), the effect of these sex hormones on the QTc-interval is more pronounced with a differing sensitivity between the LQTS genotypes.

Chromosomal abnormalities and copy number variations in fetal left-sided congenital heart defects

To demonstrate the spectrum of copy number variants (CNVs) in fetuses with isolated left‐sided congenital heart defects (CHDs), and analyse genetic content.

A Potential Diagnostic Approach for Foetal Long-QT Syndrome, Developed and Validated in Children

In patients with Long-QT Syndrome (LQTS), mechanical abnormalities have been described. Recognition of these abnormalities could potentially be used in the diagnosis of LQTS, especially in the foetus where an ECG is not available and DNA-analysis is invasive. We aimed to develop and validate a marker for these mechanical abnormalities in children and to test its feasibility in foetuses as a proof of principle. We measured the myocardial contraction duration using colour Tissue Doppler Imaging (cTDI) in 41 LQTS children and age- and gender-matched controls. Children were chosen to develop and validate the measurement of the myocardial contraction duration, due to the availability of a simultaneously recorded ECG. Feasibility of this measurement in foetuses was tested in an additional pilot study among seven LQTS foetuses and eight controls. LQTS children had a longer myocardial contraction duration compared to controls, while there was no statistical difference in heart rate. Measuring the myocardial contraction duration in children had a high inter- and intra-observer validity and reliably correlated with the QT-interval. There was an area under the curve (AUC) of 0.71, and the optimal cut-off value showed an especially high specificity in diagnosing LQTS. Measuring the myocardial contraction duration was possible in all foetuses and had a high inter- and intra-observer validity (ICCu2009=u20090.71 and ICCu2009=u20090.88, respectively). LQTS foetuses seemed to have a longer myocardial contraction duration compared to controls. Therefore, a prolonged contraction duration may be a potential marker for the prenatal diagnosis of LQTS in the future. Further studies are required to support the measurement of the myocardial contraction duration as a diagnostic approach for foetal LQTS.

Pregnancy complications in singleton pregnancies with isolated fetal heart defects

As the prenatal detection rates of congenital heart defects (CHDs) increase, obstetricians are more frequently faced with pregnancies complicated by a fetal CHD. Congenital anomalies in general are associated with preterm birth and fetal demise. The aim of this study was to gain insight into the prevalence of preterm birth and fetal demise in singleton pregnancies with fetuses with isolated CHDs.