Background/Objectives: Severe unstable hemoglobinopathies may cause transfusion dependence from early childhood, and allogeneic hematopoietic cell transplantation (allo-HCT) is the only established curative option. Pediatric experience with allo-HCT for unstable hemoglobinopathies is limited to isolated reports, and long-term outcomes remain poorly characterized. The objective of this study was to characterize the clinical and molecular features, transplant approaches, and long-term outcomes of two Brazilian patients with unstable hemoglobinopathies, in the context of the published pediatric literature. Methods: We performed a retrospective analysis of two children with unstable hemoglobinopathies who underwent allo-HCT at a Brazilian center. PubMed/MEDLINE and Scopus were searched for pediatric cases published between 2002 and 2025 using terms related to unstable hemoglobin variants and hematopoietic transplantation. Published cases were combined with the Brazilian patients to form an aggregated cohort. Clinical, molecular, transplant, and follow-up data were analyzed descriptively. Results: The aggregated cohort included 13 patients and 15 allo-HCT procedures, using matched sibling, haploidentical, and other alternative donors. All patients were transfusion-dependent before transplantation. Two patients required retransplantation after graft failure. At last follow-up, the nine published patients with available outcome data and both Brazilian patients were alive and transfusion independent. The Brazilian patients maintained complete donor chimerism and transfusion independence for 8 and 9 years, the longest follow-up reported in this population. One remained transfusion independent after retransplantation for secondary graft failure. Conclusions: Allo-HCT may achieve durable transfusion independence in children with severe unstable hemoglobinopathies, but the small number of reported cases limits the interpretation of these findings. Our series adds long-term follow-up data supporting this approach and highlights the need for larger, prospective studies to guide donor selection and conditioning strategies in this rare population.
Background/Objectives: Beta-thalassemia and sickle cell disorders are among the most common inherited hemoglobin disorders affecting tribal populations in India, with marked ethnic and geographic heterogeneity. Although exploratory multivariate approaches have been used, only limited evidence is available regarding the distribution and clustering patterns of these disorders among Scheduled Tribe populations in Tamil Nadu. This study aimed to examine the distribution and population-specific clustering of beta-thalassemia- and sickle cell-related disorders among hematologically confirmed cases of the scheduled tribes from the selected districts. Methods: A cross-sectional analytical study was conducted among the Scheduled Tribe populations in the selected districts of Tamil Nadu. Confirmed cases of hemoglobin disorders were identified through complete blood count, peripheral smear examination, reticulocyte count, and high-performance liquid chromatography (HPLC). A total of 89 confirmed cases were included in the exploratory analysis. Disease forms were categorised as beta (β)-thalassemia related disorders and sickle cell- related disorders, including sickle cell β-thalassemia. Chi-square tests were performed to assess associations with socio-demographic and environmental variables. Correspondence analysis and multidimensional scaling were applied to identify clustering patterns and structural relationships. Results: Of the 89 confirmed cases, 48 (53.9%) had β-thalassemia and related disorders (predominantly beta-thalassemia minor), while 41 (46.1%) had sickle cell-related and combined forms (predominantly sickle cell trait). There were significant associations between disease forms and tribal affiliation (p < 0.001), drinking water source (p < 0.001), and altitude of residence (p = 0.003). Correspondence analysis demonstrated distinct clustering of β-thalassemia- and sickle cell-related disorders across tribes and districts. Multidimensional scaling further indicated that population structure and geographic context were more strongly associated with disease distribution than individual demographic variables. Conclusions: Hemoglobinopathy disease forms among Scheduled Tribes in the selected districts of Tamil Nadu showed clear eco-geographical and population-specific clustering patterns. The combination of correspondence analysis and multidimensional scaling revealed latent clustering patterns beyond those identified using traditional statistical analyses, emphasizing the intricate relationship between mutation distribution, environment, and population structure. These results highlight the significance of tribe-specific, equity-focused screening and genetic counselling programmes. To close diagnostic gaps and improve precision-based approaches in underserved populations, public health interventions must be tailored to intra-tribal heterogeneity. These findings may help inform future studies on targeted, population-specific screening and decentralised diagnostic strategies to reduce health inequities in the selected Scheduled Tribe populations.
Background/Objectives: The background of the research shows that β-thalassemia is a hemoglobinopathy which is characterized by ineffective erythropoiesis and iron overload and this is kept in balance by hepcidin hormone due to BMP/SMAD and JAK/STAT3 pathways. However, it is not known how exactly these signaling pathways are involved in iron metabolism disorders for different forms of β-thalassemia, therefore, the aim of the present research was to analyze circulating levels of hepcidin, STAT3, SMAD1 and SMAD4 in participants with β-thalassemia and evaluate their exploratory discriminatory potential. Methods: The methodology of the research includes a comparative cross-sectional study of 135 patients with β-thalassemia major, intermedia and minor, as well as healthy control individuals based on hemoglobinopathy typing with the high-performance liquid chromatography. The circulating hepcidin levels, SMAD1 and SMAD4 concentrations as well as plasma STAT3 levels were identified and measured by ELISA method. Statistical processing methods include one-way ANOVA, multinomial logistic regression and ROC curve analysis based on ten-fold cross-validation. Results: Hepcidin and SMAD1 levels showed heterogeneity among groups, whereas differences in STAT3 and SMAD4 were not statistically significant. In multinomial logistic regression, lower hepcidin was associated with β-thalassemia major and lower SMAD1 with β-thalassemia intermedia. ROC analysis showed moderate in-sample discrimination for hepcidin and stronger discrimination for SMAD1. Conclusions: Altered circulating hepcidin and SMAD1 patterns may reflect dysregulation of BMP-SMAD/hepcidin signaling across β-thalassemia subtypes. These findings are exploratory and require independent validation before clinical application.
Background: β-Thalassemia and other β-hemoglobinopathies arise from defective β-globin production, and reactivating fetal hemoglobin (HbF) is a well-established strategy to ameliorate disease severity. Two principal gene-therapy approaches—erythroid-specific γ-globin gene addition and shRNA/shmiRNA-mediated knockdown of the γ-globin repressor BCL11A—have each shown clinical promise, but their combination within a single vector remains largely unexplored. Methods: Here we developed and compared three compact, C1-insulated lentiviral vectors driven by the micro-locus control region (μLCR): a BCL11A-targeting shmiRNA vector, a γ-globin cDNA vector, and a dual construct combining both elements. Results: All vectors were produced at high titers, and incorporating both cassettes into a single construct did not compromise vector production or cell viability. In CD34+ hematopoietic stem and progenitor cells from healthy donors and β-thalassemia patients, transduction did not impair proliferation, erythroid differentiation, or progenitor colony formation. All three vectors significantly increased the proportion of HbF-expressing cells, with the combined shmiRNA + γ-globin cDNA vector achieving the highest induction, reaching approximately 25% HbF-positive cells in the enucleated erythroid population of thalassemic cells versus approximately 10% in untransduced controls. Notably, all constructs significantly reduced reactive oxygen species levels, indicating alleviation of oxidative stress. Conclusions: Together, these findings support the feasibility and therapeutic potential of combining complementary HbF-inducing mechanisms within a single lentiviral vector for β-thalassemia.
Background: Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic anemia, recurrent pain episodes, and multi-organ complications, which collectively impact patients’ quality of life and functional capacity. Exercise and physical activity are recognized as essential components of general health and well-being; however, their role in individuals with SCD remains underexplored due to concerns regarding safety, tolerance, and the potential to precipitate vaso-occlusive crises. This study aimed to assess the patterns and frequency of exercise and physical activity among patients with sickle cell disease using a validated questionnaire. Methods: We conducted a cross-sectional study on patients diagnosed with sickle cell disease at King Abdulaziz University Hospital in Jeddah, Saudi Arabia. After obtaining ethical approval, we contacted the patients by phone or met them in person and administered the Global Physical Activity Questionnaire (GPAQ). Data on age, gender, comorbid conditions, disease-related variables, and weekly physical activity were collected. Total physical activity was expressed in metabolic equivalent of task (MET)-minutes per week, and participants achieving ≥600 MET-minutes per week were classified as meeting the World Health Organization (WHO) recommendation. Results: Of the 97 patients, males represented 52.6% of the participants, with a median age of 33 years. Overall, 70.1% of the patients were on hydroxyurea, and 14.4% had undergone splenectomy. More than half of the patients (56.7%) reported difficulties with exercise. According to the findings, 39% of the patients were getting enough physical activity each week, as recommended by the WHO. Male patients were significantly more likely to meet the WHO physical activity recommendation (p = 0.003), whereas no statistically significant associations were observed for age, nationality, body mass index, hemoglobin level, hydroxyurea use, splenectomy, hospital admissions, transfusion history, comorbidities, or exercise-related symptoms (all p > 0.05). Conclusions: Our data suggest that a significant proportion of patients with SCD did not achieve the WHO-recommended physical activity level, with adherence observed in only about forty percent of participants, and that adherence was more common in male patients (adjusted odds ratio 3.30, 95% CI 1.36–8.52, after multivariable adjustment for age, body mass index, hemoglobin, and transfusion status). This association was concentrated in occupational rather than recreational activity and was not explained by the clinical variables measured. Because no comparison group was studied, the extent to which this shortfall is attributable to SCD itself, rather than to the population-level inactivity already documented in Saudi Arabia, cannot be determined from these data. These findings identify a potential area for targeted intervention, particularly among women, and underscore the need for further research into disease-specific and sociocultural barriers before tailored programs can be developed. Further larger, controlled, multi-center studies are necessary to clarify the specific contribution of SCD to inactivity and to guide individualized physical activity promotion in this population.
