Anemias raras y fallos medulares hereditarios

Rare anemias and inherited bone marrow failure syndromes are characterized, respectively, by decreased concentrations of hemoglobin or defects in the production of hematopoietic cells leading to single to multiple lineage cytopenias. They are rare and difficult to diagnose due to clinical, cytological and genetic heterogeneity. In this paper, we first address the diagnosis of rare anemias and their causes including marrow failures, erythrocyte defects and disorders of red cell metabolism factors involved in erythrocyte maturation. Finally, we introduce inherited bone marrow failure syndromes and their associated pathologies such as congenital malformations and tumor predisposition, with particular emphasis on the most common diseases: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia and Shwachman-Diamond syndrome.Las anemias raras y los fallos medulares hereditarios son enfermedades hematológicas caracterizadas, respectivamente, por una disminución de la concentración de hemoglobina o por diversos grados de defectos en la producción de células hematopoyéticas que conducen desde una citopenia de un solo linaje hasta una de múltiples linajes. Son enfermedades raras y difíciles de diagnosticar debido a la heterogeneidad clínica, citológica y genética. En este artículo abordaremos en primer lugar el diagnóstico de las anemias raras y sus causas principales: fallos medulares, defectos del hematíe y trastornos del metabolismo de los factores de maduración eritrocitario. Seguidamente introduciremos los fallos medulares hereditarios y su patología asociada, como son las malformaciones congénitas y la predisposición tumoral, haciendo especial hincapié en los más frecuentes: la anemia de Fanconi, la disqueratosis congénitca, la anemia de Diamond-Blackfan y el síndrome de Shwachman-Diamond

First description of phosphofructokinase deficiency in Spain: identification of a novel homozygous missense mutation in the PFKM gene

Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-years-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anemia. After ruling out the most common causes of chronic haemolytic anemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells (RBCs) from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain

Red Blood Cell Membrane Conductance in Hereditary Haemolytic Anaemias

Congenital haemolytic anaemias are inherited disorders caused by red blood cell membrane and cytoskeletal protein defects, deviant hemoglobin synthesis and metabolic enzyme deficiencies. In many cases, although the causing mutation might be known, the pathophysiology and the connection between the particular mutation and the symptoms of the disease are not completely understood. Thus effective treatment is lagging behind. As in many cases abnormal red blood cell cation content and cation leaks go along with the disease, by direct electrophysiological measurements of the general conductance of red blood cells, we aimed to assess if changes in the membrane conductance could be a possible cause. We recorded whole-cell currents from 29 patients with different types of congenital haemolytic anaemias: 14 with hereditary spherocytosis due to mutations in α-spectrin, β-spectrin, ankyrin and band 3 protein; 6 patients with hereditary xerocytosis due to mutations in Piezo1; 6 patients with enzymatic disorders (3 patients with glucose-6-phosphate dehydrogenase deficiency, 1 patient with pyruvate kinase deficiency, 1 patient with glutamate-cysteine ligase deficiency and 1 patient with glutathione reductase deficiency), 1 patient with β-thalassemia and 2 patients, carriers of several mutations and a complex genotype. While the patients with β-thalassemia and metabolic enzyme deficiencies showed no changes in their membrane conductance, the patients with hereditary spherocytosis and hereditary xerocytosis showed largely variable results depending on the underlying mutation

First Description of Phosphofructokinase Deficiency In Spain: Identification Of A Novel Homozygous Missense Mutation In The PFKM Gene

Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-year-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anaemia. After ruling out the most common causes of chronic haemolytic anaemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain

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. © 2014 Aguilar Martinez et al. licensee BioMed Central Ltd.SCOPUS: re.jinfo:eu-repo/semantics/publishe

First description of phosphofructokinase deficiency in Spain: identification of a novel homozygous missense mutation in the PFKM gene

Phosphofructokinase deficiency is a very rare autosomal recessive disorder, which belongs to group of rare inborn errors of metabolism called glycogen storage disease. Here we report on a new mutation in the phosphofructokinase (PFK) gene PFKM identified in a 65-years-old woman who suffered from lifelong intermittent muscle weakness and painful spasms of random occurrence, episodic dark urines, and slight haemolytic anemia. After ruling out the most common causes of chronic haemolytic anemia, the study of a panel of 24 enzyme activities showed a markedly decreased PFK activity in red blood cells (RBCs) from the patient. DNA sequence analysis of the PFKM gene subsequently revealed a novel homozygous mutation: c.926A>G; p.Asp309Gly. This mutation is predicted to severely affect enzyme catalysis thereby accounting for the observed enzyme deficiency. This case represents a prime example of classical PFK deficiency and is the first reported case of this very rare red blood cell disorder in Spain

Combining microfluidics with machine learning algorithms for RBC classification in rare hereditary hemolytic anemia

Combining microfuidics technology with machine learning represents an innovative approach to conduct massive quantitative cell behavior study and implement smart decision-making systems in support of clinical diagnostics. The spleen plays a key-role in rare hereditary hemolytic anemia (RHHA), being the organ responsible for the premature removal of defective red blood cells (RBCs). The goal is to adapt the physiological spleen fltering strategy for in vitro study and monitoring of blood diseases through RBCs shape analysis. Then, a microfuidic device mimicking the slits of the spleen red pulp area and video data analysis are combined for the characterization of RBCs in RHHA. This microfuidic unit is designed to evaluate RBC deformability by maintaining them fxed in planar orientation, allowing the visual inspection of RBC's capacity to restore their original shape after crossing microconstrictions. Then, two cooperative learning approaches are used for the analysis: the majority voting scheme, in which the most voted label for all the cell images is the class assigned to the entire video; and the maximum sum of scores to decide the maximally scored class to assign. The proposed platform shows the capability to discriminate healthy controls and patients with an average efciency of 91%, but also to distinguish between RHHA subtypes, with an efciency of 82%

A previously unrecognized Ca2+-inhibited nonselective cation channel in red blood cells

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Red Cell Properties after Different Modes of Blood Transportation

Transportation of blood samples is unavoidable for assessment of specific parameters in blood of patients with rare anemias, blood doping testing, or for research purposes. Despite the awareness that shipment may substantially alter multiple parameters, no study of that extent has been performed to assess these changes and optimize shipment conditions to reduce transportation-related artifacts. Here we investigate the changes in multiple parameters in blood of healthy donors over 72 h of simulated shipment conditions. Three different anticoagulants (K3EDTA, Sodium Heparin, and citrate-based CPDA) for two temperatures (4°C and room temperature) were tested to define the optimal transportation conditions. Parameters measured cover common cytology and biochemistry parameters (complete blood count, hematocrit, morphological examination), red blood cell (RBC) volume, ion content and density, membrane properties and stability (hemolysis, osmotic fragility, membrane heat stability, patch-clamp investigations, and formation of micro vesicles), Ca(2+) handling, RBC metabolism, activity of numerous enzymes, and O2 transport capacity. Our findings indicate that individual sets of parameters may require different shipment settings (anticoagulants, temperature). Most of the parameters except for ion (Na(+), K(+), Ca(2+)) handling and, possibly, reticulocytes counts, tend to favor transportation at 4°C. Whereas plasma and intraerythrocytic Ca(2+) cannot be accurately measured in the presence of chelators such as citrate and EDTA, the majority of Ca(2+)-dependent parameters are stabilized in CPDA samples. Even in blood samples from healthy donors transported using an optimized shipment protocol, the majority of parameters were stable within 24 h, a condition that may not hold for the samples of patients with rare anemias. This implies for as short as possible shipping using fast courier services to the closest expert laboratory at reach. Mobile laboratories or the travel of the patients to the specialized laboratories may be the only option for some groups of patients with highly unstable RBCs