Academic literature on the topic 'Congenital dyserythropoietic anemia type II'

The most frequent form of congenital dyserythropoiesis (CDA) is congenital dyserythropoietic anemia II (CDA II). CDA II is a rare genetic anemia in humans, inherited in an autosomally recessive mode, characterized by hepatosplenomegaly normocytic anemia and hemolytic jaundice. Patients are usually transfusion-independent except in severe type. We are here reporting a case of severe transfusion-dependent type II congenital dyserythropoietic anemia in a 5-year-old patient who has undergone allogeneic hematopoietic stem cell transplantation (HSCT) at our bone marrow transplantation centre. Patient has had up until now more than 14 mL/kg/month of packed cell volume (PCV), which he required every 15 to 20 days to maintain his hemoglobin of 10 gm/dL and hematocrit of 30%. His pre-HSCT serum ferritin was 1500 ng/mL and he was on iron chelating therapy. Donor was HLA identical sibling (younger brother). The preparative regimen used was busulfan, cyclophosphamide, and antithymocyte globulin (Thymoglobulin). Cyclosporine and short-term methotrexate were used for graft versus host disease (GVHD) prophylaxis. Engraftment of donor cells was quick and the posttransplant course was uneventful. The patient is presently alive and doing well and he has been transfusion-independent for the past 33 months after HSCT.

Abstract Herein is described the case of a young woman presenting with iron overload and macrocytosis. The initial diagnosis was hereditary hemochromatosis. Severe anemia developed after a few phlebotomies, and she was also found to have congenital dyserythropoietic anemia that, though not completely typical, resembled type II. Only genetic testing allowed the definition of the coexistence of the 2 diseases, both responsible for the iron overload. This report points out the need to consider congenital dyserythropoietic anemia in patients with hemochromatosis and unexplained macrocytosis and, conversely, to check for the presence of hereditary hemochromatosis in patients with congenital dyserythropoietic anemia and severe iron overload. To the authors' knowledge, this is the first report of homozygosity for the C282Y mutation of the HFE gene in a patient affected by congenital dyserythropoietic anemia.

Herein is described the case of a young woman presenting with iron overload and macrocytosis. The initial diagnosis was hereditary hemochromatosis. Severe anemia developed after a few phlebotomies, and she was also found to have congenital dyserythropoietic anemia that, though not completely typical, resembled type II. Only genetic testing allowed the definition of the coexistence of the 2 diseases, both responsible for the iron overload. This report points out the need to consider congenital dyserythropoietic anemia in patients with hemochromatosis and unexplained macrocytosis and, conversely, to check for the presence of hereditary hemochromatosis in patients with congenital dyserythropoietic anemia and severe iron overload. To the authors' knowledge, this is the first report of homozygosity for the C282Y mutation of the HFE gene in a patient affected by congenital dyserythropoietic anemia.

Abstract Recessive mutations in SEC23B gene cause congenital dyserythropoietic anemia type II (CDAII), a rare hereditary disorder hallmarked by ineffective erythropoiesis, iron overload, and reduced expression of hepatic hormone hepcidin (Iolascon, 2013). The most recently described hepcidin regulator is the erythroblast-derived hormone erythroferrone (ERFE), a member of TNF-α superfamily that specifically inhibits hepcidin production in experimental models (Kautz, 2014). However, the function of ERFE in humans remains to be investigated. To determine whether dysregulation of ERFE expression is associated with ineffective erythropoiesis and iron-loading in CDAII, we studied the ERFE-encoding FAM132B gene expression in 48 SEC23B-related CDAII patients and 29 age and gender matched healthy controls (HCs). Twelve new cases and four novel SEC23B mutations were described. Samples were obtained after informed consent, according to the Declaration of Helsinki. Genomic DNA, mutational screening, RNA isolation, cDNA preparation, and qRT-PCR were performed as previously described (Russo, 2013). All patients were young adults (17.0±2.5 years at diagnosis), with increased serum ferritin (395.4±67.6 ng/mL) and transferrin saturation (71.9±5.4 %). We observed a statistically significant overexpression of FAM132B gene in peripheral blood mononuclear cells from CDAII patients (9.09±0.08) compared to HCs (8.32±0.12, p<0.0001). A similar trend was obtained when evaluating FAM132B expression in reticulocytes from a subset of patients and HCs. Of note, a statistically significant correlation between peripheral blood and reticulocyte FAM132B expression from the same patients was observed (Spearman ρ= 0.78, p=0.02). Although the role of ERFE in peripheral blood is still unknown, our observations suggested that the evaluation of FAM132B mRNA in peripheral blood is a reliable and easy-to-measure marker of ERFE levels. When we divided CDAII patients into two sub-groups accordingly to FAM132B gene expression, we observed a statistically significant reduction in hemoglobin (Hb) level in the high-FAM132B subset (8.6±0.4 g/dL) respect to low-FAM132B one (10.1±0.5 g/dL, p=0.02). Of note, the expression level of FAM132B did not correlate with the transfusion regimen. The higher amount of ERFE reflects the increased iron demand for Hb production as well as the expanding abnormal erythropoiesis, as attested by the increased RDW and sTfR (although not significant) in high-FAM132B patients. This in turn leads to reduced hepcidin in high-FAM132B group (4.2±1.8 nM) compared to low-FAM132B one (5.9±1.8 nM, p=0.05), resulting in augmented iron delivery to the erythron. Although the iron balance data do not differ significantly between the two groups, a tendency to decreased hepcidin/ferritin ratio and increased transferrin saturation was observed in high-FAM132B patients. Thus, FAM132B overexpression seems to contribute to the inappropriate suppression of hepcidin with subsequent hemosiderosis observed in CDAII. Consistent with our previous studies, we observed a reduced SEC23B expression in our patients compared to HC. Indeed, FAM132B and SEC23B gene expression exhibited an inverse correlation (Spearman ρ=-0.36, p=0.01). We confirmed the ex vivo data about inverse correlation between FAM132B and SEC23B expression observed in our patients by establishing K562 SEC23B-silenced cells. To knockdown SEC23B gene expression in K562 cells two different pGIPZ Lentiviral shRNAmir for SEC23B (shSEC23B-70/-74) were used. We observed a higher expression of FAM132B at 5 days of erythroid differentiation in K562 SEC23B-silenced cell compared to not-silenced ones. Conversely, SEC23B expression was lower in both shSEC23B compared to sh-CTR at 2 and 5 days of differentiation. Although the mechanisms of hemin-induced differentiation are quite different from EPO-induced ones, we can hypothesize that FAM132B over-expression is related to the maturative arrest and the subsequent increased number of erythroid precursors. This study provides the first analysis on ERFE regulation in humans. Our data suggest that ERFE over-expression in CDAII patients is the result of both physiological and pathological mechanisms leading to hepcidin suppression in condition of dyserythropoiesis. Nevertheless, it seems that ERFE cannot be the main erythroid regulator of hepcidin suppression, at least in CDAII patients. Disclosures No relevant conflicts of interest to declare.

Abstract Congenital dyserythropoietic anemia type II (CDA-II) is the most common form of inherited dyserythropoiesis. Previous studies have shown that the anion transporter (band 3) is narrower and it migrates faster on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE); this aspect was related to insufficient glycosylation. Biochemical data support the hypothesis that this disease is due to a deficiency of N-acetylglucosaminyltransferase II (GnT II) or α-Mannosidase II (α-Man II), which represent the key to glycosylation. In addition, a third candidate gene is α-Man IIx, which shows a strong homology with α-Man II. The knowledge of the chromosomal localization of these putative genes allowed us to perform a linkage study using three sets of microsatellite markers flanking the candidate genes. Six families with two or more affected children were enrolled in this study. The data obtained exclude linkage to all three candidate genes. In consideration of the biochemical data (reduction of enzymatic activity) of the same enzymes, our results suggest the hypothesis that a defect in an unknown transcriptional factor is involved in CDA-II.

Congenital Dyserythropoietic Anemias (CDAs) are subtypes of bone marrow failure syndromes, hallmarked by ineffective erythropoiesis. The most common form is CDA type II (CDAII), showing moderate/severe anemia, relative reticulocytopenia, jaundice, splenomegaly, and iron overload. It is inherited as an autosomal recessive disorder due to loss-of-function mutations in the SEC23B gene. Molecular pathogenesis of CDA II still has to be investigated because the described animal models did not recapitulate the clinical features observed in humans. To date, treatments for CDAII patients consist of supportive therapy, such as erythrocyte transfusions, or bone marrow transplantation or splenectomy in transfusion-dependent cases. Recently, members of TGF-β superfamily have been studied as potential regulators of erythropoiesis, especially the growth differentiation factor 11 (GDF11). Through the binding of specific receptors, GDF11 leads to an inhibited late-stage erythropoiesis. Indeed, two GDF11 inhibitors, ACE-011 and ACE-536, have been associated with an improvement of hematologic parameters. Studies with the mouse counterpart of ACE-011, RAP-011, on a mouse model of β-thalassemia showed increased differentiation of erythroid cells, improvement of the anemic condition and reduced iron overload in treated mice. The first aim of our study was the establishment of a cellular model of CDA II, that could reproduce the main defects of the disease, such as the lack of the erythroid differentiation due to the low or absent expression of SEC23B gene. For this aim, we selected the K562 cell line and, through short-hairpin RNA-based strategy, we obtained two different clones of K562 showing a stable silencing of SEC23B. Then, we decided to assess the effects of RAP-011 on this CDA II model, by investigating the pathway involved in the GDF11 signaling. This treatment simulated the ligand trap function played by RAP-011 towards GDF11. The administration of RAP-011 resulted in a reduction of SMAD2 phosphorylation induced by GDF11 and, moreover, in an increase of different erythroid differentiation markers.

The Congenital Dyserythropoietic Anemias (CDA) are rare hereditary hemolytic disorders with large bi- to multi-nucleated erythroblasts in the bone marrow. Hemolysis is negative in a direct antiglobulin test (DAT). Based on morphology and clinical picture, three major forms of CDAs, type I, II, and III have been defined. CDA III, dominantly inherited, constitutes the rarest type with a majority of cases belonging to a family in Västerbotten, Sweden. The genetic background of CDA I and CDA II has been linked to mutations in CDAN1 and SEC23B respectively. The mutation of CDA III has been linked to 15q22 in earlier studies. In this project we have defined the causative genetic lesion in two families with CDA III. The novel mutation KIF23 c.2747C>G (p.P916R) was shown to segregate with CDA III in the Swedish and American CDA III families and was absent in 356 healthy controls. KIF23 encodes mitotic kinesin-like protein 1 (MKLP1), which plays a central role in the last step of cytokinesis. RNAi-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, resulting in increasing number of bi-nuclear cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23, encoding MKLP1, a conserved mitotic kinesin crucial for cytokinesis. Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis, is also seen in CDA II, while reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55, and CD59 on erythrocytes in CDA III. We found no abnormality of the erythrocyte membrane in CDA III and concluded that standard flow cytometry cannot be used to discriminate between CDA III and normal controls. In CDA I and CDA II a majority of patients, including those who are not transfusion dependent, suffer from iron overload, which, according to earlier studies, is not the case in CDA III. We found that individuals of the Västerbotten CDA III family carry mutations in the hemochromatosis (HFE) gene. Three CDA III patients with heterozygous or compound HFE mutations need treatment with phlebotomy due to iron overload. One of them carries heterozygous H63D mutation, which is not reported to lead to iron overload by itself in otherwise healthy individuals. We propose that molecular genetic testing of the HFE gene is indicated in all patients with CDA, including CDA III.