The Rare Anaemias

Anaemia is a common worldwide disorder mainly due to iron or vitamins deficiency. However, among the rare diseases (RD), there is a group associated with anaemia as main clinical manifestation or rare anaemias (RA). RA are mostly hereditary, and since they are little known, even for professionals, they remain undiagnosed, or misdiagnosed, for very long periods of time. This creates in patients, or, in their parents (if they are children) a permanent situation of stress due to the absence of a diagnosis, the impossibility to predict the course of the disease, and to the impossibility to perform, genetic counselling for future pregnancies. About 83 different RA have been described and their mechanism is in general a bone marrow or a red blood cell (RBC) defect. The most well-known RA are Fanconi anaemia, the thalassemia syndromes, sickle cell disease, hereditary haemolytic anaemias and paroxysmal nocturnal haemoglobinuria (PNH). The main objective of this chapter is to offer a review of the state of the art of RA knowledge and a way to facilitate their identification and final diagnosis through clinical manifestations and laboratory diagnostic tests

The Impact of Migrations on the Health Services for Rare Diseases in Europe: The Example of Haemoglobin Disorders

Migration from different parts of the world to several European countries leads to the introduction of haemoglobinopathy genes into the population, which creates several demanding needs for prevention and treatment services for Hb disorders. In this paper we examined the degree to which European health services have responded to such challenges and in particular to health services necessary to address the needs of patients with thalassaemia and sickle cell disease (SCD). Information on available services was obtained from international organizations, collaborated European project, and the Thalassaemia International Federation (TIF) Databases, which include information from published surveys, registries, field trips, and delegation visits to countries and regions by expert advisors, local associations, and other collaborators' reports. Results show that countries with traditional strong prevention and treatment programs are well prepared to face the above challenges, while others are urgently needed to address these problems in a systematic way. The Thalassaemia International Federation (TIF) is committed to monitor the progress, raise awareness, and support the promotion of more immigrant-oriented health policies to ensure their integration in society and their access to appropriate, adequate, and timely health services

Congenital Defects with Impaired Red Blood Cell Deformability – The Role of Next-Generation Ektacytometry

The red blood cells (RBCs) carry oxygen from the lungs to the tissues, and for this, they must be able to deform. Accordingly, an impairment of RBC deformability is the cause of RBCs trapping and removal by the spleen and haemolysis. The most common causes for the decline in red cell deformability are the RBC membrane defects (abnormal shape or ionic transport imbalance), haemoglobinopathies (increased rigidity), or enzyme deficiencies (decreased anti-oxidant defences or ATP content). The most common cause of hereditary anaemia in childhood is hereditary spherocytosis (HS), characterised by a marked RBC deformabiity. A decreased RBC deformability has been found in hereditary haemolytic anaemias (HHAs) using the new-generation osmotic gradient ektacytometry (OGE), probably due to a combination of membrane protein defects and ionic imbalance. Therefore, OGE is currently considered the gold standard for the measurement of RBC deformability and the most useful complementary tool for the differential diagnosis of HHAs. Moreover, since several new forms of treatment are currently developed for hereditary RBC defects, the clinical interest of OGE is increasing. The aim of this chapter is to provide further information about the use of RBC deformability in clinical diagnosis and the OGE as a new challenge to decrease the frequency of undiagnosed rare anaemias

New e-health services for the European Network for Rare and Congenital Anaemias (e-ENERCA)

Rare Anaemias (RA) are a group of Rare Diseases (RD) with prevalence, in Europe, less than 5 per 10.000 individuals. Major forms of RAs require red blood cell transfusions, iron chelation, splenectomy, and/or in very severe cases, bone marrow transplantation, as main therapeutic options. Beta-thalassaemia major is predominant in Italy and Cyprus, and sickle cell disease (SCD) in African population. During the last 30 years, SCD is increasing in Europe due to African immigration, leading to an important impact on health care burden in several countries. Preventive programs, aiming to epidemiological control, and improvement of diagnosis and clinical management of major RA, are crucial for decreasing the affected birth rate and achieving an efficient balance between morbidity and patient’s life expectancy. Since 2003, the European Network for Rare and Congenital Anaemias (ENERCA) has taken an active role for improving this situation by the following actions: a) the identification of Centres of Expertise on RAs in Europe according to the recommendations of ENERCA White Book b) the promotion of best clinical and laboratory practices by the publication of ENERCA recommendations c) the improving of continuous medical education, by organising topic-specific training courses, workshops and symposia, e) the empowerment of patients, by cooperation with Patient’s Associations, and co-organizing a bi-annual European Symposium on RAs with interactive patients-health professionals sessions. In September 2013, a new phase of the project called e-ENERCA has started with the aim to provide, patients and professionals with e-Health tools for assure the same access to health services in RAs across Europe, independently from the country of practise and origin of the patients. e-Health services will be developed through the set-up of three different e-platforms endorsed by ENERCA website (http://www.enerca.org) : 1) e-Registry, a Pan European registry of RAs for gathering patient’s data necessary to achieve the required sample size for epidemiological surveillance and clinical research 2) e-Learning , a teaching platform for the dissemination of knowledge, continuous medical education, and best practices awareness and promotion through Internet, and 3) e-Medicine , a platform to provide, at distance, expertise (telexpertise) and diagnostic facilities (telediagnosis), avoiding, when possible, the need of travelling. Finally, e-ENERCA will also promote the recognition of the previously identified Centres of Expertise in RAs (White Book) by the national health authorities, a mandatory condition for ENERCA final recognition as European Reference Network in Rare Anaemias (RA-ERN)

European expert network on rare communicable diseases and other rare diseases linked to mobility and globalisation focused on ealth care provision (EURaDMoG): a feasibility study.

INTRODUCTION NlmCategory: BACKGROUND content: In the current mobility and globalization context, there is a growing need to identify potential changes on the pattern of diseases in the European Union (EU)/European Economic Area (EEA) and provide accurate diagnosis and treatment for the population. The pattern of rare communicable diseases that can affect people returning to EU/EEA from travel abroad, visiting EU/EEA or establishing in the EU/EEA is of special relevance. The objective of this manuscript is to give an overview about the EURaDMoG study and discuss the feasibility of establishing a European network on rare communicable diseases and other rare conditions linked to mobility and globalization. - Label: METHODS NlmCategory: METHODS content: We undertook a three-steps process where we first conducted a narrative review to estimate the prevalence and incidence and to list rare communicable and non-communicable diseases linked to mobility and globalization in the EU/EEA; second, we organized an international consultation workshop with experts in the diseases previously selected; and finally, the feasibility study analysed how successful a European expert network on rare diseases linked to mobility and globalization focused on health care provision would be, accounting for different operational and also sustainability criteria. - Label: RESULTS NlmCategory: RESULTS content: "First, considering the areas or topics that the network should cover, it was concluded that communicable and non-communicable rare diseases linked to mobility and globalization should be differentiated. Second, since all non-communicable rare diseases linked to mobility and globalization identified are already covered by different European Reference Networks (ERNs), there is no need for them to be included in a new European network. Three scenarios were considered for establishing a potential European network for rare communicable diseases linked to Mobility and Globalisation with a focus on Health Care provision: 1) To maintain the current situation \"Status Quo\" scenario; 2) to create a specific European expert network (EEN) on rare communicable diseases linked to mobility and globalisation; 3) to develop a new ERN on communicable rare diseases linked to mobility and globalisation." - Label: CONCLUSIONS NlmCategory: CONCLUSIONS content: Since the focus is the provision of health care, an ERN could have the potential to better boost the quality of care being facilitated by technological tools and online platforms that permit the safe and ethically acceptable exchange of data. However, this potential new network should not eclipse current existing networks and they should be complementary

Concomitant Hereditary Spherocytosis and Pyruvate Kinase Deficiency in a Spanish Family with Chronic Hemolytic Anemia : Contribution of Laser Ektacytometry to Clinical Diagnosis

Background: Hereditary spherocytosis (HS) and pyruvate kinase deficiency (PKD) are the most common causes of hereditary chronic hemolytic anemia. Here, we describe clinical and genetic characteristics of a Spanish family with concomitant β-spectrin (SPTB) c.647G>A variant and pyruvate kinase (PKLR) c.1706G>A variant. Methods: A family of 11 members was studied. Hematological investigation, hemolysis tests, and specific red cell studies were performed in all family members, according to conventional procedures. An ektacytometric study was performed using the osmoscan module of the Lorca ektacytometer (MaxSis. RR Mechatronics). The presence of the SPTB and PKLR variants was confirmed by t-NGS. Results: The t-NGS genetic characterization of the 11 family members showed the presence of a heterozygous mutation for the β-spectrin (SPTB; c.647G>A) in seven members with HS, three of them co-inherited the PKLR variant c.1706G>A. In the remaining four members, no gene mutation was found. Ektacytometry allowed a clear diagnostic orientation of HS, independently from the PKLR variant. Conclusions: This family study allows concluding that the SPTB mutation, (c.647G>A) previously described as likely pathogenic (LP), should be classified as pathogenic (P), according to the recommendations for pathogenicity of the American College of Medical Genetics and the Association for Molecular Pathology. In addition, after 6 years of clinical follow-up of the patients with HS, it can be inferred that the chronic hemolytic anemia may be attributable to the SPTB mutation only, without influence of the concomitant PKLR. Moreover, only the family members with the SPTB mutation exhibited an ektacytometric profile characteristic of HS

European expert network on rare communicable diseases and other rare diseases linked to mobility and globalisation focused on health care provision (EURaDMoG) : a feasibility study

Introduction: In the current mobility and globalization context, there is a growing need to identify potential changes on the pattern of diseases in the European Union (EU)/European Economic Area (EEA) and provide accurate diagnosis and treatment for the population. The pattern of rare communicable diseases that can affect people returning to EU/EEA from travel abroad, visiting EU/EEA or establishing in the EU/EEA is of special relevance. The objective of this manuscript is to give an overview about the EURaDMoG study and discuss the feasibility of establishing a European network on rare communicable diseases and other rare conditions linked to mobility and globalization. Methods: We undertook a three-steps process where we first conducted a narrative review to estimate the prevalence and incidence and to list rare communicable and non-communicable diseases linked to mobility and globalization in the EU/EEA; second, we organized an international consultation workshop with experts in the diseases previously selected; and finally, the feasibility study analysed how successful a European expert network on rare diseases linked to mobility and globalization focused on health care provision would be, accounting for different operational and also sustainability criteria. Results: First, considering the areas or topics that the network should cover, it was concluded that communicable and non-communicable rare diseases linked to mobility and globalization should be differentiated. Second, since all non-communicable rare diseases linked to mobility and globalization identified are already covered by different European Reference Networks (ERNs), there is no need for them to be included in a new European network. Three scenarios were considered for establishing a potential European network for rare communicable diseases linked to Mobility and Globalisation with a focus on Health Care provision: 1) To maintain the current situation "Status Quo" scenario; 2) to create a specific European expert network (EEN) on rare communicable diseases linked to mobility and globalisation; 3) to develop a new ERN on communicable rare diseases linked to mobility and globalisation. Conclusions: Since the focus is the provision of health care, an ERN could have the potential to better boost the quality of care being facilitated by technological tools and online platforms that permit the safe and ethically acceptable exchange of data. However, this potential new network should not eclipse current existing networks and they should be complementary

Haemoglobinopathies in Europe: health & migration policy perspectives

BACKGROUND: Major haemoglobinopathies (MH), such as thalassaemia syndromes (Thal) and sickle cell disorders (SCD), are genetic defects associated with chronic anaemia and other complications. In Europe, MH are rare diseases (RD) but their prevalence is significantly growing in many countries due to mobility and migration flows. This creates a growing health problem in the EU that has not yet been effectively addressed by Member States (MS) authorities. The present study has been conducted with the aim of: (i) providing an overview of policies for MH in 10 EU member states (MS) (ii) analysing the challenges linked to these RD due to growing requirements imposed by population, mobility and migration trends and (iii) identifying gaps, proposing improvements on existing policies, or developing new ones to fit the identified needs. METHODS: The study has been undertaken by a group of members of the European Network for Rare and Congenital Anaemias (ENERCA) and the Thalassaemia International Federation (TIF), in collaboration with the public affairs firm Burson-Marsteller Brussels. Data from 10 EU countries have been gathered using targeted desk research and one-to-one interviews with local stakeholders, including healthcare professionals, patients and public health officers/providers. RESULTS: 1. MH are the most common RD in all the 10 countries, 2. Data on prevalence, overall burden, trends, and clinical follow up costs are lacking in most countries. 3. Neonatal screening practices show a wide variation across and within countries. 4. Awareness on MH and their related complications is very low, exception made of Italy, Greece, Cyprus and UK, 5. No disaggregated data is available to understand the impact of mobility and migration on the prevalence of haemoglobinopathies, and how healthcare delivery systems should adapt to respond to this situation. 6. Targeted policy measures and/or actions are generally lacking and/or delayed. CONCLUSIONS: Ten policy recommendations have been drawn from this study, building on 2006 WHO recommendations for MH to include haemoglobinopathies in National Plans of Actions for Rare Diseases

In vitro release of arachidonic acid metabolites glutathione peroxidase, and oxygen-free radicals from platelets of asthmatic patients with and whithout aspirin intolerance

Background: An abnormal platelet release of oxygen-free radicals has been described in acetylsalicylic acid (aspirin)-induced asthma, a finding which might suggest the existence of an intrinsic, specific platelet abnormality of arachidonic acid metabolism in these patients. The objective of this study was to evaluate platelet arachidonic acid metabolism in asthmatic patients with or without intolerance to aspirin. Methods: Thirty subjects distributed into three groups were studied: group 1, 10 healthy subjects; group 2, 10 asthmatic patients with aspirin tolerance; and group 3, 10 aspirin-intolerant asthmatics. Platelets were isolated from blood, preincubated with 3H-arachidonic acid for 30 minutes and then incubated for 10 minutes with platelet activating factor (PAF) and aspirin. Cyclo-oxygenase (thromboxane, PGE2, PGF2 alpha, and HHT) and lipoxygenase (12-HETE) arachidonic acid metabolites were measured by high pressure liquid chromatography. Release of oxygen free radicals after incubation with PAF and aspirin was measured by chemiluminescence. Platelet levels of glutathione peroxidase (GSH-Px) were also measured using spectrophotometry. Results: Platelets from aspirin-intolerant asthmatic patients produced higher quantities of arachidonic acid metabolites than the control group at baseline conditions. This increase was significant only for lipoxygenase products. No differences were found amongst the three groups in the response of arachidonic acid metabolism to PAF and aspirin. Incubation with aspirin but not with PAF caused an increase in oxygen-free radical production in aspirin-intolerant patients whereas in aspirin-tolerant patients PAF, rather than aspirin, was the more potent stimulus for oxygen-free radical production. No differences in GSH-Px levels were found amongst the three groups. Conclusions: These results suggest that the platelet lipoxygenase pathway is activated in aspirin-intolerant patients and that the production of oxygen-free radicals may differentiate aspirin-tolerant from aspirin-intolerant asthmatic subjects. Our study, however, does not support the hypothesis that an increase in lipoxygenase products may be responsible for oxygen-free radical production. Moreover, a lowered platelet GSH-Px activity does not seem to be involved in this phenomenon