Genetic causes of inherited cardiac hypertrophy: Robert L. Frye Lecture

Cardiac hypertrophy is well recognized as a cardiac manifestation of systemic disorders such as hypertension or intrinsic myocardial disease, but it can also reflect an underlying genetic defect. Molecular studies of inherited forms of cardiac hypertrophy have defined 2 novel pathways that lead to cardiac remodeling in adults, discoveries that increasingly provide insights relevant for both diagnosis and management. This article reviews the genetic studies that led to the current molecular understanding of hypertrophic cardiomyopathy and discusses more recently discovered causes of inherited cardiac hypertrophy.     

Genetics of dementia

Many neurodegenerative diseases are exceedingly complex disorders (Fig. 6). In the past decade, we have made tremendous advances in our understanding [figure: see text] of the genetic basis of these disorders. One common characteristic of these disorders is the existence of rare families in which a given disease is inherited as a Mendelian trait. In this article, we have reviewed the genetics of several common neurodegenerative disorders that are associated with cognitive disturbances and for which causative genes have been identified. Further genetic analysis should clarify the roles of known genes in the pathogenesis of common sporadic forms of these various diseases. Investigation of the normal and aberrant functions of these genes should provide insight into the underlying mechanisms of these disorders. Such research should facilitate new strategies for therapeutic interventions. Although molecular genetics has helped to clarify the etiology of these disorders, clinicians have played a critical role in the careful identification and classification of many families who were involved in the eventual mapping and cloning of causative mutations. The role of the clinician should not be underestimated. Future clinical and molecular genetics findings hold many clinical implications. It is likely that new diagnostic and therapeutic strategies for dementing disorders are just on the horizon.     

Genetics of inherited cardiomyopathies

Cardiomyopathies are the most common disorders resulting in heart failure, with dilated cardiomyopathy being responsible for the majority of cases. Other forms of cardiomyopathy, especially hypertrophic forms, are also important causes of heart failure. The mortality rate due to cardiomyopathy in the USA is over 10,000 deaths per year, and the costs associated with heart failure are approximately US$200 million per year in the USA alone. Over the past few years, breakthroughs have occurred in understanding the basic mechanisms of these disorders, potentially enabling clinicians to devise improved diagnostic strategies and therapies. As at least 30 to 40% of cases are inherited, it is now imperative that the genetic basis for these disorders is clearly recognized by caregivers and scientists. However, it has also become clear that these diseases are genetically highly heterogeneous, with multiple genes identified for each of the major forms of cardiomyopathy, and most patients having private mutations. These data suggest that the genetic diagnosis of most patients with cardiomyopathy will be impractical with current technologies. However, there are a few exceptions, such as patients with X-linked cardiomyopathies, with or without the concomitant abnormalities of cyclic neutropenia and 3-methylglutaconic aciduria, or patients with cardiomyopathy associated with conduction disease: these appear to be associated with mutations in a small subset of genes, and can be investigated by certified diagnostic laboratories. This review will summarize current knowledge of the genetics of inherited cardiomyopathies and how findings from research laboratories may be translated into the diagnostic laboratory.     

Magnetic resonance spectroscopy and metabolic imaging in white matter diseases and pediatric disorders

This review provides the reader with an overview of the magnetic resonance spectroscopy technique and the clinical, pathological, imaging, and metabolic features for select white matter disorders of interest. With this composite summary, the reader should find it easier to implement and interpret spectroscopy in the clinical setting for the diagnosis and monitoring of patients with white matter disorders.     

Genetics of inherited cardiomyopathies

Cardiomyopathies are the most common disorders resulting in heart failure, with dilated cardiomyopathy being responsible for the majority of cases. Other forms of cardiomyopathy, especially hypertrophic forms, are also important causes of heart failure. The mortality rate due to cardiomyopathy in the USA is over 10,000 deaths per year, and the costs associated with heart failure are approximately 200 million US dollars per year in the USA alone. Over the past few years, breakthroughs have occurred in understanding the basic mechanisms of these disorders, potentially enabling clinicians to devise improved diagnostic strategies and therapies. As at least 30 to 40% of cases are inherited, it is now imperative that the genetic basis for these disorders is clearly recognized by caregivers and scientists. However, it has also become clear that these diseases are genetically highly heterogeneous, with multiple genes identified for each of the major forms of cardiomyopathy, and most patients having private mutations. These data suggest that the genetic diagnosis of most patients with cardiomyopathy will be impractical with current technologies. However, there are a few exceptions, such as patients with X-linked cardiomyopathies, with or without the concomitant abnormalities of cyclic neutropenia and 3-methylglutaconic aciduria, or patients with cardiomyopathy associated with conduction disease: these appear to be associated with mutations in a small subset of genes, and can be investigated by certified diagnostic laboratories. This review will summarize current knowledge of the genetics of inherited cardiomyopathies and how findings from research laboratories may be translated into the diagnostic laboratory.     

The genetics of cardiac disease associated with sudden cardiac death: a paper from the 2011 william beaumont hospital symposium on molecular pathology

Sudden cardiac death due to ventricular arrhythmia most commonly occurs in the setting of coronary artery disease. However, a number of inherited syndromes have now been identified that carry a significant risk of sudden cardiac death and that are disproportionately represented in the young. Arrhythmia in such conditions may result from genetically mediated structural heart disease (eg, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy) or from altered function of cardiac ion channels in the absence of overt structural disease (eg, Brugada syndrome and long QT syndrome). The past 15 years have seen considerable progress in our understanding of the genetic underpinnings of these disorders. With the advent of clinical genetic testing as a routine part of clinical care, a new knowledge base is required of practicing cardiologists and genetic testing facilities, particularly related to the rational ordering of genetic testing and the interpretation of results. This review addresses the latest findings in regard to the genetic causes of inherited syndromes associated with sudden cardiac death and summarizes recently published guidelines for the genetic testing of affected individuals and their families.     

Multiple sclerosis: update in diagnosis and review of prognostic factors

The cornerstone of the diagnosis of multiple sclerosis is the neurologic history and examination. Support for the diagnosis as well as aid in the exclusion of other disorders can be obtained from other investigations. Analysis of cerebrospinal fluid can provide evidence of a central nervous system inflammatory process; evoked potential studies can provide evidence of subclinical multifocal involvement of the central nervous system. Magnetic resonance imaging can reveal dissemination of white matter lesions and help in the exclusion of other neurologic disorders. These tests have been incorporated into the modern diagnostic criteria for multiple sclerosis. The natural history of multiple sclerosis is variable; accordingly, early in the clinical course of the disorder, predicting the prognosis for a specific patient is usually difficult. Nevertheless, some features have limited predictive value.     

Biochemistry and molecular genetics of muscle diseases

The inherited skeletal muscle diseases form a highly heterogeneous group of disorders covering single enzyme defects, complex metabolic disorders, storage diseases, dystrophies and malignant hyperthermia. Whereas these myopathies may be caused by a large number of different biochemical and genetic defects their clinical presentation by contrast is relatively monotonous. with only a few specific findings pointing to a particular molecular defect. This review of the biochemical and molecular genetic basis of these diseases concentrates on 1) disorders in fuel utilization and energy production. 2) disorders in structural integrity or mechanical function, and 3) disorders in contractility and electrophysiological properties of the muscle cell. The authors address the questions of organ-specificity and of a possible relationship between clinical, biochemical, and genetic heterogeneity of metabolic defects, and also try to present the current state of chromosome mapping for such disorders.     

Aminoglycoside-induced translational read-through in disease: overcoming nonsense mutations by pharmacogenetic therapy

A third of inherited diseases result from premature termination codon mutations. Aminoglycosides have emerged as vanguard pharmacogenetic agents in treating human genetic disorders due to their unique ability to suppress gene translation termination induced by nonsense mutations. In preclinical and pilot clinical studies, this therapeutic approach shows promise in phenotype correction by promoting otherwise defective protein synthesis. The challenge ahead is to maximize efficacy while preventing interaction with normal protein production and function.     

Inherited Platelet Disorders: Diagnosis and Management

Inherited platelet disorders are rare but they can have considerable clinical impacts, and studies of their causes have advanced understanding of platelet formation and function. Effective hemostasis requires adequate circulating numbers of functional platelets. Quantitative, qualitative and combined platelet disorders with a bleeding phenotype have been linked to defects in platelet cytoskeletal elements, cell surface receptors, signal transduction pathways, secretory granules and other aspects. Inherited platelet disorders have variable clinical presentations, and diagnosis and management is often challenging. Evaluation begins with detailed patient and family histories, including a bleeding score. The physical exam identifies potential syndromic features of inherited platelet disorders and rules out other causes. Laboratory investigations include a complete blood count, blood film, coagulation testing and Von Willebrand factor assessment. A suspected platelet function disorder is further assessed by platelet aggregation, flow cytometry, platelet dense granule release and/or content, and genetic testing. The management of platelet function disorders aims to minimize the risk of bleeding and achieve adequate hemostasis when needed. Although not universal, platelet transfusion remains a crucial component in the management of many inherited platelet disorders.     

The diagnosis of genetic disorders before birth.

Genetic disorders account for a significant number of the health care problems in our society. Advances in therapy and educational opportunities for the handicapped have increased both the life span and quality of life for many of those affected by genetic disorders. Recent developments in clinical and laboratory genetics have made possible the better delineation of certain malformation and/or mental retardation syndromes, so that their mode of inheritance can be understood. This information enables the genetic counselor to predict the risk for occurrence of a large number of genetic disorders. Most genetic counseling is done, however, only after the birth of at least one affected individual has alerted the family to their predilection for having children with a genetic disorder. The carrier state of a certain number of genetic disorders can now be detected, so that even before the birth of their first child, a family can be forewarned that they are at increased risk. Previously this knowledge often influenced couples to decide against having any children. The advent of prenatal diagnosis of genetic disease, however, which was pioneered in the 1960s, allows specific diagnoses of inherited disorders in the fetus; parents no longer have only a mathematical risk figure for guidance. The technics which permit a preview of the genotype of the fetus with respect to a certain disorder constitute an exciting new field or medicine. They are not now available for use in routine pregnancies, but in high-risk situations the collaboration of the primary care physician and the medical geneticist can contribute significantly to the prevention of certain severely handicapping genetic disorders. The field is new and promises to offer much more in the future as more of the inherited disorders are biochemically characterized and become subject to prenatal detection.     

Iron overload

Iron overload disorders represent a heterogenous group of conditions resulting from inherited and acquired causes. With the discovery of new proteins and genetic defects we have gained greater insight into their causation at the molecular level and the complex mechanisms of normal and disordered iron homeostasis. Here we review the normal mechanisms and regulation of gastrointestinal iron absorption and liver iron transport and their dysregulation in iron overload states. Advances in the understanding of the natural history of iron overload disorders and new methods for clinical detection and management of hereditary hemochromatosis are also reviewed.     

Functional brain networks and abnormal connectivity in the movement disorders

Clinical manifestations of movement disorders, such as Parkinson's disease (PD) and dystonia, arise from neurophysiological changes within the cortico-striato-pallidothalamocortical (CSPTC) and cerebello-thalamo-cortical (CbTC) circuits. Neuroimaging techniques that probe connectivity within these circuits can be used to understand how these disorders develop as well as identify potential targets for medical and surgical therapies. Indeed, network analysis of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has identified abnormal metabolic networks associated with the cardinal motor symptoms of PD, such as akinesia and tremor, as well as PD-related cognitive dysfunction. More recent task-based and resting state functional magnetic resonance imaging studies have reproduced several of the altered connectivity patterns identified in these abnormal PD-related networks. A similar network analysis approach in dystonia revealed abnormal disease related metabolic patterns in both manifesting and non-manifesting carriers of dystonia mutations. Other multimodal imaging approaches using magnetic resonance diffusion tensor imaging in patients with primary genetic dystonia suggest abnormal connectivity within the CbTC circuits mediate the clinical manifestations of this inherited neurodevelopmental disorder. Ongoing developments in functional imaging and future studies in early patients are likely to enhance our understanding of these movement disorders and guide novel targets for future therapies.     

Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities

The muscular dystrophies are a heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness. These disorders present a large clinical variability regarding age of onset, patterns of skeletal muscle involvement, heart damage, rate of progression and mode of inheritance. Difficulties in classification are often caused by the relatively common sporadic occurrence of autosomal recessive forms as well as by intrafamilial clinical variability. Furthermore recent discoveries, particularly regarding the proteins linking the sarcolemma to components of the extracellular matrix, have restricted the gap existing between limb girdle (LGMD) and congenital muscular dystrophies (CMD). Therefore a renewed definition of boundaries between these two groups is required. Molecular genetic studies have demonstrated different causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. These novel skeletal muscle genes encode highly diverse proteins with different localization within or at the surface of the skeletal muscle fibre, such as the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), the extracellular matrix (alpha2 laminin, collagen VI), the sarcomere (telethonin, myotilin, titin, nebulin and ZASP), the muscle cytosol (calpain-3, TRIM32), the nucleus (emerin, lamin A/C) and the glycosilation pathway enzymes (fukutin and fukutin related proteins). The accumulating knowledge about the role of these different proteins in muscle pathology has led to a profound change in the original phenotype-based classification and shed new light on the molecular pathogenesis of these disorders.     

Peripheral neuropathies of childhood

This article has provided a brief overview of the most common inherited and acquired peripheral nerve diseases encountered in childhood. The diagnostic approach of peripheral neuropathies in children often relies on some combination of careful history taking, physical examination findings, a careful determination of family history, electrodiagnostic studies, molecular genetic studies, sural nerve biopsy, and occasionally metabolic laboratory studies. Although pediatric mononeuropathies may have different causes than those observed in adults, the clinical presentations, diagnostic evaluation, and management of mononeuropathies are frequently similar in adults and children. Encouraging progress is being made in the management of acute inflammatory demyelinating polyneuropathy (AIDP), which is the most common acquired neuropathy of childhood. Rapid advances in molecular genetics over the past decade have had a significant impact on our diagnostic approach to hereditary motor sensory neuropathy in particular. In the future it is likely that the sequencing of genes, characterization of protein structure and function, and further elucidation of pathophysiology will have significant impacts on the treatment of many inherited peripheral neuropathies of childhood.     

Gene-specific therapy for inherited arrhythmogenic diseases

In the last few years, major advancement has been made in the understanding of the genetic basis of inherited arrhythmogenic diseases. Interestingly, the information obtained with the application of molecular genetics to these diseases is now influencing their clinical management, allowing gene-specific risk stratification and gene-specific management. The first attempt for a gene-specific therapy was made in 1995 with the use of mexiletine in long-QT syndrome (LQTS) patients with mutations in the SCN5A gene. Since then, several investigators have proposed novel therapeutic approaches based on the identification of the functional consequences of genetic mutations. In some instances, these novel therapies have already been introduced in clinical practice, and data are being collected to establish their long-term efficacy. In this review, we will summarize the current understanding of the molecular bases of inherited arrhythmias, with a specific focus toward discussing the most recent advancements toward the development of gene-specific therapies.     

Inherited thrombocytopenias frequently diagnosed in adults

The diagnosis of inherited thrombocytopenias is difficult, for many reasons. First, as they are all rare diseases, they are little known by clinicians, who therefore tend to suspect the most common forms. Second, making a definite diagnosis often requires complex laboratory techniques that are available in only a few centers. Finally, half of the patients have forms that have not yet been described. As a consequence, many patients with inherited thrombocytopenias are misdiagnosed with immune thrombocytopenia, and are at risk of receiving futile treatments. Misdiagnosis is particularly frequent in patients whose low platelet count is discovered in adult life, because, in these cases, even the inherited origin of thrombocytopenia may be missed. Making the correct diagnosis promptly is important, as we recently learned that some forms of inherited thrombocytopenia predispose to other illnesses, such as leukemia or kidney failure, and affected subjects therefore require close surveillance and, if necessary, prompt treatments. Moreover, medical treatment can increase platelet counts in specific disorders, and affected subjects can therefore receive drugs instead of platelet transfusions when selective surgery is required. In this review, we will discuss how to suspect, diagnose and manage inherited thrombocytopenias, with particular attention to the forms that frequently present in adults. Moreover, we describe four recently identified disorders that belong to this group of disorders that are often diagnosed in adults: MYH9‐related disease, monoallelic Bernard–Soulier syndrome, ANKRD26‐related thrombocytopenia, and familial platelet disorder with predisposition to acute leukemia.     

Automated measurement of local white matter lesion volume

It has been hypothesized that white matter lesions at different locations may have different etiology and clinical consequences. Several approaches for the quantification of local white matter lesion load have been proposed in the literature, most of which rely on a distinction between lesions in a periventricular region close to the ventricles and a subcortical zone further away. In this work we present a novel automated method for local white matter lesion volume quantification in magnetic resonance images. The method segments and measures the white matter lesion volume in 43 regions defined by orientation and distance to the ventricles, which allows a more spatially detailed study of lesion load. The potential of the method was demonstrated by analyzing the effect of blood pressure on the regional white matter lesion volume in 490 elderly subjects taken from a longitudinal population study. The method was also compared to two commonly used techniques to assess the periventricular and subcortical lesion load. The main finding was that high blood pressure was primarily associated with lesion load in the vascular watershed area that forms the border between the periventricular and subcortical regions. It explains the associations found for both the periventricular and subcortical load computed for the same data, and that were reported in the literature. But the proposed method can localize the region of association with greater precision than techniques that distinguish between periventricular and subcortical lesions only.     

Genomic diagnosis of thrombophilia in women: clinical relevance

The detection of the DNA-sequence of human coagulation factors and inhibitors has introduced the possibility of differentiated mutation analysis in patients with venous thrombosis. Since venous thromboembolism is a multifactorial disease, women are at an increased risk to develop venous thrombosis due to hormonal contraception, during pregnancy and the puerperium. In addition, pregnancy complications like early or late fetal loss, pregnancy-induced hypertensive disorders and very recently recurrent embryo implantation failure have been suspected to be associated with thrombophilia. Therefore, it is of major importance to define inherited thrombophilic disorders, in which genetic diagnosis is of clinical relevance. While most of the genetic defects described so far represent a risk factor for venous thrombosis, only a minority of these defects actually needs DNA analysis to be detected: mutation analysis is clinically relevant, when factor V Leiden mutation is suspected, because relative risks concerning venous thrombosis as well as pregnancy complications clearly differ between homozygote and heterozygote forms of this frequently observed mutation. Similarly detection of the prothrombin mutation G20210A is of clinical relevance, although data for the very rarely observed homozygote variant are not sufficiently available. In contrast, detection of the homozygote variant of the MTHFR-mutation C677T is not useful, since clinical relevance could not be proven in a majority of studies concerning women specific risk situations. Inherited deficiencies of antithrombin, protein C and protein S are rare with high rates of different mutations. Genetic analysis seems only useful in patients with wide intraindividual variations of coagulation inhibitor activities. Genetic analysis concerning the PAI-1 4G/5G polymorphism or the factor XIII Val34Leu polymorphism can not be recommended in women specific risk situations because of insufficient data.     

A murine model of a familial prion disease

We have produced a mouse model of a familial prion disorder by introduction of a transgene that encodes the moPrP homolog of a nine-octapeptide insertional mutant associated with an inherited form of CJD in humans. These mice develop progressive neurologic symptoms, display neuropathologic changes, and accumulate a form of mutant PrP in their brains and peripheral tissues that displays some of the biochemical properties of PrPSc. These mice have been extremely valuable for analyzing the cellular and biochemical mechanisms involved in inherited prion disorders and correlating the appearance of the PrPSc-like form with clinical and neuropathologic findings. Because the mutant protein in the mice is highly neurotoxic but appears to lack infectivity, further analysis of its properties promises to shed new light on the molecular distinction between pathogenic and infectious forms of PrP.