Drug induced phospholipidosis: An acquired lysosomal storage disorder

There is a strong association between lysosome enzyme deficiencies and monogenic disorders resulting in lysosomal storage disease. Of the more than 75 characterized lysosomal proteins, two thirds are directly linked to inherited diseases of metabolism. Only one lysosomal storage disease, Niemann–Pick disease, is associated with impaired phospholipid metabolism. However, other phospholipases are found in the lysosome but remain poorly characterized. A recent exception is lysosomal phospholipase A2 (group XV phospholipase A2). Although no inherited disorder of lysosomal phospholipid metabolism has yet been associated with a loss of function of this lipase, this enzyme may be a target for an acquired form of lysosomal storage, drug induced phospholipidosis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.     

Fundamental research is the basis for understanding and treatment of many human diseases

There are numerous examples of how fundamental research has been required to understand and treat human disease. This article focuses on three human diseases of lipid metabolism in which advancements in understanding and treatment would not have been possible without basic research. Fabry disease is an inherited metabolic disorder caused by the lack of a specific enzyme in glycosphingolipid catabolism. Cardiovascular disease is a complex and multifactorial disease but as many as half of the cases can be attributed to abnormal levels of plasma cholesterol. The incidence of liver disease is increasing due to the current epidemic of obesity. It is only recently that curiosity-driven research has yielded valuable insight into the mechanism by which liver disease evolves.     

Human Complex Trait Genetics: Lifting the Lid of the Genomics Toolbox - from Pathways to Prediction

During the initial stages of the genome revolution human genetics was hugely successful in discovering the underlying genes for monogenic diseases. Over 3,000 monogenic diseases have been discovered with simple patterns of inheritance. The unravelling and identification of the genetic variants underlying complex or multifactorial traits, however, is proving much more elusive. There have been over 1,000 significant variants found for many quantitative and binary traits yet they explain very little of the estimated genetic variance or heritability evident from family analysis. There are many hypotheses as to why this might be the case. This apparent lack of information is holding back the clinical application of genetics and shedding doubt on whether more of the same will reveal where the remainder of the variation lies. Here we explore the current state of play, the types of variants we can detect and how they are currently exploited. Finally we look at the future challenges we must face to persuade the human genome to yield its secrets.     

Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder

Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6?years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.     

Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism

Background

Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine.

Results

We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome.

Conclusions

We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-1090) contains supplementary material, which is available to authorized users.     

Overview of nutritional approach in hematopoietic stem cell transplantation: COVID-19 update

The coronavirus disease 2019 (COVID-19) is caused by the newly discovered SARS-CoV-2. Hematopoietic stem cell transplantation (HSCT) is a high-risk procedure. The novelty of COVID-19 has created more uncertainty during all phases of HSCT. It is thought that HSCT patients taking immunosuppressive agents are more likely to contract COVID-19 than healthy individuals are. Appropriate care precautions should be taken with patients undergoing HSCT to minimize the risk of COVID-19, and appropriate treatment methods must be followed in patients infected with COVID-19. Malnutrition has become a significant problem in HSCT patients during the COVID-19 pandemic. The causes of malnutrition in HSCT patients are multifactorial. However, the most important reason is the decrease in energy and nutrient intake. The HSCT procedure can lead to many complications such as dysgeusia, mucositis, diarrhea, constipation, xerostomia and vomiting/nausea. Improving the nutritional status of HSCT patients by managing each of these special complications with an appropriate nutritional approach is essential for successful engraftment. This review aims to provide a comprehensive overview of the specific complications affecting the nutritional status of HSCT patients and their nutritional approach during the challenging COVID-19 pandemic.     

Kinetic studies of lipoprotein metabolism in the metabolic syndrome including effects of nutritional interventions

Nutritional interventions may favourably regulate dyslipoproteinemia and, hence, decrease cardiovascular disease risk. Lipoprotein kinetic studies afford a powerful approach to understanding and defining the mechanisms by which such interventions modulate lipoprotein metabolism. Stable isotope tracers and compartment models are now commonly employed for such studies. We review the recent application of tracer methodologies to the study of dyslipoproteinemia in the metabolic syndrome. We also focus on the effects of nutritional intervention studies that have addressed the effects of weight loss, n-3 fatty acids, plant sterols and alcohol on very low density lipoprotein, LDL and HDL metabolism. The potential for statin treatment as an adjunct to dietary modification is also discussed. New tracer methodologies are discussed, specifically those referring to reverse cholesterol transport. The nutritional interventions discussed in this review are readily transferable into clinical preventive practice. The potential benefits to be gained by weight loss and fish oil supplementation in the metabolic syndrome extend beyond their specific and positive effects on lipoprotein metabolism. Furthermore, recent developments in tracer methodologies afford new tools for probing the in-vivo pathways of lipoprotein metabolism in future studies.     

Protein and amino acid supplementation in older humans

The aging process is a continuum throughout life and often associated with deterioration of body function as well as accumulation of chronic disabilities and of disease. The impact of nutritional status on morbidity and mortality is unquestioned. Malnutrition increases the risk for frailty and nutritional deficits can influence immune status, response to medical treatments and recovery from acute illnesses, including surgery. Health-promoting interventions implemented individually, such as exercise programs, preventive home visits, comprehensive geriatric evaluation and management, and attention to adequate nutrition with or without nutritional supplements, have been shown in separate studies to be both feasible and effective in reducing age-related deterioration. Protein and its constituent amino acids (AA) are key components of any healthy diet. Sarcopenia, the slow but progressive loss of lean muscle mass associated with advancing age, has been the focus of many studies but there is no clear-cut answer to the question of how to restrain the process. The more general question of how the requirements for protein and specific AA change with age continues to be investigated. A shift towards studying the efficacy and safety of specific AA or combination of AA that may sustain and/or enhance physiologic processes, ranging from specific tissue metabolism to overall function (e.g. exercise performance, immune function, cognition, and chronic disease development) has occurred. This review focuses on recent studies examining the use of specific AA or mixtures as supplements in the elderly and whether/how AA may assist in the maintenance of health and independence.     

Genetics of type 2 diabetes

Identification and characterization of genetic variants that either cause or predispose to diabetes are a major focus of biomedical research. As of early 2007, the molecular basis of most forms of monogenic diabetes resulting from beta-cell dysfunction is known and, in particular, there has been recent success in delineating the genetic aetiology of neonatal diabetes. Finding genes predisposing to more common, multifactorial forms of type 2 diabetes represents a far greater challenge, and only a handful of robust, well-replicated examples have been established. Nevertheless, 2006 heralded identification of the most important type 2 diabetes susceptibility gene known so far, TCF7L2, and in 2007 large-scale genome-wide association studies are destined to provide novel insights into the genetic architecture and biology of type 2 diabetes.     

Pathophysiology and genetics of obesity

Obesity, a global problem, is a multifactorial disorder. The factors are environmental, metabolic and genetic and their interaction with each other regulates the body weight. Imbalance in either of the factors may be responsible for weight gain. With advancement of research techniques in the last decade, genetic studies have been undertaken for several different causative mutations involving obesity loci on different chromosomes. Monogenic and polygenic obesity has been observed however, polygenic forms are more common. So far more than 200 genes in mouse and more than 100 genes in humans have been identified which result in phenotypes that affect body weight regulation. In spite of this knowledge, the field of obesity has still not been explored extensively. There remain a lot of lacuna regarding causes and treatment of obesity. Challenges are still there to identify the exact cause of weight gain and the use of current knowledge for development of anti-obesity drugs targeted for body weight regulation. In this review, we have explained neuropathophysiologic regulation of feeding behaviour and some aspects of obesity-genetics especially with single nucleotide polymorphism of selected candidate genes and their functional aspects mainly in monogenic obesity.     

Genetic susceptibility to ageing-associated diseases

The constant and rapid increase of life expectancy in western countries is associated with a major ageing of our populations. In these conditions, we can expect an epidemic progression of most chronic diseases, especially cardiovascular, neurodegenerative and metabolic disorders, the main causes of death in the world. The global burden of these diseases will have a dramatic impact on the health and on the socio-economical context of our societies. From a global point of view, the occurrence and progression of these multifactorial diseases rely upon the nature and intensity of the environmental determinants we are exposed to all life long, but also to our individual genetic susceptibility. Through the determination of this higher susceptibility to an environmental risk factor and the understanding of its mechanisms of action, prevention and management efforts will be better focused. In such multifactorial affections, the development and the transmission of the disease do not follow the simple laws of monogenic Mendelian models. The complexity of this transmission is associated with the influence, at various degrees, of several genes and of a close interaction between this particular genetic susceptibility and environmental risk factors. With the recent development of automated and high throughput molecular biology techniques and their use in epidemiological studies, gene expression regulation and post genomic studies, the determination of sub-groups facing a higher individual genetic susceptibility has begun. This determination will offer new clues for a better-targeted disease management.     

Effects of protein malnutrition and ascorbic acid levels on drug metabolism

The duration of action of drugs (or other environmental chemicals) is dependent on their rate of metabolic deactivation and elimination from the body. Termination of activity is achieved either through excretion of the drug via the kidney and bile or, more commonly, through metabolic deactivation by enzymes of the liver and other tissues. In recent years, it has become increasingly obvious that nutritional status is one of the major factors capable of modifying the pharmacological effect of drugs. Numerous studies have indicated that the process of drug metabolism may be affected by acute starvation, undernutrition, protein nutrition, and deficiencies of minerals, vitamins, and lipids. Although most of the evidence concerning the effects of nutrition on the metabolism of drugs has been derived from studies on experimental animals, there is significant fragmentary human data to show that the same effects may occur in man. This paper will discuss the influence of nutritional status with particular references to protein and ascorbic acid on the metabolism of foreign compounds including drugs. The interrelationships of nutrition and the metabolism of drugs are an important consideration in view of the widespread recurrence of primary malnutrition in the developing countries, and of secondary malnutrition in more affluent societies, especially in debilitated chronically ill patients, in postoperative patients, and in those whose dietary manipulations are carried out in weight-reducing regimens. The effects of nutrition on drug metabolism may be viewed as an extension of the search for one of the environmental factors that modify drug action.     

Modellvorstellungen zur Genetik multifaktorieller Krankheiten

In contrast to monogenic diseases, a straightforward genotype–phenotype relationship is unlikely for multifactorial diseases because of a number of genetic and nongenetic factors, including genetic heterogeneity, gene–gene and gene–environment interactions, and epigenetic mechanisms. As a consequence, the relative risk of particular genetic variants will generally be small, which implies that large sample sizes are required for their initial identification. No conclusions as to the frequency and diversity of the causative genetic variation can generally be drawn from the prevalence of a disease alone. Homogenization of the genetic background of the study population and the use of simple and clearly defined phenotypes together with “educated guesses” in candidate gene and gene–environment studies appear to be the most promising way to identify the genetic factors underlying multifactorial diseases. Replication of initial disease association findings, particularly for rare variants, should be carried out in populations that are genetically as similar as possible to the original population.     

Monogenic traits are not simple: lessons from phenylketonuria.

The classification of genetic disease into chromosomal, monogenic and multifactorial categories is an oversimplification. Phenylketonuria (PKU) is a classic 'monogenic' autosomal recessive disease in which mutation at the human PAH locus was deemed sufficient to explain the impaired function of the enzyme phenylalanine hydroxylase (enzymic phenotype), the attendant hyperphenylalaninemia (metabolic phenotype) and the resultant mental retardation (cognitive phenotype). In the era of molecular genetics, expectations for a consistently close correlation between the mutant genotype and variant phenotype have been somewhat disappointed, and PKU is used here to illustrate how and why this might be the case. So-called monogenic traits do, indeed, conform to long-accepted ideas about the expression of 'major' loci and their importance in determining parameters of phenotype, but the associated features are as complex, in their own ways, as those in so-called complex traits.     

Genetic determinants of platelet function in thromboembolic diseases

Within the past decade our understanding of thromboembolic disorders has become even more sophisticated as recent discoveries have suggested the influence of gene variants on the development of atherosclerotic disease and arterial thrombosis. Candidate genes encode proteins involved in processes relevant to atherosclerosis, ranging from cholesterol metabolism to arterial thrombosis. Platelets are key elements in primary hemostasis, but also in arterial thrombosis. Moreover, a number of genetic polymorphisms of platelet proteins may also induce gain or loss of function, supporting a role predisposing some individuals to thrombotic events. However, after thousands of studies, much controversy remains whether individual platelet polymorphisms contribute to an increased likelihood of thromboembolic disorders. Although platelet polymorphisms are a promising addition to more established cardiovascular risk factors, identifying genetic variants as a single cause of cardiovascular disease would be an oversimplification; instead, the contribution of these polymorphisms should also be considered in the context of a multifactorial disease. Gene-gene and gene-environment studies would identify specific combinations associated with a high risk to suffer from these diseases. The platelet's genetic heterogeneity should also be considered in every aspect of clinical medicine, ranging from susceptibility to diseases, pathogenesis, and clinical outcome to diversity in responses to drug treatment (pharmacogenomics), and bleeding.     

Clinical applications of tumour necrosis factor

Tumour necrosis factor (TNF) is a polypeptide hormone produced in vivo by activated macrophages and lymphocytes. TNF has diverse effects in vivo and has a physiological role as an immune modulator, as a mediator of the immune response, both through activation of neutrophils and eosinophils, and also affects the vascular endothelium. TNF also has antiviral activity and causes alterations in lipid metabolism. In disease states excessive production of TNF may have adverse affects. TNF has been implicated as a mediator of endotoxic shock, inflammatory joint disease, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. When used in pharmacological doses, TNF is cytotoxic to many malignant cells in vitro and in vivo. The mechanisms underlying cytotoxicity are not fully elucidated but involve both a direct toxic effect to the cell and an indirect effect on tumour vasculature. Cytotoxicity is not universal and TNF may act as a differentiating agent or growth factor for some haematological cell types. So far the clinical application of TNF has been as a treatment for cancer in Phase I and II trials in patients with advanced disease and its efficacy here is still unproven. TNF may have potential for clinical application in combination therapy for cancer. There is experimental evidence for its interaction with other biological agents and cytotoxic drugs. The use of specific antibodies to inhibit production of TNF, or other agents to antagonise the toxic effects of TNF may have clinical relevance in counteracting septic shock and the clinical manifestations of TNF in inflammatory and neoplastic disease.     

Haemophilia A: from mutation analysis to new therapies

Haemophilia is caused by hundreds of different mutations and manifests itself in clinical conditions of varying severity. Despite being inherited in monogenic form, the clinical features of haemophilia can be influenced by other genetic factors, thereby confounding the boundary between monogenic and multifactorial disease. Unlike sufferers of other genetic diseases, haemophiliacs can be treated successfully by intravenous substitution of coagulation factors. Haemophilia is also the most attractive model for developing gene-therapy protocols, as the normal life expectancy of haemophiliacs allows the side effects of gene therapy, as well as its efficiency, to be monitored over long periods.