Search

Fanconi anemia is a genetically-transmitted disease caused by biallelic inactivating mutations in more than 20 genes. While its main symptoms include severe anemia, other cytopenias and skin pigmentation impairments, the aspect which concerns both patients and caregivers is the connection between Fanconi anemia and the development of several malignancies, especially breast, skin and blood-related cancers, as well as squamous cell carcinomas. Current treatment methods rely on anemia correction through stem cell transplantation, however it has become more and more evident that modern and more efficient therapies need to be developed. This needs-led literature review provides an overview of the main highlights in Fanconi anemia current and emerging therapeutic directions in order to improve the patients’ quality of life.

Part 1: New crossroads. The first part describes two new concepts in an attempt to unravel novel pathophysiological features of hereditary anemias. Chapter 2 reviews the pathophysiological aspects of pyruvate kinase (PK) deficiency, focusing on the interplay between PK-activity and reticulocyte maturation, stretching the importance of adequate oxidative control for normal mitophagy, which forms the fulfilling step of reticulocyte maturation. We propose late-stage ineffective erythropoiesis as a key pathophysiological concept in pyruvate kinase deficiency. Chapter 3 and 4 focusses on the erythropoietin (EPO)-fibroblast growth factor 23 (FGF23) signaling pathway in hereditary anemias. This, only briefly, previously described link between EPO and FGF23 may add to the understanding of (insufficient) EPO upregulation or responsiveness in hereditary anemias, as well as the bone mineralization disorders complicating these diseases. We speculate on a potential role for this pathway, not directly linked to erythroferrone (ERFE), as a target for treatment with the opportunity to ameliorate ineffective erythropoiesis and development of disease complications. Part 2: The challenge called heterogeneity. This part includes three articles that discuss unique disease characteristics and unique phenotypic appearances. Sickle cell disease earned a unique place among the hemolytic anemias as an important part of hemolysis does not occur extravascular (e.g. in the spleen or liver), but in the (micro)circulation itself. The relative balance between intra- and extravascular hemolysis seems to determine one’s risk of vasculopathic disease complications. In chapter 5 we introduce a ratio of two laboratory markers that represents the contribution of intravascular hemolysis to total hemolysis in an individual sickle cell disease patient, and this simple ratio was clearly associated with pulmonary hypertension and early death. Chapter 6 describes the unique monocyte transcriptome of sickle cell disease patients, sketching the balance of both pro- and anti-inflammatory pathways. In this chapter, we highlight the leading role of heme-oxygenase 1, an enzyme that breaks down heme, in determining this balance. Chapter 7 describes our attempt to untangle the relation between genotypes and phenotypes in hereditary spherocytosis. Which turned out to be an unproductive attempt. This led us speculating on the importance of other (genetic and non-genetic) modifying factors in determining phenotypic profiles. Part 3: About iron. This part focusses on the interplay between iron and erythropoiesis. Chapter 8 functions as a bridge between part 2 and part 3, as it reports on disease- specific patterns of the EPO-ERFE-hepcidin signaling pathway regulating iron. However, with the notion that broad inter-individual variety exists in each disease. Chapter 9 reflects on old, previously unpublished iron absorption and ferrokinetic data. This data provides an answer on the question what happens with intestinally absorbed iron in an already saturated portal circulation. And finally, chapter 10 describes the results of the PPI shine again study, a phase III randomized, placebo-controlled trial in a cross-over design investigating the efficacy of proton pump inhibitors in the prevention and treatment of iron-loading in patients with non-transfusion-dependent hereditary anemias.

Part 1: New crossroads. The first part describes two new concepts in an attempt to unravel novel pathophysiological features of hereditary anemias. Chapter 2 reviews the pathophysiological aspects of pyruvate kinase (PK) deficiency, focusing on the interplay between PK-activity and reticulocyte maturation, stretching the importance of adequate oxidative control for normal mitophagy, which forms the fulfilling step of reticulocyte maturation. We propose late-stage ineffective erythropoiesis as a key pathophysiological concept in pyruvate kinase deficiency. Chapter 3 and 4 focusses on the erythropoietin (EPO)-fibroblast growth factor 23 (FGF23) signaling pathway in hereditary anemias. This, only briefly, previously described link between EPO and FGF23 may add to the understanding of (insufficient) EPO upregulation or responsiveness in hereditary anemias, as well as the bone mineralization disorders complicating these diseases. We speculate on a potential role for this pathway, not directly linked to erythroferrone (ERFE), as a target for treatment with the opportunity to ameliorate ineffective erythropoiesis and development of disease complications. Part 2: The challenge called heterogeneity. This part includes three articles that discuss unique disease characteristics and unique phenotypic appearances. Sickle cell disease earned a unique place among the hemolytic anemias as an important part of hemolysis does not occur extravascular (e.g. in the spleen or liver), but in the (micro)circulation itself. The relative balance between intra- and extravascular hemolysis seems to determine one’s risk of vasculopathic disease complications. In chapter 5 we introduce a ratio of two laboratory markers that represents the contribution of intravascular hemolysis to total hemolysis in an individual sickle cell disease patient, and this simple ratio was clearly associated with pulmonary hypertension and early death. Chapter 6 describes the unique monocyte transcriptome of sickle cell disease patients, sketching the balance of both pro- and anti-inflammatory pathways. In this chapter, we highlight the leading role of heme-oxygenase 1, an enzyme that breaks down heme, in determining this balance. Chapter 7 describes our attempt to untangle the relation between genotypes and phenotypes in hereditary spherocytosis. Which turned out to be an unproductive attempt. This led us speculating on the importance of other (genetic and non-genetic) modifying factors in determining phenotypic profiles. Part 3: About iron. This part focusses on the interplay between iron and erythropoiesis. Chapter 8 functions as a bridge between part 2 and part 3, as it reports on disease- specific patterns of the EPO-ERFE-hepcidin signaling pathway regulating iron. However, with the notion that broad inter-individual variety exists in each disease. Chapter 9 reflects on old, previously unpublished iron absorption and ferrokinetic data. This data provides an answer on the question what happens with intestinally absorbed iron in an already saturated portal circulation. And finally, chapter 10 describes the results of the PPI shine again study, a phase III randomized, placebo-controlled trial in a cross-over design investigating the efficacy of proton pump inhibitors in the prevention and treatment of iron-loading in patients with non-transfusion-dependent hereditary anemias.

Anemia affects about the 25% of the global population and can provoke severe diseases, ranging from weakness and dizziness to pregnancy problems, arrhythmias and hearth failures. About 10% of the patients are affected by rare anemias of which 80% are hereditary. Early differential diagnosis of anemia enables prescribing patients a proper treatment and diet, which is effective to mitigate the associated symptoms. Nevertheless, the differential diagnosis of these conditions is often difficult due to shared and overlapping phenotypes. Indeed, the complete blood count and unaided peripheral blood smear observation cannot always provide a reliable differential diagnosis, so that biomedical assays and genetic tests are needed. These procedures are not error-free, require skilled personnel, and severely impact the financial resources of national health systems. Here we show a differential screening system for hereditary anemias that relies on holographic imaging and artificial intelligence. Label-free holographic imaging is aided by a hierarchical machine learning decider that works even in the presence of a very limited dataset but is enough accurate for discerning between different anemia classes with minimal morphological dissimilarities. It is worth to notice that only a few tens of cells from each patient are sufficient to obtain a correct diagnosis, with the advantage of significantly limiting the volume of blood drawn. This work paves the way to a wider use of home screening systems for point of care blood testing and telemedicine with lab-on-chip platforms.

The hereditary anemias are a relatively heterogeneous set of disorders that can show wide clinical and genetic heterogeneity, which often hampers correct clinical diagnosis. The classical diagnostic workflow for these conditions generally used to start with analysis of the family and personal histories, followed by biochemical and morphological evaluations, and ending with genetic testing. However, the diagnostic framework has changed more recently, and genetic testing is now a suitable approach for differential diagnosis of these patients. There are several approaches to this genetic testing, the choice of which depends on phenotyping, genetic heterogeneity, and gene size. For patients who show complete phenotyping, single-gene testing remains recommended. However, genetic analysis now includes next-generation sequencing, which is generally based on custom-designed targeting panels and whole-exome sequencing. The use of next-generation sequencing also allows the identification of new causative genes, and of polygenic conditions and genetic factors that modify disease severity of hereditary anemias. In the research field, whole-genome sequencing is useful for the identification of non-coding causative mutations, which might account for the disruption of transcriptional factor occupancy sites and cis-regulatory elements. Moreover, advances in high-throughput sequencing techniques have now resulted in the identification of genome-wide profiling of the chromatin structures known as the topologically associating domains. These represent a recurrent disease mechanism that exposes genes to inappropriate regulatory elements, causing errors in gene expression. This review focuses on the challenges of diagnosis and research into hereditary anemias, with indications of both the advantages and disadvantages. Finally, we consider the future perspectives for the use of next-generation sequencing technologies in this era of precision medicine.

BACKGROUND: Genetic red cell disorders are common in Arabic countries with a significant burden on healthcare systems. OBJECTIVES: We aimed was to assess the level of awareness of Saudi females toward potential risk of the most common inherited anemia in the region. METHODS: A cross-sectional questionnaire-based study was undertaken on 386 undergraduate students. RESULTS: The majority (60%) of participants have a poor knowledge score. The self-reported incidence of sickle cell anemia, glucose-6-phosphate dehydrogenase deficiency, and thalassemia among them was 7.3%, 4.9%, and 3.4%, respectively. Even though the majority (86.8%) expressed a positive attitude toward premarital screening tests, a wrong perception was noticed as 45.1% of them believe that irrespective of the test result, marriage decision will not be changed and 38.9% will refuse to marry a person who is a carrier of inherited anemia even if she is free of same disorder. Only 47.4% will refuse to marry a carrier if she was the carrier of some genetic disorders. CONCLUSION: Inadequate knowledge and wrong perception reflect the need to raise their awareness. Mass media should be greatly encouraged. Long-term regular targeted health education campaigns should be designed for adult Saudi, thereby reducing the burden and detrimental effect of these disorders in the community.

β-Thalassemia (β-thal) is a common hereditary anemia due to decreased or absent synthesis of the β-globin chains. Here, we report a patient found to be a novel compound heterozygote for the rare IVS-II-5 (G > C) (NG_000007.3: g.71044G > C) and IVS-II-672 (A > C) (NG_000007.3: g.71711A > C) mutations, which may be silent mutations that are associated with consistent residual output of β chains, normal red blood cell (RBC) indices and normal or borderline Hb A2 levels.

Chronic blood transfusions are necessary for patients with hereditary anemia such as thalassemia, and for patients with myelodysplastic syndrome (MDS) who become anemic and transfusion-dependent. A common consequence of chronic transfusion is iron accumulation that can lead to organ damage. While there is general agreement regarding the value of iron chelation therapy to reduce the detrimental effects of iron overload in thalassemia major, the same is not true for MDS. The malignant nature of the disease and the relatively high cost of iron chelation therapy make cost-effectiveness an issue of great concern. Furthermore, the positive assessment of a drug's cost-effectiveness in one country does not necessarily justify its use in another country. More prospective studies are needed to identify the best iron chelator for patients with MDS as well as to identify those patients who will benefit most from iron chelation therapy.

β-Thalassemia (β-thal) is the most common hereditary anemia in humans. With improvement of treatment protocols, patients are living longer and new complications have emerged. Few articles have reported the occurrence of malignancies among patients with β-thal in different parts of the world. We herein report the first pediatric patient with β-thal major (β-TM), who developed acute lymphoblastic leukemia in Egypt with analysis of the different theories of pathogenesis.

Hereditary spherocytosis is the most frequent hereditary anemia excluding beta thalassemia in Argentina. Historical, demographic, genetic and pathogenic aspects of the disease are reviewed, and confirmatory laboratory tests are described. Special characteristics on the outcome of the disease in our population and prevalent protein deficiencies in our country are described. Emphasis is given on new available laboratory tests, which allow an earlier diagnosis using volume of blood samples significantly smaller than required for conventional tests.

β-Thalassemia (thal) is a common hereditary anemia caused by mutations that reduce or abolish expression from the β-globin genes. More than 180 different β-thal mutations have been reported, the va...

The hereditary anemia is the more common monogenetic illnessesin the Brazilian population. Among hemoglobinopaties, mostprevalent they are the ones that involve hemoglobin S and C, thatlead characteristic the clinical picture when in homozygosis orheterozygosity bearers of hemoglobin in couples with congenitaldiseases of hemoglobin.. With the objective to determine the frequencyof carriers of the heterozygote form of hemoglobinopaties, 748samples of blood of healthful women and its just born had beenanalyzed, enlisted in all the maternities of Aracaju-Sergipe. Thesamples that had presented abnormal hemoglobin had beensubmitted to the test of solubility and electrophoreses of hemoglobinin acid gel of agarosis. The frequency of puerperal women carryingof Hb S was 4.0%, Hb AC 1.9% and Hb AJ 0.3%. Among newbornwas observed Hb FAS 4.5%, Hb FAC 1,3% and Hb FAJ 0.5%. Thejoined results suggest to be raised the frequency of healthful womenand its children in Aracaju, and denote the necessity of implantationof gratuitous universal neonatal selection for hemoglobinopaties inthe state of Sergipe as well as in all Brazil, the example of whatalready it occurs in some states. The identification of carriersassociated to the individual genetic counseling to of the couplesmakes possible a conscientious decision with regard to futuregestations. Rev. Bras. Hematol. Hemoter. 2009

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T18:43:21Z No. of bitstreams: 1 S1676-24442006000600004.pdf: 148115 bytes, checksum: d83c239a191ded822a0dfb19511ab3de (MD5) Made available in DSpace on 2013-08-22T18:43:21Z (GMT). No. of bitstreams: 1 S1676-24442006000600004.pdf: 148115 bytes, checksum: d83c239a191ded822a0dfb19511ab3de (MD5) Previous issue date: 2006-12-01 Made available in DSpace on 2013-09-30T19:30:58Z (GMT). No. of bitstreams: 2 S1676-24442006000600004.pdf: 148115 bytes, checksum: d83c239a191ded822a0dfb19511ab3de (MD5) S1676-24442006000600004.pdf.txt: 27259 bytes, checksum: 1a941172f3b45817b695710cbd42fdb1 (MD5) Previous issue date: 2006-12-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T15:08:30Z No. of bitstreams: 2 S1676-24442006000600004.pdf: 148115 bytes, checksum: d83c239a191ded822a0dfb19511ab3de (MD5) S1676-24442006000600004.pdf.txt: 27259 bytes, checksum: 1a941172f3b45817b695710cbd42fdb1 (MD5) Made available in DSpace on 2014-05-20T15:08:30Z (GMT). No. of bitstreams: 2 S1676-24442006000600004.pdf: 148115 bytes, checksum: d83c239a191ded822a0dfb19511ab3de (MD5) S1676-24442006000600004.pdf.txt: 27259 bytes, checksum: 1a941172f3b45817b695710cbd42fdb1 (MD5) Previous issue date: 2006-12-01 As anemias hereditárias, em especial as talassemias e hemoglobinas (Hb) variantes, são as mais comuns das alterações genéticas humanas; sua freqüência na população brasileira é muito variável, dependendo dos grupos raciais formadores de cada região. O povoamento de Goiás, que teve início logo após o seu descobrimento, em 1726, motivado pela procura de ouro, foi composto principalmente por portugueses e escravos africanos, contexto que favoreceu a mestiçagem entre eles. Considerando que esses povos apresentam genes para as hemoglobinas anormais com freqüências variadas, é esperado que se encontrem essas alterações genéticas na nossa população. O objetivo deste trabalho foi avaliar a prevalência de talassemias e hemoglobinas variantes na população de Goiás. Para isso a casuística foi composta por 404 alunos participantes dos diversos cursos da Universidade Católica de Goiás (UCG), oriundos de 55 cidades do estado de Goiás. A prevalência de anemia hereditária por talassemias e hemoglobinas variantes em Goiás foi de 10,1%, cuja ordem decrescente foi a seguinte: talassemia alfa heterozigótica (5,2%), heterozigose para hemoglobina S (Hb AS) (2,2%), heterozigose para hemoglobina C (Hb AC) (1%), talassemia beta menor (0,7%), associação entre talassemia alfa e heterozigose para Hb S (0,5%), associação entre talassemia alfa e heterozigose para Hb C (0,3%) e heterozigose para hemoglobina D (Hb AD) (0,3%). Nenhum caso de homozigose foi encontrado no presente estudo. Este trabalho demonstrou a dispersão dos genes para Hb S, Hb C e Hb D, bem como de talassemias alfa e beta em uma população do estado de Goiás. Por essa razão, concluímos que é importante realizar programas com maior abrangência da população para estudo da epidemiologia das talassemias e hemoglobinas variantes no estado de Goiás. The hereditary anemias, especially the thalassemies and hemoglobinopathies are the most common human genetic abnormalities. Their frequency in the Brazilian population is very variable depending on the racial groups typical of each region. The settlement of Goiás, that had its beginning after discovery in 1726 owing to the search for gold, was composed basically by Portuguese and African slaves, a context that favored the racial mixing among them. Considering that these groups present genes for abnormal hemoglobins with varied frequencies it is expected the finding of these genetic abnormalities within our population. The objective of this study was to evaluate the prevalence of thalassemies and variant hemoglobins in the population of Goiás. For this purpose the sample was composed by 404 participating students from several graduate courses of the Catholic University of Goiás originally from 55 cities of the state of Goiás. Laboratory tests were used taking into account the historical and demographic factors of the population. The prevalence of hereditary anemias by thalassemias and variant hemoglobins in Goiás was 10.1%, in which the decreasing order of these abnormalities was: alfa heterozygous thalassemy (5.2%); heterozygous hemoglobin S (Hb AS) (2.2%); heterozygous hemoglobin C (Hb AC) (1%); beta short thalassemy (0.7%); association between alpha thalassemy and heterozygous for hemoglobin S (0.5%); association between alpha thalassemy and heterozygous for hemoglobin C (0.3%); and heterozygous for hemoglobin D (0.3%). No homozygosity was found in the study group. This study demonstrates the need for large scale screening in human populations for epidemiological studies of the thalassemies and variant hemoglobins in the state of Goiás. Universidade Federal de Goiás (UFG) Universidade Católica de Goiás Departamento de Biomedicina UNESP Academia de Ciência e Tecnologia UFG Instituto de Ciências Biológicas Departamento de Biologia Geral UCG Departamento de Biomedicina Laboratório de Estudo e Pesquisa de Anemia Hereditária Prof. Dr. Paulo Cesar Naoum UFG ICB Laboratório de Rádiobiologia e Mutagênese UNESP Academia de Ciência e Tecnologia

Beta-thalassemia, the most common hereditary anemia in the Mediterranean area, results from over 200 causative mutations in the beta-globin locus. The aim of this study was to validate a denaturing high-performance liquid chromatography (dHPLC)-based assay for postnatal and prenatal molecular diagnosis of beta-thalassemia in Southern Italy. Sixty beta-thalassemic patients, affected either by thalassemia intermedia or thalassemia major, were analyzed in a blind study. We also carried out prenatal molecular diagnosis in 12 couples at-risk for having affected offspring. Chorionic villi samples were subjected to dHPLC analysis upon molecular characterization of the parental beta-globin alleles. Direct sequence analysis was used to validate each result, showing an accuracy rate of 100% for dHPLC. Overall, our protocol was able to identify the responsible mutations in all 96 analyzed subjects (including 12 prenatals in at-risk pregnancies), detecting the eight most common mutations in Southern Italy. Three rare mutations (one of which, reported here for the first time) that standard mutation detection methods failed to reveal, were also identified. dHPLC assay proved to be a reliable, rapid, and sensitive method for detecting both common and rare mutations within the beta-globin gene. Because of this property our protocol has the potential to be implemented for mutational screening in different areas of high prevalence for beta-thalassemia.

A family suggesting cosegregation of beta-thalassemia minor and bipolar affective disorder was reported. The monogenic hereditary anemia was surveyed over three generations in this family, and three patients with the beta-thalassemia and the bipolar affective disorder were observed over two generations. The localization of a gene responsible for bipolar affective disorder was discussed on the basis of previous reports.

Hemochromatosis has been reported in several patients with chronic hemolytic anemia due to pyruvate kinase deficiency. We describe here a further patient with such an association and review the literature on the subject. We hypothesize that iron overload may occur in patients with pyruvate kinase deficiency who are also carriers of the hereditary hemochromatosis gene.

Abnormalities of erythroid cells in the bone marrow of anemic CFO mice (hea/hea) with hereditary congenital erythroblastic anemia were not evident, while abundant erythroblasts, especially orthochromatophilic erythroblasts, were observed in the circulation and many showed abnormalities. Among them by electron microscopy, cytoplasmic aggregations of ribosomes and cytoplasmic lattice-like inclusions were characteristic of the hereditary congenital erythroblastic anemia.

The homozygous young of the dominant white mouse ordinarily live throughout the whole period of gestation and not infrequently for several days after birth. No evidence is found that their prenatal death-rate is greater than that of the normal individuals of the same litter. They are characterized, at least from the sixteenth day of gestation, by a special form of anemia which is the real cause of death.

This hereditary anemia is most severe in young mice and tends to diminish with increasing age. Erythrocytes show great variation in size and form, with hypochromia and formation of target cells. Though the anemia occurs on a normal diet, it responds rapidly to iron-dextran injection. It may represent an unusual primary disturbance of iron metabolism.