Haplotype sharing test maps genes for familial cardiomyopathies.

Identifying a mutation in a heterogeneous disease such as inherited cardiomyopathy is a challenge because classical methods, like linkage analysis, can often not be applied as there are too few meioses between affected individuals. However, if affected individuals share the same causal mutation, they will also share a genomic region surrounding it. High-density genotyping arrays are able to identify such regions shared among affected individuals. We hypothesize that the longest shared haplotype is most likely to contain the disease-causing mutation. We applied this method to two pedigrees: one with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one with dilated cardiomyopathy (DCM), using high-density genome-wide SNP arrays. In the ARVC pedigree, the largest haplotype was on chromosome 12 and contained a causative PKP2 mutation. In the DCM pedigree, a causative MYH7 mutation was present on a large shared haplotype on chromosome 14. We calculated that a pedigree containing at least seven meioses has a high chance of correctly detecting the mutation-containing haplotype as the largest. Our data show that haplotype sharing analysis can assist in identifying causative genes in families with low penetrance Mendelian diseases, in which standard tools cannot be used due to lack of sufficient pedigree information.

Founder mutations in the Netherlands: SCN5a 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide.

In this part of a series on founder mutations in the Netherlands, we review a Dutch family carrying the SCN5a 1795insD mutation. We describe the advances in our understanding of the premature sudden cardiac deaths that have accompanied this family in the past centuries. The mutation carriers show a unique overlap of long-QT syndrome (type 3), Brugada syndrome and progressive cardiac conduction defects attributed to a single mutation in the cardiac sodium channel gene SCN5a. It is at present one of the largest and best-described families worldwide and we have learned immensely from the mouse strains with the murine homologue of the SCN5a 1795insD mutation (SCN5a 1798insD). From the studies currently performed we are about to obtain new insights into the phenotypic variability in this monogenic arrhythmia syndrome, and this might also be relevant for other arrhythmia syndromes and the general population. (Neth Heart J 2009;17:422-8.).

Absorption spectra of human fetal and adult oxyhemoglobin, de-oxyhemoglobin, carboxyhemoglobin, and methemoglobin.

We determined the millimolar absorptivities of the four clinically relevant derivatives of fetal and adult human hemoglobin in the visible and near-infrared spectral range (450-1000 nm). As expected, spectral absorption curves of similar shape were found, but the small differences between fetal and adult hemoglobin absorptivity were important enough that they should be taken into account in multicomponent analysis of hemoglobin derivatives. Common pulse oximeters, however, involving light of 660 and 940 nm, are so insensitive to the presence of fetal hemoglobin that they can be used safely in neonates. The error in pulse oximetry caused by the presence of carboxyhemoglobin is insubstantial, but methemoglobin gives either an understimation or an overestimation at high or low oxygen saturation, respectively, the turning point being near 70% saturation.

Dissociation of body weight and lean body mass during cancer chemotherapy.

Body weight and lean body mass are different reflections of the nutritional status of patients receiving cancer chemotherapy. In the present study, the relation between lean body mass and body weight during cytostatic treatment was investigated in 3 groups of newly-diagnosed children and young adults with acute lymphocytic leukemia, osteosarcoma, or a small round cell sarcoma. Body weight and lean body mass were determined before and after an initial period of cytostatic treatment. Lean body mass was derived from total body water volume, which was assessed by deuterium oxide dilution. A significant dissociation between body weight and lean body mass was observed in leukemia patients (n = 8, P = 0.008, paired t-test), and in osteosarcoma patients (n = 13, P = 0.001). No dissociation was found in patients with a small round cell sarcoma (n = 8, P = 0.839). We conclude that during cancer chemotherapy periodic assessment of body weight may give a false picture of the preservation of lean body mass. Considering the course of body weight alone may prevent the establishment of a timely diagnosis of malnutrition, which is mandatory for optimal supportive care.

Estimation of extracellular volume in preterm infants less than 1500 g, children, and adults by sucrose dilution.

Extracellular volume can be estimated from the distribution volume of sucrose (Vdsucrose). The purpose of this study was to establish sucrose pharmacokinetics in preterm infants less than 1500 g compared to children and adults and to define an optimal sampling scheme. In five preterm infants, 10 children, and five adults Vdsucrose after a single injection was calculated with the two-compartment model (Vdsucrose-TCM) and with the one-compartment model applied only to the elimination phase of the same concentration-time curve (Vdsucrose-OCM). In preterm infants Vdsucrose-TCM was 417 +/- 45 mL/kg (mean +/- SD). Vdsucrose-OCM was only 3.0 +/- 2.3% higher, because sucrose elimination half-life was on average 250 times longer than distribution half-life. Therefore Vdsucrose-OCM, requiring only four blood samples between 2 to 5 h after injection, gave an adequate estimate of Vdsucrose in preterm infants less than 1500 g. Vdsucrose-TCM in children and adults was 188 +/- 26 and 189 +/- 17 mL/kg, respectively. Vdsucrose-OCM was 10 to 65% higher. Therefore, in children and adults only Vdsucrose-TCM gives a reliable estimate of Vdsucrose. This requires 10 to 15 blood samples. The reduced sampling scheme was used in an extension of the study of preterm infants including five additional infants. Vdsucrose-OCM in the preterm infants was 462 +/- 47 mL/kg at birth and 425 +/- 46 mL/kg at maximal postnatal wt loss. Postnatal wt loss (mean -83 +/- 44 g) was not significantly different from postnatal reduction of Vdsucrose-OCM (mean -82 +/- 56 mL), suggesting that postnatal wt loss mainly represents extracellular fluid loss.