Acquired Elliptocytosis as a Manifestation of Myelodysplastic Syndrome with Ring Sideroblasts and Multilineage Dysplasia.

Acquired elliptocytosis is a known but rarely described abnormality in the myelodysplastic syndromes (MDS). Here we report the case of an elderly male who was admitted to the hospital with chest pain, dyspnea, and fatigue and was found to be anemic with an elliptocytosis that had only recently been noted on peripheral smears of his blood. After bone marrow biopsy he was diagnosed with MDS with ring sideroblasts and multilineage dysplasia and acquired elliptocytosis. Here we report a rare case of acquired elliptocytosis cooccurring with MDS with ring sideroblasts and multilineage dysplasia

Hemoglobinuria paroxística nocturna: estudio de la enfermedad y sus tratamientos

Paroxysmal nocturnal hemoglobinuria (PNH), term established by Enneking in 1925, is a rare, clonal, and acquired disease of the hematopoietic stem cells. Generally, it starts with a mutation in the PIG -A gene, causing a deficiency of membrane proteins, such as CD55 and CD59. However, recent studies treveal that the clonal architecture of the disease is far more complex. Due to the deficiency of these proteins, there is an uncontrolled activation of the complement, which is associated with hemolysis and other clinical manifestations very variable among patients. PNH is also associated with aplastic anemia, in fact, it has been observed that both diseases are closely related, being able to derive one from the other over time. Because of the great variability of symptoms, the diagnosis of the disease has always been an arduous task. But this paper study a recent technique that has facilitated this work: flow cytometry. Until recently, there were only two main therapies for patients with PNH; allogeneic bone marrow transplantation and supportive treatment against symptoms. But at the beginning of the millennium, Eculizumab, marketed as Soliris®, a huma nized anti -C5 monoclonal antibody, protein of the complement system, was introduced, which has been a major advance in the treatment of the disease. As a result of its discovery, new strategies of complement inhibition have been investigated. Due to the hi gh morbimortality and the great impact on patients with PNH, the latest advances in research during the last decade could not be more encouragingLa Hemoglobinuria Paroxística N octurna (HPN), término establecido en 1925 por Enneking, es una enfermedad rara, clonal y adquirida de las células madr e hematopoyéticas. Generalmente se inicia con una mutación en el gen PIG -A, causando una deficiencia de proteínas membranales, como CD55 y CD59. Sin embargo, estudios más recientes ponen de manifiesto que la arquitectura clonal de la enfermedad es bastante más compleja. Debido a la deficiencia de dichas proteínas, se produce una activación descontrolada del complement o, que se asocia a hemó lisis y a otras manifestaciones clínicas muy variables entre pacientes. La HPN también se asocia a la anemia aplásica, de hecho, se ha observado que ambas enfermedades están estrechamente relacionadas, pudiendo derivar una en la otra con el tiempo. A causa de la gran variabilidad de síntomas, el diagnóstico de la enfermedad ha sido siempre una ardua tarea. En este ensayo se estudia una técnica recien te que ha facilitado esta labor, la citometría de flujo. Hasta hace poco, solo existí an dos terapias principales para los pacientes con HPN; el trasplante alogénico de médula ósea y el tratamiento de apoyo contra los síntomas. Pero a principios del milenio, se introdujo en el esquema terapéutico el Eculizumab, comercializado como Soliris®, un anticuerpo monoclonal humanizado anti -C5, proteína del sistema del complemento. Ha constituido un avance primordial para el tratamiento de la enfermedad, a raíz de su descubrimiento, se ha comenzado a investigar nuevas estrategias de inhibición del complemento. Debido a la alta morbimortalidad y el gran impacto que supone la HPN en quien la padece, que se esté avanzando tanto en la última década resulta alentadorUniversidad de Sevilla. Grado en Farmaci

Atypical hemolytic uremic syndrome : update on the complement system and what is new

Atypical hemolytic uremic syndrome (aHUS) is a rare disease of microangiopathic hemolytic anemia, thrombocytopenia, and predominant renal impairment. It is characterized by the absence of Shiga toxin-producing bacteria as a triggering factor. During the last decade, aHUS has been demonstrated to be a disorder of the complement alternative pathway dysregulation, as there is a growing list of mutations and polymorphisms in the genes encoding the complement regulatory proteins that alone or in combination may lead to aHUS. Approximately 60% of aHUS patients have so-called 'loss-of-function' mutations in the genes encoding the complement regulatory proteins, which normally protect host cells from complement activation: complement factor H (CFH), factor I (CFI) and membrane cofactor protein (MCP or CD46), or have 'gain-of-function' mutations in the genes encoding the complement factor B or C3. In addition, approximately 10% of aHUS patients have a functional CFH deficiency due to anti-CFH antibodies. Recent advances in understanding the pathogenesis of aHUS have led to a revised classification of the syndrome. Normal plasma levels of CFH and CFI do not preclude the presence of a mutation in these genes. Further, genotype-phenotype correlations of aHUS have clinical significance in predicting renal recovery and transplant outcome. Therefore, it is important to make a comprehensive analysis and perform genetic screening of the complement system in patients with aHUS to allow a more precise approach, especially before transplantation. This may also provide opportunities for more specific treatments in the near future, as complement inhibition could represent a therapeutic target in these patients who have a considerably poor prognosis in terms of both mortality and progression to end-stage renal disease and a great risk of disease recurrence after transplantation

Absence of CD59 in guinea pigs: Analysis of the Cavia porcellus genome suggests the evolution of a CD59 pseudogene

CD59 is a membrane-bound regulatory protein that inhibits the assembly of the terminal membrane attack complex (C5b-9) of complement. From its original discovery in humans almost 30 years ago, CD59 has been characterized in a variety of species, from primates to early vertebrates, such as teleost fish. CD59 is ubiquitous in mammals; however, we have described circumstantial evidence suggesting that guinea pigs (Cavia porcellus) lack CD59, at least on erythrocytes. In this study, we have used a combination of phylogenetic analyses with syntenic alignment of mammalian CD59 genes to identify the only span of genomic DNA in C. porcellus that is homologous to a portion of mammalian CD59 and show that this segment of DNA is not transcribed. We describe a pseudogene sharing homology to exons 2 through 5 of human CD59 present in the C. porcellus genome. This pseudogene was flanked by C. porcellus homologs of two genes, FBXO3 and ORF91, a relationship and orientation that were consistent with other known mammalian CD59 genes. Analysis using RNA sequencing confirmed that this segment of chromosomal DNA was not transcribed. We conclude that guinea pigs lack an intact gene encoding CD59; to our knowledge, this is the first report of a mammalian species that does not express a functional CD59. The pseudogene we describe is likely the product of a genomic deletion event during its evolutionary divergence from other members of the rodent order

Splanchnic vein thrombosis in myeloproliferative neoplasms: Pathophysiology and molecular mechanisms of disease

Myeloproliferative neoplasms (MPNs) are the most common underlying prothrombotic disorder found in patients with splanchnic vein thrombosis (SVT). Clinical risk factors for MPN-associated SVTs include younger age, female sex, concomitant hypercoagulable disorders, and the JAK2 V617F mutation. These risk factors are distinct from those associated with arterial or deep venous thrombosis (DVT) in MPN patients, suggesting disparate disease mechanisms. The pathophysiology of SVT is thought to derive from local interactions between activated blood cells and the unique splanchnic endothelial environment. Other mutations commonly found in MPNs, including CALR and MPL, are rare in MPN-associated SVT. The purpose of this article is to review the clinical and molecular risk factors for MPN-associated SVT, with particular focus on the possible mechanisms of SVT formation in MPN patients

Complement System Part II: Role in Immunity

International audienceThe complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target

The dynamics of causes and conditions: the rareness of diseases in French and Portuguese patients' organizations' engagement in research

http://www.csi.mines-paristech.fr/Items/WorkingPapers/Download/DLWP.php?wp=WP_CSI_026.pdfHighlights the emergence of a "hybrid collective model" of collaboration between patients and experts through a systematic study in the field of rare diseases in France and Portugal, with attention to the reflexive work carried out by patients' organizations on the notion of rareness

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs