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β-Thalassemia is caused by reduced (β + ) or absent (β 0 ) synthesis of the β-globin chains of hemoglobin. Three clinical and hematological conditions of increasing severity are recognized: the β-thalassemia carrier state, thalassemia intermedia, and thalassemia major, a severe transfusion-dependent anemia. The severity of disease expression is related mainly to the degree of α-globin chain excess, which precipitates in the red blood cell precursors, causing both mechanic and oxidative damage (ineffective erythropoiesis). Any mechanism that reduces the number of unbound α-globin chains in the red cells may ameliorate the detrimental effects of excess α-globin chains. Factors include the inheritance of mild/silent β-thalassemia mutations, the coinheritance of α-thalassemia alleles, and increased γ-globin chain production. The clinical severity of β-thalassemia syndromes is also influenced by genetic factors unlinked to globin genes as well as environmental conditions and management. Transfusions and oral iron chelation therapy have dramatically improved the quality of life for patients with thalassemia major. Previously a rapidly fatal disease in early childhood, β-thalassemia is now a chronic disease with a greater life expectancy. At present, the only definitive cure is bone marrow transplantation. Therapies undergoing investigation are modulators of erythropoiesis and stem cell gene therapy. Genet Med advance online publication 03 November 2016

Heart disease is among the primary causes of morbidity and mortality in β-thalassemia major (β-TM). Conventional echocardiography has failed to identify myocardial dysfunction at an early stage among these patients, thus speckle tracking echocardiography (STE) has been lately used. The objectives of this review were to 1) identify all published studies having evaluated myocardial strain among β-TM patients, 2) gather their results, 3) compare their findings and 4) propose recommendations based on these data. Literature search was conducted in PubMed, SCOPUS and Cohrane Library. Data regarding left ventricular global longitudinal (LV-GLS), circumferential (LV-GCS) and radial strain (LV-GRS), right ventricular longitudinal strain (RV-GLS), left and right atrial strain were extracted. Thirty-five studies (34 original articles and 1 meta-analysis) have met the inclusion criteria. LV-GLS has been reported being worse in patients compared to controls in 13 of 21 studies, LV-GCS in 7 of 11 studies, LV-GRS in 6 of 7 studies, RV-GLS in 2 of 3 studies and left atrial strain in all case–control studies. Myocardial iron overload (MIO) patient subgroups had worse LV-GLS in 6 of 15 studies, LV-GCS in 2 of 7 studies and LV-GRS in none of 7 studies. A small number of studies suggest left atrial strain correlation with electrical atrial ectopy and atrial fibrillation. It is suggested that STE should be applied supplementary to conventional echocardiography for early identification of myocardial dysfunction among β-TM patients. Potential myocardial strain utilities could be screening for myocardial iron overload, left ventricular diastolic dysfunction and atrial fibrillation.

The thalassemias are a group of inherited hematologic disorders caused by defects in the synthesis of one or more of the hemoglobin chains. Alpha thalassemia is caused by reduced or absent synthesis of alpha globin chains, and beta thalassemia is caused by reduced or absent synthesis of beta globin chains. Imbalances of globin chains cause hemolysis and impair erythropoiesis. Silent carriers of alpha thalassemia and persons with alpha or beta thalassemia trait are asymptomatic and require no treatment. Alpha thalassemia intermedia, or hemoglobin H disease, causes hemolytic anemia. Alpha thalassemia major with hemoglobin Bart's usually results in fatal hydrops fetalis. Beta thalassemia major causes hemolytic anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major. Persons with thalassemia should be referred for preconception genetic counseling, and persons with alpha thalassemia trait should consider chorionic villus sampling to diagnose infants with hemoglobin Bart's, which increases the risk of toxemia and postpartum bleeding. Persons with the thalassemia trait have a normal life expectancy. Persons with beta thalassemia major often die from cardiac complications of iron overload by 30 years of age.

Alternative splicing is a major cellular mechanism in metazoans for generating proteomic diversity. A large proportion of protein-coding genes in multicellular organisms undergo alternative splicing, and in humans, it has been estimated that nearly 90 % of protein-coding genes—much larger than expected—are subject to alternative splicing. Genomic analyses of alternative splicing have illuminated its universal role in shaping the evolution of genomes, in the control of developmental processes, and in the dynamic regulation of the transcriptome to influence phenotype. Disruption of the splicing machinery has been found to drive pathophysiology, and indeed reprogramming of aberrant splicing can provide novel approaches to the development of molecular therapy. This review focuses on the recent progress in our understanding of alternative splicing brought about by the unprecedented explosive growth of genomic data and highlights the relevance of human splicing variation on disease and therapy.

Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload. In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A \"moving window\" approach was taken to understand the strength of the association at different levels of iron overload. The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, <20ms, r2 = 0.92; 2) T2* = 20-30ms, r2 = 0.48; 3) T2*>30ms, weak relationship. All subjects with T2*<20ms had low T1; among those with T2*>20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1. In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.

ObjectivesThalassaemia is a genetic disorder of haemoglobin synthesis characterised by life-long chronic anaemia. Although the endocrine and cardiac complications of thalassaemia are well-studied, hepatic and renal complications are understudied. This study aims to describe the hepatic and renal functions and to understand their determinants among paediatric patients with β-thalassaemia.DesignCross-sectional study.SettingTwo largest thalassaemia centres in Sri Lanka.ParticipantsAll haematologically confirmed patients with β-thalassaemia aged 1–16 years attending the study sites were recruited between 1 January and 31 March 2023. Data were collected by interviewing parents and patients, performing physical examinations and perusing clinical records.Results72 children (girls 52.8%) were recruited. The mean age was 7.3 years (SD 3.8). A majority (44 (61.1%)) had β-thalassaemia major, while 22 (30.6%) had haemoglobin E β-thalassaemia. 55 children (76.4%) were transfusion dependent. Hepatomegaly was found in 47 (65.3%), while 28 (38.9%) had elevations of both alanine and aspartate transaminases. Haemoglobin E β-thalassaemia type (OR 13.6, 95% CI 2.0 to 92, p=0.008) and high ferritin above 1000 ng/mL (OR 6.2, 95% CI 1.0 to 38, p=0.047) were independent factors associated with high transaminases. 11 (15.5%) patients had an estimated glomerular filtration rate (eGFR) below 90 mL/min. The proportion of children with low eGFR was higher in β-thalassaemia major (23.3%), transfusion-dependent (18.5%) and deferasirox treatment (18.5%) groups.ConclusionsElevation of hepatic transaminases is common among children with thalassaemia, especially among the subset of patients with haemoglobin E β-thalassaemia and those with high ferritin. Milder reductions in eGFR are noted in some patients with transfusion-dependent β-thalassaemia major.

Background Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce. Aims We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity. Methods We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded. Results Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels ( p  = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased ( p  = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient ( p  = 0.007) while in TDT no correlation was found. Conclusion Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.

Ramos et al. report a crucial role for macrophages in erythroblast development in mice. Under conditions that induce new red blood cell formation, macrophage depletion impaired red blood cell recovery. Conversely, macrophage depletion normalized red blood cell counts in mouse models of polycythemia vera and ®-thalassemia, pointing to a potential new therapeutic strategy for these diseases. Findings similar to these are reported in an accompanying paper by Chow et al. Regulation of erythropoiesis is achieved by the integration of distinct signals. Among them, macrophages are emerging as erythropoietin-complementary regulators of erythroid development, particularly under stress conditions. We investigated the contribution of macrophages to physiological and pathological conditions of enhanced erythropoiesis. We used mouse models of induced anemia, polycythemia vera and β-thalassemia in which macrophages were chemically depleted. Our data indicate that macrophages contribute decisively to recovery from induced anemia, as well as the pathological progression of polycythemia vera and β-thalassemia, by modulating erythroid proliferation and differentiation. We validated these observations in primary human cultures, showing a direct impact of macrophages on the proliferation and enucleation of erythroblasts from healthy individuals and patients with polycythemia vera or β-thalassemia. The contribution of macrophages to stress and pathological erythropoiesis, which we have termed stress erythropoiesis macrophage-supporting activity, may have therapeutic implications.

To assess gonadal function in adolescent male patients with β-thalassemia who underwent earlier successful hematopoietic stem cell transplantation (HSCT). Fifty-two male patients with β-thalassemia, aged ≥10 years, who had undergone HSCT ≥2 years previously were included. Clinical data, such as age, genital Tanner (GT) stage at HSCT and enrollment, and serum ferritin levels, were collected. Gonadal function was evaluated through measurements of serum luteinizing hormone, follicle-stimulating hormone (FSH), testosterone, inhibin B levels, and semen analysis. Age at enrollment and HSCT were 17 (10-31) and 9 (1-19) years, respectively. The duration from HSCT to enrollment was 7.5 (2-20) years. Of 52 patients, 46 (88%) exhibited Sertoli cell dysfunction. Thirty-one patients had relatively small testes for their GT stage, 34 of 44 with GT V had elevated FSH of ≥5 IU/L, and 20 of 49 with GT stages 2-5 had low serum inhibin B levels. None of the patients with GT stage 5 showed Leydig cell dysfunction or gonadotropin deficiency. Serum FSH ≥8 IU/L showed the best diagnostic accuracy for detecting oligo- and azoo-spermia. All 39 patients who underwent semen analysis had >1 abnormal parameters. Having relatively small testes for GT stage and serum FSH ≥8 IU/L were associated with oligospermia or azoospermia (p<0.01). Male patients with β-thalassemia after HSCT experienced universal impaired spermatogenesis and frequent Sertoli cell dysfunction but their Leydig cell function appeared to be preserved. Male patients and/or their guardians should be informed of the high likelihood of future subfertility before HSCT.

Background Malnutrition is a significant concern in children with β-thalassemia, impacting their growth and overall health. This study aimed to establish optimal thresholds for predicting malnutrition risk in children with β-thalassemia using muscle mass indicators derived from Bioelectrical Impedance Analysis (BIA). Methods A cross-sectional study was conducted with 162 pediatric patients diagnosed with β-thalassemia. Nutritional status of them was assessed using the World Health Organization (WHO) Child Growth Standards and references. BIA was performed to obtain fat-free mass (FFM), skeletal muscle mass (SMM), and soft lean mass (SLM). Propensity score matching (PSM) was used to control for age and gender. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance. Results SLM-change < 6% demonstrated the highest sensitivity [0.82, 95% confidence interval (CI) 0.72–0.92] and a negative predictive value of 0.83 (95% CI 0.74–0.93), while FFM-change < 4% showed more balanced performance with a sensitivity of 0.58 (95% CI 0.45–0.71) and a specificity of 0.65 (95% CI 0.56–0.74). Percentage change indicators (FFM-change, SLM-change, and SMM-change) exhibited remarkable stability before and after PSM, indicating minimal influence from age and gender. Conclusions This study established novel, age-adaptive thresholds (SLM-change < 6% and FFM-change < 4%) for predicting malnutrition risk in children with β-thalassemia. The findings suggest that these thresholds could serve as effective references to assess nutritional status across different age groups, providing new perspectives for personalized nutritional management strategies.