Heterotaxy Syndrome

Primary Ciliary Dyskinesia - An Update on the Genetics of Underlying Pathological Mechanisms

One of the rapidly growing groups of diseases known as ciliopathies is primary ciliary dyskinesia (PCD), a rare hereditary illness of the motile cilia. Different clinical symptoms of primary ciliary dyskinesia include infertility, left-right lateralization abnormalities, and chronic upper and lower respiratory tract disorders. Our knowledge of the genetics underlying primary ciliary dyskinesia has significantly increased in recent years. Involved in the formation, shape, and operation of motile cilia are axonemal, cytoplasmic, and regulatory proteins that are encoded by a rising number of disease-associated genes and pathogenic mutations. We now have a better grasp of the clinical signs and symptoms of motile ciliopathies because of advances in our understanding of cilia genetics and the function of the proteins expressed. These developments have altered how we approach primary ciliary dyskinesia diagnostic testing. The clinical characteristics of primary ciliary dyskinesia, the evolution of diagnostics, and the discovery of previously unknown genotype-phenotype connections in primary ciliary dyskinesia will all be covered in this review paper.

Perinatal Outcome in Pregnant Women with Heart Disease

With improved technology and better access to health care, the number of pregnant women with heart diseases is increasing. Due to various physiological changes in pregnancy, women with heart diseases are at increased risk of both maternal and fetal complications. Thus, pregnancy with heart disease is considered a high-risk pregnancy. In the near future, the burden on the healthcare system will increase and we will be required to answer various questions about the different outcomes possible and their management. If women are made aware of the various risks associated with their pregnancies, they can make informed life choices. This can only be achieved if more objective data is offered to her [1]. In this article, we review the available data on the observed perinatal outcomes in mothers with heart disease, their management, and what lacunas need to be filled, so as to be able to provide better care. Relevant articles were referred and data was summed. We concluded that in the majority of studies, the odds for adverse neonatal outcomes like preterm birth, low birth weight, stillbirth, low Apgar score and admissions to neonatal intensive care unit were higher among pregnant women with heart disease as compared to women with no heart disease.

Physiological Properties, Functions, and Trends in the Matrix Metalloproteinase Inhibitors in Inflammation-Mediated Human Diseases

Background: Matrix metalloproteinases (MMPs), also known as metalloproteinases, are enzymes that degrade proteins and require the presence of active metal atoms. There are more than 20 types of MMPs, and they promote cell migration through the proteolytic degradation of the extracellular basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM). In other words, they decompose most of the components related to the ECM, in their roles as key enzymes in cellular and pathophysiological events in the body.

Introduction: Zn²⁺-containing endo-type peptidases directly degrade and remodel the ECM region in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins in the ECM and the basement membranous region, which are the supporting structures of cells.

Methods: This review describes the developments in the research examining the general and selective inhibitors for MMP associated with various human diseases over the past 20 years in terms of structure remodeling, substrate-recognizing specificities, and pharmacological applicability.

Results: Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa, while MMP-9 is termed gelatinase-B with a 92 kDa. Both of these play a key role in this action. Therefore, both enzymatic expression levels coincide during the onset and progression of diseases. Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP- 9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance that inhibits MMPs would be very important for preventing and treating various MMP-dependent diseases.

Conclusion: Considerable research has examined MMP inhibitors, but most of these have been synthetic compounds. Research using natural products as MMP inhibitors has only recently become a subject of interest. This review intends to discuss recent research trends regarding the physiological properties, functions, and therapeutic agents related to MMPs.

Modeling Neuronal Diseases in Zebrafish in the Era of CRISPR

Background: Danio rerio is a powerful experimental model for studies in genetics and development. Recently, CRISPR technology has been applied in this species to mimic various human diseases, including those affecting the nervous system. Zebrafish offer multiple experimental advantages: external embryogenesis, rapid development, transparent embryos, short life cycle, and basic neurobiological processes shared with humans. This animal model, together with the CRISPR system, emerging imaging technologies, and novel behavioral approaches, lay the basis for a prominent future in neuropathology and will undoubtedly accelerate our understanding of brain function and its disorders.

Objective: Gather relevant findings from studies that have used CRISPR technologies in zebrafish to explore basic neuronal function and model human diseases.

Methods: We systematically reviewed the most recent literature about CRISPR technology applications for understanding brain function and neurological disorders in D. rerio. We highlighted the key role of CRISPR in driving forward our understanding of particular topics in neuroscience.

Results: We show specific advances in neurobiology when the CRISPR system has been applied in zebrafish and describe how CRISPR is accelerating our understanding of brain organization.

Conclusion: Today, CRISPR is the preferred method to modify genomes of practically any living organism. Despite the rapid development of CRISPR technologies to generate disease models in zebrafish, more efforts are needed to efficiently combine different disciplines to find the etiology and treatments for many brain diseases.

NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment

Approximately 25-50 million Americans, 30 million Europeans, and 8% of the Australian population have a rare disease. Rare diseases are thus a common problem for clinicians and account for enormous healthcare costs worldwide due to the difficulty of establishing a specific diagnosis. In this article, we review the milestones achieved in our understanding of rare diseases since the emergence of next-generation sequencing (NGS) technologies and analyze how these advances have influenced research and diagnosis. The first half of this review describes how NGS has changed diagnostic workflows and provided an unprecedented, simple way of discovering novel disease-associated genes. We focus particularly on metabolic and neurodevelopmental disorders. NGS has enabled cheap and rapid genetic diagnosis, highlighted the relevance of mosaic and de novo mutations, brought to light the wide phenotypic spectrum of most genes, detected digenic inheritance or the presence of more than one rare disease in the same patient, and paved the way for promising new therapies. In the second part of the review, we look at the limitations and challenges of NGS, including determination of variant causality, the loss of variants in coding and non-coding regions, and the detection of somatic mosaicism variants and epigenetic mutations, and discuss how these can be overcome in the near future.

Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.

Changing Faces of Transcriptional Regulation Reflected by Zic3

The advent of genomics in the study of developmental mechanisms has brought a trove of information on gene datasets and regulation during development, where the Zic family of zinc-finger proteins plays an important role. Genomic analysis of the modes of action of Zic3 in pluripotent cells demonstrated its requirement for maintenance of stem cells pluripotency upon binding to the proximal regulatory regions (promoters) of genes associated with cell pluripotency (Nanog, Sox2, Oct4, etc.) as well as cell cycle, proliferation, oncogenesis and early embryogenesis. In contrast, during gastrulation and neurulation Zic3 acts by binding the distal regulatory regions (enhancers, etc) associated with control of gene transcription in the Nodal and Wnt signaling pathways, including genes that act to break body symmetry. This illustrates a general role of Zic3 as a transcriptional regulator that acts not only alone, but in many instances in conjunction with other transcription factors. The latter is done by binding to adjacent sites in the context of multi-transcription factor complexes associated with regulatory elements.

Congenital Heart Disease: The Crossroads of Genetics, Epigenetics and Environment

Congenital heart diseases (CHDs) are recognized as the most common type of birth malformations. Although recent advances in pre- and neonatal diagnosis as well as in surgical procedures have reduced the morbidity and mortality for many CHD, the etiology for CHD remains undefined. In non-syndromic and isolated (without a familial history or a Mendelian inheritance) forms of CHDs, a multifactorial pathogenesis with interplay between inherited and non-inherited causes is recognized. In this paper, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal cardiac development in non-syndromic and isolated CHD, including mutations in cardiac transcription factors, the role of somatic mutations and epigenetic alterations as well as the influence of gene-environment interactions. In the near future, the advent of high-throughput genomic technologies with the integration of system biology will expand our understanding of isolated, non-syndromic CHDs for their prevention, early diagnosis and therapy.

Resuscitation of the Patient with the Functionally Univentricular Heart

Neonates and infants with functional single ventricle anatomy face nearly certain early mortality without cardiac transplantation or successive palliation through a pathway of staged interventions. Patients with single ventricle variants typically have multiple hospitalizations and high incidence of cardiac arrest. Few studies have directly addressed the physiology, pharmacology, techniques or outcomes of resuscitation of this high-risk group. The unique challenge posed by resuscitation of this patient group was recently recognized within the 2010 International Liaison Committee on Resuscitation consensus statement, where, for the first time, two worksheets were devoted exclusively to the resuscitation of the single ventricle patient before and after S1P and those patients with bidirectional Glenn/hemi-Fontan and Fontan physiology. This article will review the consensus on science, treatment recommendations, and areas of uncertainty in the resuscitation of the infants and children with single ventricle physiology during each stage of surgical repair.

The Patient with a Single Cardiac Ventricle

Patients born with a single cardiac ventricle are one of the most complex and challenging subgroups of congenital heart disease to manage, from their initial diagnosis to their long-term post-surgical sequelae. Advances in antenatal detection, operative techniques, and post-operative strategies have led to improved outcomes over the past two decades, yet morbidity and mortality remain high relative to other congenital heart lesions. Optimal management and outcome depend in part on a thorough understanding of the anatomy and physiology unique to these infants by all caregivers that may be involved including neonatologists, primary care pediatricians, emergency medicine physicians, and pediatric intensivists. This review will discuss in detail the course of these infants, from their birth through to their three stage surgical palliations and beyond. This review will also highlight many of the most recent medical and surgical innovations available to these infants.

Indications for Heart Transplantation in Congenital Heart Disease

In this review we have looked at indications for cardiac transplantation in congenital heart disease. An outline of the general principles of the use of transplant as a management strategy both as a first line treatment and following other surgical interventions is discussed. We explore the importance of the timing of patient referral and the evaluations undertaken, and how the results of these may vary between patients with congenital heart disease and patients with other causes of end-stage heart failure. The potential complications associated with patients with congenital heart disease need to be both anticipated and managed appropriately by an experienced team. Timing of transplantation in congenital heart disease is difficult to standardize as the group of patients is heterogeneous. We discuss the role and limitations of investigations such as BNP, 6 minute walk, metabolic exercise testing and self estimated physical functioning. We also discuss the suitability for listing. It is clear that congenital heart patients should not be considered to be at uniform high risk of death at transplant. Morbidity varies greatly in the congenital patient population with the failing Fontan circulation having a far higher risk than a failing Mustard circulation. However the underlying issue of imbalance between donor organ supply and demand needs to be addressed as transplant teams are finding themselves in the increasingly difficult situation of supporting growing numbers of patients with a diverse range of pathologies with declining numbers of donor organs.

Orthotopic Heart Transplantation in Patients with Univentricular Physiology

Parallel advancements in surgical technique, preoperative and postoperative care, as well as a better understanding of physiology in patients with duct-dependent pulmonary or systemic circulation and a functional single ventricle, have led to superb results in staged palliation of most complex congenital heart disease (CHD) [1]. The Fontan procedure and its technical modifications have resulted in markedly improved outcomes of patients with single ventricle anatomy [2,3,4]. The improved early survival has led to an exponential increase of the proportion of Fontan patients surviving long into adolescence and young adulthood [5]. Improved early and late survival has not yet abolished late mortality secondary to myocardial failure, therefore increasing the referrals for cardiac transplantation [6]. Interstage attrition [7] is moreover expected in staged palliation towards completion of a Fontan-type circulation, while Fontan failure represents a growing indication for heart transplantation [8]. Heart transplantation has therefore become the potential “fourth stage” [9] or a possible alternative to a high-risk Fontan operation [10] in a strategy of staged palliation for single ventricle physiology. Heart transplant barely accounts for 16% of pediatric solid organ transplants [11]. The thirteenth official pediatric heart transplantation report- 2010 [11] indicates that pediatric recipients received only 12.5% of the total reported heart transplants worldwide. Congenital heart disease is not only the most common recipient diagnosis, but also the most powerful predictor of 1-year mortality after OHT. Results of orthotopic heart transplantations (OHT) for failing single ventricle physiology are mixed. Some authors advocate excellent early and mid-term survival after OHT for failing Fontan [9], while others suggest that rescue-OHT after failing Fontan seems unwarranted [10]. Moreover, OHT outcome appears to be different according to the surgical staging towards the Fontan operation and surgical technique of Fontan completion [12].

The focus of this report is a complete review of the recent literature on OHT for failing single ventricles, outlining the clinical issues affecting Fontan failure, OHT listing and OHT outcome. These data are endorsed reporting our experience with OHT for failing single ventricle physiology in recent years.

Heart Transplantation in Biventricular Congenital Heart Disease: Indications, Techniques, and Outcomes

Heart transplantation is an accepted therapeutic modality for end-stage congenital heart disease for both biventricular and univentricular anomalies. Many transplant centers have pushed the limits of transplantation to include patients with high pulmonary vascular resistance, high panel reactive antibodies, positive cross-matches, and ABOincompatibility. Excellent results have been possible, particularly with the development of improved diagnostic and therapeutic algorithms to prevent and treat rejection, infection, and post-transplant lymphoproliferative disease. Late graft failure and chronic rejection remain vexing problems. The vast majority of patients with biventricular congenital heart disease have undergone prior cardiac surgical procedures. Indications for transplantation in this subgroup are primarily progressive refractory heart failure following prior cardiac surgical reconstructive procedures. Contraindications to transplantation mimic those for other forms of end-stage heart disease. A determination of pulmonary vascular resistance is important in listing patients with biventricular congenital heart disease for heart transplantation. Modifications in the implant technique are necessary and vary depending on underlying recipient anatomy. Risk factors for perioperative outcomes in patients with biventricular congenital heart disease include the need for reoperation, the degree of anatomic reconstruction necessary during the implant procedure, and the degree of antibody sensitization, in addition to a number of other recipient and donor factors. Postoperative outcomes and survival are very good but remain inferior to those with cardiomyopathy in most series. In conclusion, patients with end-stage biventricular congenital heart disease represent a complex group of patients for heart transplantation, and require careful evaluation and management to ensure optimal outcomes.

Arrhythmias and Left Ventricular Hypertrabeculation/Noncompaction

Arrhythmias in left ventricular hypertrabeculation/noncompaction (LVHT) comprise sustained or non-sustained ventricular tachycardia (VT) (n=135), atrial fibrillation (AF) (n=96) AV block (n=55) and QT prolongation (n=47). The prevalence differs between children and adults. In children most frequent are WPW-syndrome (n=24), AV block (n=24), VT (n=17) and bradycardia (n=15). In adults most frequent arrhythmias are VT (n=118), AF (n=95), QT prolongation (n=42) and AV block (n=31). Some arrhythmias are more frequently reported in children than in adults like WPW-syndrome (24 vs. 17 patients), second-degree AV block (4 vs. 0 patients), bradycardia (15 vs. 3 patients) and ventricular fibrillation (VF) (9 vs. 5 patients). There are nearly no pediatric cases with AF (1 vs. 95 patients). In 120 patients implantable cardioverters/defibrillators have been implanted for primary or secondary prevention of sudden cardiac death. The pathomechanisms of arrhythmias in LVHT are largely unknown, especially if patients with LVHT and neuromuscular disorders are more prone to arrhythmias than patients without. There is a need to clarify risk factors for VT or VF because 19% of LVHT patients with VT or VF have a normal systolic function and demonstration of systolic dysfunction is no reliable risk marker. Data about long-term follow- up of LVHT patients with implanted cardioverters/defibrillators are necessary since the indication for prophylactic implantation is still unclear. AF in LVHT increases the embolic risk, thus it would be useful to know which LVHT patients who have sinusrhythm at baseline are prone to develop AF in order to start early with anticoagulant therapy.

Genetics of Congenital Heart Disease

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown but genetic factors are being recognized as playing an increasingly important role. Advances in our molecular understanding of normal heart development have led to the identification of numerous genes necessary for cardiac morphogenesis. This work has aided the discovery of an increasing number of monogenic causes of human cardiovascular malformations. More recently, studies have identified single nucleotide polymorphisms and submicroscopic copy number abnormalities as having a role in the pathogenesis of congenital heart disease. This review discusses these discoveries and summarizes our increasing understanding of the genetic basis of congenital heart disease.