[Prevention and control of birth defects and rare diseases in the era of genomic medicine].

Birth defects and rare diseases have become major public health problems, and early prevention and control are the most effective interventions. In recent years, with the rapid development of genomic techniques such as high-throughput sequencing, the level of screening and diagnosis of genetic birth defects and rare diseases has been greatly improved. This article reviews the application of genomic technologies in the pre-pregnancy, preimplantation, prenatal and neonatal stages, as well as the trend of clinical transformation, highlighting the broad prospects of constructing an early and precise prevention and control system in the era of genomic medicine.

[Focus on the development of preimplantation genetic testing in the field of birth defects and rare diseases prevention and control].

Birth defects and rare diseases are serious challenges in China and even in the world, and most of them lack effective treatment. Preimplantation genetic testing (PGT) prevents the occurrence of this kind of disease at the source by carrying out genetic testing in the preimplantation stage and selecting normal embryos for transplantation. In this paper, the methods of PGT for birth defects and rare diseases and their latest progress are described.

Understanding the role of the cytoprotective transcription factor nuclear factor erythroid 2-related factor 2-lessons from evolution, the animal kingdom and rare progeroid syndromes.

The cytoprotective transcriptor factor nuclear factor erythroid 2- related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2-KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2-KEAP1 system in healthy ageing and well-being.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up-to-date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE-1/2 be defined and classified?, (2) How should HAE-1/2 be diagnosed?, (3) Should HAE-1/2 patients receive prophylactic and/or on-demand treatment and what treatment options should be used?, (4) Should HAE-1/2 management be different for special HAE-1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE-1/2 management incorporate self-administration of therapies and patient support measures?

Congenital Anomalies: Cluster Detection and Investigation.

This work summarizes the main aspects to be considered around birth defects (or congenital anomalies) clusters. Most birth defects (BD), considered individually, fall into the definition of rare diseases (RD), according to their low frequency. Likewise, many RD are congenital, because their manifestations are present at birth or can be even evident before the delivery. It has been estimated that overall 7.9 million children are born each year with serious BD of genetic or partially genetic origin, and additional hundreds of thousands more are born with serious BD of post-conception origin.A "birth defect cluster" can be defined as an unusual aggregation of cases (grouped in place and time) that is suspected to be greater than expected, even though the expected number may not be known. These clusters are incidents or occurrences that let us turn the challenge of identifying the causal agent(s) involved in the origin of such clusters, into an opportunity to exert primary prevention, and thus achieve the ultimate goal of enabling infants being born healthy. Therefore, any program or system involved in BD surveillance and research should devote part of its activities to detect and investigate clusters, to ensure that such opportunity for primary prevention will be conveniently leveraged. Regardless the type of cluster, there are several phases that must be undertaken sequentially for proper control and the maximum benefit for the population: cluster detection, evaluation and investigation, management, adoption of preventive measures, and communication of the results to the public or target population.

[Scurvy. A rare differential diagnosis of rheumatic diseases]. / Skorbut. Eine seltene Differenzialdiagnose rheumatischer Erkrankungen.

BACKGROUND: In December 2014 a patient presented to our clinic with the clinical symptoms of vasculitis. However, treatment with glucocorticoids did not lead to any improvement; therefore, the differential diagnostics were extended to other indications and ultimately led to the diagnosis of scurvy. OBJECTIVE: This article describes the clinical picture of scurvy and its relationship to rheumatic diseases based on a clinical case and additional information from the literature. Differences and similarities with important rheumatological disease symptoms are presented. RESULTS: Scurvy is a rare hypovitaminosis disease which can be manifested in different forms. In addition to vasculitis the symptoms can also resemble arthritis and hemarthrosis is a typical finding. These symptoms can be accompanied by unspecific manifestations, such as muscle pain and due to impaired collagen synthesis characteristic features, such as corkscrew hair can be observed. The causal therapy of scurvy is substitution of ascorbic acid. CONCLUSION: Scurvy is a rare differential diagnosis in the context of rheumatic diseases. The indications for scurvy can be a lack of response to immunosuppressive and immunomodulatory drugs as well as individual symptoms, such as corkscrew hair.

Atypical variants of bovine spongiform encephalopathy: rare diseases with consequences for BSE surveillance and control.

INTRODUCTION: Occurring for the first time in 1986 in the United Kingdom, bovine spongiform encephalopathy (BSE), the so-called "mad-cow disease", has had unprecedented consequences in veterinary public health. The implementation of drastic measures, including the ban of meat-and-bone-meal from livestock feed and the removal of specified risk materials from the food chain has eventually resulted in a significant decline of the epidemic. The disease was long thought to be caused by a single agent, but since the introduction of immunochemical diagnostic techniques, evidence of a phenotypic variation of BSE has emerged. Reviewing the literature available on the subject, this paper briefly summarizes the current knowledge about these atypical forms of BSE and discusses the consequences of their occurrence for disease control measures.

INTRODUCTION: L'encéphalopathie spongiforme bovine (ESB) dite aussi "maladie de la vache folle", apparue pour la première fois en 1996 au Royaume-Uni, a eu des conséquences sans équivalent pour le service public vétérinaire. La mise en application de mesures de lutte drastique, telle l'interdiction d'affourager les animaux de rente avec des farines animales et le retrait de la chaine des aliments de matériels à risque a conduit à un recul significatif de l'épidémie. Durant longtemps on a considéré que la maladie n'était causée que par un seul type de l'agent infectieux. Avec l'introduction de techniques de diagnostic immunochimiques, on a toutefois des indices de variantes phénotypiques de l'ESB. Le présent article résume la littérature disponible et fait le point des connaissances quant à ces variantes atypiques de l'ESB; on y discute également les conséquences possibles de leur apparition quant à la lutte contre la maladie.

[Orphan drugs : New opportunities for the treatment of rare diseases]. / Orphan Drugs : Neue Möglichkeiten zur Behandlung seltener Erkrankungen.

Not only in Europe and USA, but also in many other countries rare disorders-so-called orphan diseases-have attracted more and more attention. The formation of specialized centers for rare disorders has enabled the diagnosis of diseases that have been widely unknown before. In addition, pharmaceutical companies have recognized orphan diseases as a profitable source of revenue. The development and marketing of new drugs for rare diseases-so-called orphan diseases-means a great challenge for all who participate in the health care system: Because the number of patients who are available for a clinical study is mostly very small, it is often very difficult or even impossible to show statistically firm evidence of efficacy. The standard placebo-controlled, double-blind clinical trial is often inappropriate for the approval procedure of an orphan drug; thus other study designs or other parameters (e.g. biomarkers) have to be used to prove clinical efficacy of the study drug. Only relatively small amounts of drugs can be sold to the generally few patients affected by an orphan disease and clinical trials require an high amount of financial investment; therefore orphan drugs have in general extremely high prices. How long these high expenses can be borne by the health care system in view of the great number of rare diseases remains questionable.

Healthcare-associated outbreaks due to Mucorales and other uncommon fungi.

BACKGROUND: Healthcare-associated outbreaks of fungal infections, especially with uncommon and emerging fungi, have become more frequent in the past decade. MATERIALS AND METHOD: Here, we reviewed the history and definition of healthcare-associated outbreaks of uncommon fungal infections and discussed the principles of investigating, containing and treatment of these outbreaks. RESULTS: In case of these uncommon diseases, occurrence of two or more cases in a short period is considered as an outbreak. Contaminated medical devices and hospital environment are the major sources of these outbreaks. Care must be taken to differentiate a real infection from colonization or contamination. Defining and identifying cases, describing epidemiologic feature of cases, finding and controlling the source of the outbreak, treating patients, and managing asymptomatic exposed patients are main steps for outbreak elimination. These fungal outbreaks are not only difficult to detect but also hard to treat. Early initiation of appropriate antifungal therapy is strongly associated with improved outcomes in infected patients. Choice of antifungal drugs should be made based on spectrum, pharmacodynamic and pharmacokinetic characteristics and adverse effects of available drugs. Combination antifungal therapy and surgical intervention may be also helpful in selected cases. CONCLUSIONS: A multidisciplinary approach and close collaboration between all key partners are necessary for successful control of fungal outbreaks.

Prenatal education for congenital toxoplasmosis.

BACKGROUND: Congenital toxoplasmosis is considered a rare but potentially severe infection. Prenatal education about congenital toxoplasmosis could be the most efficient and least harmful intervention, yet its effectiveness is uncertain. OBJECTIVES: To assess the effects of prenatal education for preventing congenital toxoplasmosis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015), and reference lists of relevant papers, reviews and websites. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of all types of prenatal education on toxoplasmosis infection during pregnancy. Cluster-randomized trials were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Two cluster-randomized controlled trials (RCTs) (involving a total of 5455 women) met the inclusion criteria. The two included trials measured the effectiveness of the intervention in different ways, which meant that meta-analysis of the results was not possible. The overall quality of the two studies, as assessed using the GRADE approach, was low, with high risk of detection and attrition bias in both included trials.One trial (432 women enrolled) conducted in Canada was judged of low methodological quality. This trial did not report on any of the review's pre-specified primary outcomes and the secondary outcomes reported results only as P values. Moreover, losses to follow-up were high (34%, 147 out of 432 women initially enrolled). The authors concluded that prenatal education can effectively change pregnant women's behavior as it increased pet, personal and food hygiene. The second trial conducted in France was also judged of low methodological quality. Losses to follow-up were also high (44.5%, 2233 out of 5023 women initially enrolled) and differential (40% in the intervention group and 52% in the control group). The authors concluded that prenatal education for congenital toxoplasmoses has a significant effect on improving women's knowledge, whereas it has no effect on changing women's behavior. In this trial 17/3949 pregnant women seroconverted for toxoplasmosis: 13/2591 (0.5%) in the intervention group and 4/1358 (0.3%) in the control group. The rate of seroconversion detected during the study did not differ between groups (risk ratio (RR) 1.70, 95% confidence interval (CI) 0.56 to 5.21; participants = 3949; studies = one, low quality evidence). The number of events was too small to reach conclusions about the effect of prenatal education on seroconversion rate during pregnancy.No other randomized trials on the effect of prenatal education on congenital toxoplasmosis rate, or toxoplasmosis seroconversion rate during pregnancy were detected. AUTHORS' CONCLUSIONS: Even though primary prevention of congenital toxoplasmosis is considered a desirable intervention, given the lack of related risks compared to secondary and tertiary prevention, its effectiveness has not been adequately evaluated. There is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis even though evidence from observational studies suggests it is. Given the lack of good evidence supporting prenatal education for congenital toxoplasmosis prevention, further RCTs are needed to confirm any potential benefits and to further quantify the impact of different sets of educational intervention.

Polish activity within Orphanet Europe--state of art of database and services.

Orphanet is an international project aiming to help in improvement the diagnostic process, care and treatment of patients with rare diseases, and to provide information on development in research and new therapy. Orphanet is currently represented in 38 countries. The infrastructure and coordination activities are jointly funded by Inserm, the French Directorate General for Health, and the European Commission. Moreover, certain services are specially funded by other partners. Orphanet's activities in each country of the network are partially financed by national institutions and(or) specific contracts. In this paper we present the Orphanet portal as well as the Polish national activity within this project.

Kidney failure: aims for the next 10 years and barriers to success.

Although in some parts of the world acute and chronic kidney diseases are preventable or treatable disorders, in many other regions these diseases are left without any care. The nephrology community needs to commit itself to reduction of this divide between high-income and low-income regions. Moreover, new and exciting developments in fields such as pharmacology, genetic, or bioengineering, can give a boost, in the next decade, to a new era of diagnosis and treatment of kidney diseases, which should be made available to more patients.

Prenatal education for congenital toxoplasmosis.

BACKGROUND: Congenital toxoplasmosis is considered a rare but potentially severe infection. Prenatal education about congenital toxoplasmosis could be the most efficient and least harmful intervention, yet its effectiveness is uncertain. OBJECTIVES: To assess the effects of prenatal education for preventing congenital toxoplasmosis. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 January 2012), PubMed (1966 to 15 January 2012), EMBASE (1980 to 15 January 2012), CINAHL (1982 to 15 January 2012), LILACS (1982 to 15 January 2012), IMEMR (1984 to 15 January 2012), and reference lists of relevant papers, reviews and websites. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials (RCTs) of all types of prenatal education on toxoplasmosis infection during pregnancy. Cluster-randomized trials were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and study quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: Two cluster-randomized controlled trials (involving a total of 5455 women) met the inclusion criteria. The two included trials measured the effectiveness of the intervention in different ways which meant that meta-analysis of the results was not possible One trial (432 women enrolled) conducted in Canada was judged of low methodological quality. The authors did not report measure of association but only provided P values (P less than 0.05) for all outcomes. Moreover, losses to follow-up were high (34%, 147 out of 432 women initially enrolled). The authors concluded that prenatal education can effectively change pregnant women's behavior as it increased pet, personal and food hygiene. The second trial conducted in France was also judged of low methodological quality. Losses to follow-up were high (44.5%, 2233 out of 5023 women initially enrolled) and differential (40% in the intervention group and 52% in the control group). The authors concluded that prenatal education for congenital toxoplasmoses has a significant effect on improving women's knowledge whereas it has no effect on changing women's behavior. In this trial 17/3949 pregnant women seroconverted for toxoplasmosis: 13/2591 (0.5%) in the intervention group and 4/1358 (0.3%) in the control group. The number of events was too small to reach conclusions about the effect of prenatal education on seroconversion rate during pregnancy.No other randomized trials on the effect of prenatal education on congenital toxoplasmosis rate, or toxoplasmosis seroconversion rate during pregnancy were detected. AUTHORS' CONCLUSIONS: Even though primary prevention of congenital toxoplasmosis is considered a desirable intervention, given the lack of related risks compared to secondary and tertiary prevention, its effectiveness has not been adequately evaluated. There is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis even though evidence from observational studies suggests it is. Given the lack of good evidence supporting prenatal education for congenital toxoplasmosis prevention, further RCTs are needed to confirm any potential benefits and to further quantify the impact of different sets of educational intervention.

Thrombosis in patients with hemorrhagic disorders.

Venous thromboembolism is common in the general population with increasing age as one of the most important risk factors. The care of hemophilia and von Willebrand disease has improved in recent decades, resulting in the expectation of a growing population of aging people with these disorders. Thrombosis seems rare in hemorrhagic disorders but studies documenting the true epidemiology are virtually lacking. Events have been reported, however, primarily catheter-related thrombophlebitis in hemophilia, but also deep vein thrombosis and pulmonary embolism have been described in von Willebrand disease, usually in conjunction with major surgery and prolonged replacement therapy with high factor levels. Thromboprophylaxis is likely not warranted in most cases. Instead, well-designed therapy and careful monitoring are important measures to prevent risk. In von Willebrand disease particularly, the variation of the phenotype and products used for replacement are challenges, as infusion of von Willebrand factor will increase the endogenous level of factor VIII. Long-term replacement therapy into old age is becoming more common in hemophilia but will not increase occurrence of thromboembolic disease, as factor levels still will be low and have a preventive effect.

Coming together to combat rare diseases.

The European Commission is increasingly supporting collaborative initiatives focused on research into treatments and drugs for rare diseases, but lack of funding continues to be an issue.