Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension,lactic acidemia,and failure to thrive

COX5A is a nuclear‐encoded subunit of mitochondrial respiratory chain complex IV (cytochrome c oxidase). We present patients with a homozygous pathogenic variant in the COX5A gene. Clinical details of two affected siblings suffering from early‐onset pulmonary arterial hypertension, lactic acidemia, failure to thrive, and isolated complex IV deficiency are presented. We show that the variant lies within the evolutionarily conserved COX5A/COX4 interface domain, suggesting that it alters the interaction between these two subunits during complex IV biogenesis. In patient skin fibroblasts, the enzymatic activity and protein levels of complex IV and several of its subunits are reduced. Lentiviral complementation rescues complex IV deficiency. The monomeric COX1 assembly intermediate accumulates demonstrating a function of COX5A in complex IV biogenesis. A potential therapeutic lead is demonstrated by showing that copper supplementation leads to partial rescue of complex IV deficiency in patient fibroblasts.     

Choice of surrogate tissue influences neonatal EWAS findings

Background

Epigenomes are tissue specific and thus the choice of surrogate tissue can play a critical role in interpreting neonatal epigenome-wide association studies (EWAS) and in their extrapolation to target tissue. To develop a better understanding of the link between tissue specificity and neonatal EWAS, and the contributions of genotype and prenatal factors, we compared genome-wide DNA methylation of cord tissue and cord blood, two of the most accessible surrogate tissues at birth.

Methods

In 295 neonates, DNA methylation was profiled using Infinium HumanMethylation450 beadchip arrays. Sites of inter-individual variability in DNA methylation were mapped and compared across the two surrogate tissues at birth, i.e., cord tissue and cord blood. To ascertain the similarity to target tissues, DNA methylation profiles of surrogate tissues were compared to 25 primary tissues/cell types mapped under the Epigenome Roadmap project. Tissue-specific influences of genotype on the variable CpGs were also analyzed. Finally, to interrogate the impact of the in utero environment, EWAS on 45 prenatal factors were performed and compared across the surrogate tissues.

Results

Neonatal EWAS results were tissue specific. In comparison to cord blood, cord tissue showed higher inter-individual variability in the epigenome, with a lower proportion of CpGs influenced by genotype. Both neonatal tissues were good surrogates for target tissues of mesodermal origin. They also showed distinct phenotypic associations, with effect sizes of the overlapping CpGs being in the same order of magnitude.

Conclusions

The inter-relationship between genetics, prenatal factors and epigenetics is tissue specific, and requires careful consideration in designing and interpreting future neonatal EWAS.

Trial registration

This birth cohort is a prospective observational study, designed to study the developmental origins of health and disease, and was retrospectively registered on 1 July 2010 under the identifier NCT01174875.

     

Oral health literacy and associated oral conditions: A systematic review

Background

The authors systematically reviewed the scientific evidence regarding an association between oral health literacy (OHL) and oral conditions.

Current challenges in interventional mitral valve treatment

Transcatheter mitral valve therapies have emerged as an alternative option in high surgical risk or inoperable patients with severe and symptomatic mitral regurgitation (MR). As multiple technologies and different approaches will become available in the field of mitral valve interventions, different challenges are emerging, both patient- (clinical challenges) and procedure-related (technical challenges). This review will briefly explore the current open challenges in the evolving fields of interventional mitral valve treatment.     

Detection of Sp110 by Flow Cytometry and Application to Screening Patients for Veno-occlusive Disease with Immunodeficiency

Mutations in Sp110 are the underlying cause of veno-occlusive disease with immunodeficiency (VODI), a combined immunodeficiency that is difficult to treat and often fatal. Because early treatment is critically important for patients with VODI, broadly usable diagnostic tools are needed to detect Sp110 protein deficiency. Several factors make establishing the diagnosis of VODI challenging: (1) Current screening strategies to identify severe combined immunodeficiency are based on measuring T cell receptor excision circles (TREC). This approach will fail to identify VODI patients because the disease is not associated with severe T cell lymphopenia at birth; (2) the SP110 gene contains 17 exons, making it a challenge for Sanger sequencing. The recently developed next-generation sequencing (NGS) platforms that can rapidly determine the sequence of all 17 exons are available in only a few laboratories; (3) there is no standard functional assay to test for the effects of novel mutations in Sp110; and (4) it has been difficult to use flow cytometry to identify patients who lack Sp110 because of the low level of Sp110 protein in peripheral blood lymphocytes. We report here a novel flow cytometric assay that is easily performed in diagnostic laboratories and might thus become a standard assay for the evaluation of patients who may have VODI. In addition, the assay will facilitate investigations directed at understanding the function of Sp110.     

Pixel-Level Deep Segmentation: Artificial Intelligence Quantifies Muscle on Computed Tomography for Body Morphometric Analysis

Pretreatment risk stratification is key for personalized medicine. While many physicians rely on an “eyeball test” to assess whether patients will tolerate major surgery or chemotherapy, “eyeballing” is inherently subjective and difficult to quantify. The concept of morphometric age derived from cross-sectional imaging has been found to correlate well with outcomes such as length of stay, morbidity, and mortality. However, the determination of the morphometric age is time intensive and requires highly trained experts. In this study, we propose a fully automated deep learning system for the segmentation of skeletal muscle cross-sectional area (CSA) on an axial computed tomography image taken at the third lumbar vertebra. We utilized a fully automated deep segmentation model derived from an extended implementation of a fully convolutional network with weight initialization of an ImageNet pre-trained model, followed by post processing to eliminate intramuscular fat for a more accurate analysis. This experiment was conducted by varying window level (WL), window width (WW), and bit resolutions in order to better understand the effects of the parameters on the model performance. Our best model, fine-tuned on 250 training images and ground truth labels, achieves 0.93 ± 0.02 Dice similarity coefficient (DSC) and 3.68 ± 2.29% difference between predicted and ground truth muscle CSA on 150 held-out test cases. Ultimately, the fully automated segmentation system can be embedded into the clinical environment to accelerate the quantification of muscle and expanded to volume analysis of 3D datasets.     

Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging

Objectives: We sought to determine cardiac morphological and functional differences between light-chain (AL), mutant-type transthyretin (ATTRmt) and wild-type TTR (ATTRwt) amyloidosis using contrast-enhancement cardiac magnetic resonance imaging (CE-CMR). Finally, we attempted to establish the diagnostic and prognostic impact of these findings. Introduction: The most common forms of cardiac amyloid are AL and ATTR amyloidosis, but the clinical courses of these variants are quite heterogeneous. While CE-CMR is used to evaluate patients with cardiac amyloidosis, its ability to predict prognosis in these patients is debatable.

Methods: About 130 patients with cardiac amyloidosis (AL, n?=?62; ATTRmt, n?=?30, ATTRwt, n?=?33) were assessed by CE-CMR (cardiac morphology, cardiac function, late gadolinium enhancement).

Results: Left ventricular (LV) mass, basal and mid-ventricular maximal wall thickness, and thickness of the inter-atrial septum were higher in ATTRwt when compared to AL and ATTRmt amyloidosis. Tricuspid annular excursion was lower in ATTRwt amyloidosis than in AL amyloidosis. CE was observed in 94.6% of the patients (AL 80.6%; ATTRmt 90%; ATTRwt 87.9%) with significant differences in quality and intensity between the groups. Differentiation of amyloid types was achieved by combination of age, number of organs, the presence of inferolateral CE-CMR, thickness of inter-atrial septum and troponin T. Overall 1-year-survival rates were 93.3, 93.9 and 70.5% in ATTRwt, ATTRmt and AL amyloidosis, respectively. LV mass, mitral annular excursion and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness and troponin T in ATTRwt amyloidosis, and finally NT-proBNP and renal function in ATTRmt amyloidosis were independent predictors of outcome.

Conclusions: This study demonstrates that CE-CMR can highlight morphological and functional differences between different types of cardiac amyloidosis. In addition, CE-CMR and cardiac biomarkers provide useful prognostic information in patients with cardiac amyloidosis.     

Primary preventive cardioverter‐defibrillator implantation (Pro‐ICD) in patients awaiting heart transplantation. A prospective,randomized, controlled 12‐year follow‐up study

The aim of this study was to evaluate whether short‐term primary preventive cardioverter‐defibrillator (ICD) implantation as bridge to heart transplantation (HTX) provides any survival benefit. Thirty‐three patients awaiting HTX were randomized to either conventional therapy (control group) or primary preventive ICD implantation (ICD group). Fourteen patients had ischemic cardiomyopathy (ICM) and 19 patients had dilated cardiomyopathy (DCM). Sixteen patients were randomized to the ICD group and 17 patients were randomized to the control group. Twenty patients (61%) were transplanted after a waiting time of 10 ± 9 months. The remaining 13 patients (39%) were not transplanted because of clinical improvement (n = 5), cerebral hemorrhage (n = 3), or death (n = 5). On the waiting list, 3 ICD patients with DCM developed slow VTs without ICD intervention, two patients with ICM (6%) had fast VT terminated by the ICD, and no arrhythmic death was observed. After 11.9 years (median), 13 of 20 HTX patients (65%) and 5 of 13 non‐HTX patients (38%) were alive. Survivors had a higher LVEF (22 ± 6 vs. 17 ± 4%, P = 0.0092) and a better exercise capacity (75 ± 29 vs. 57 ± 24 Watt, P = 0.0566) at baseline as compared to nonsurvivors. This study may not support the general use of primary preventive ICDs as a short‐term bridge to heart transplantation.