bims-conane Biomed News
on Congenital anemias
Issue of 2025–02–02
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Comprehensive Hematological and molecular Characterization of hemoglobin Hekinan [α27(B8)Glu→Asp(α1), HBA1:c.84G > T] in a Large Thai cohort.
  2. Erythrocytapheresis as a strategy to manage anemia and iron overload in nondeletional hemoglobin H disease.
  3. Comparison of Asymptomatic Brain Lesions Between Thalassemia Major and Sickle Cell Anemia Patients.
  4. Fetal hematological phenotypes of various hemoglobinopathies and demonstration of embryonic hemoglobins on capillary electrophoresis: a large cohort data from prenatal screening program.
  5. Hemoglobin Variants as Targets for Stabilizing Drugs.
  6. Non-Transfusion-Dependent Thalassemia: An Image Gallery Worth a Thousand Words.
  7. Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia.
  8. Relevance of Next-Generation Sequencing in the Diagnosis of Thalassemia and Hemoglobinopathies: The Experience of Four Italian Diagnostic Hubs.
  9. Efficacy and safety of hydroxyurea therapy on patients with β-thalassemia: a systematic review and meta-analysis.
  10. Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis.
  11. Mitapivat: a step forward across different hemolytic diseases.
  12. Waking up the silenced beauty: CRISPR/Cas9 mediated reactivation of fetal hemoglobin genes to treat severe beta-thalassemia in young patients.
  13. Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
  1. Hematology. 2025 Dec;30(1): 2456679
    Comprehensive Hematological and molecular Characterization of hemoglobin Hekinan [α27(B8)Glu→Asp(α1), HBA1:c.84G > T] in a Large Thai cohort.
    Amornchai Suksusut, Jidapa Jaitheang, Manussavee Prapphal, Pranee Sutcharitchan, Ponlapat Rojnuckarin, Noppacharn Uaprasert.
       BACKGROUND: Hemoglobin (Hb) Hekinan is a prevalent α-globin variant frequently missed in thalassemia screening centers using high-performance liquid chromatography (HPLC) or capillary electrophoresis. This study aims to investigate the hematological and molecular characteristics of Hb Hekinan in a large cohort.
    METHODS: Hb variants were identified using isoelectric focusing (IEF) and HPLC. Hb Hekinan was confirmed by direct DNA sequencing. Additional genetic determinants, including α-thalassemia, β-thalassemia and other variants, were detected using multiplex GAP-PCR, ARMS-PCR or direct DNA sequencing as appropriate.
    RESULTS: Among 61,997 Hb typing samples, 149 cases of Hb Hekinan were identified in Thai individuals and classified into 8 genotypic groups. These included 104 Hb Hekinan heterozygotes, 10 Hb Hekinan coexisting with α+-thalassemia, 3 Hb Hekinan with non-deletional α-variants, 6 Hb Hekinan with α0-thalassemia, 21 double heterozygote for Hb Hekinan and HbE, 3 Hb Hekinan with β-thalassemia trait, 1 triple heterozygotes (Hb Hekinan/α0-thalassemia/Hb E) and 1 quadruple heterozygote for Hb Hekinan/α+-thalassemia/Hb E/Hb Hope. Hb Hekinan was well-separated from Hb A using IEF but was frequently missed with HPLC. On HPLC, Hb Hekinan could only be identified when coexisting with α0-thalassemia. All cases presented with either normal Hb levels or mild anemia.
    CONCLUSIONS: Hb Hekinan is a prevalent α-globin variant that is often undetected by HPLC but reliably identified using IEF. These findings highlight the importance of incorporating IEF for accurate diagnosis of Hb Hekinan. Most cases are clinically benign, even when interacting with other thalassemia syndromes or Hb variants.
    Keywords:  Hemoglobin Hekinan; genotypes; isoelectric focusing; phenotypes; α-globin variant
    DOI:  https://doi.org/10.1080/16078454.2025.2456679
  2. EJHaem. 2025 Feb;6(1): e21089
    Erythrocytapheresis as a strategy to manage anemia and iron overload in nondeletional hemoglobin H disease.
    Ke Zhang, John Bliamptis, Janice Park, Patricia Kopko, Amber P Sanchez, Srila Gopal.
      Hemoglobin H (HbH) disease is associated with anemia, ineffective erythropoiesis, and iron overload. We report a case of a patient with HbH/Hb Constant Spring disease, who was maintained on chronic transfusions as an adult due to symptomatic anemia. Over time, he developed iron overload and was started on chelation therapy but did not have an adequate response to chelation. We then added erythrocytapheresis to chelation therapy and were able to successfully decrease his iron burden while managing his anemia. Therapeutic erythrocytapheresis may be an effective treatment strategy for iron overload in HbH disease that is refractory to chelation.
    Keywords:  erythrocytapheresis; iron overload; thalassemia
    DOI:  https://doi.org/10.1002/jha2.1089
  3. Medicina (Kaunas). 2025 Jan 19. pii: 159. [Epub ahead of print]61(1):
    Comparison of Asymptomatic Brain Lesions Between Thalassemia Major and Sickle Cell Anemia Patients.
    Derya Yavuz Demiray, Özge Eriş Davut, Gönül Oktay.
      Background and Objectives: This study aimed to identify asymptomatic brain lesions in patients with β-thalassemia major (TM) and sickle cell anemia (SCA) and evaluate the correlation of these lesions with factors such as splenectomy, thrombocytosis, and blood transfusions. Materials and Methods: A total of 26 patients with thalassemia major and 23 patients with sickle cell anemia were included. Ischemic lesions were categorized as lacunar, small vessel, or multifocal. Variables including age, years of education, presence and type of MRI-detected ischemia, smoking status, hemoglobin, hematocrit, platelet count, ferritin levels, vitamin B12 levels, fasting blood sugar, splenectomy status, chelation therapy, and hydroxyurea treatment were compared between the two groups. Results: The mean age was 27.33 years in the thalassemia major group and 32.65 years in the sickle cell anemia group (p = 0.010). No statistically significant difference was observed in the distribution of ischemia types between the groups (p = 0.303). The thalassemia major group had a lower mean hemoglobin level (8.37 g/dL) compared to the sickle cell anemia group (9.57 g/dL) (p = 0.003). Ferritin levels were significantly higher in the thalassemia major group (2018.92 ng/mL) than in the sickle cell anemia group (660.39 ng/mL) (p < 0.001). Conclusions: Although ischemic lesions were more frequently observed in patients with sickle cell anemia, the difference was not statistically significant. These findings emphasize the importance of ongoing surveillance and individualized management to mitigate cerebrovascular risks in both patient populations.
    Keywords:  blood levels; complications; depression; management; neuropathic pain; sickle cell anemia; silent infarct; thalassemia major; vascular pathology
    DOI:  https://doi.org/10.3390/medicina61010159
  4. Diagnosis (Berl). 2025 Jan 30.
    Fetal hematological phenotypes of various hemoglobinopathies and demonstration of embryonic hemoglobins on capillary electrophoresis: a large cohort data from prenatal screening program.
    Kritsada Singha, Supawadee Yamsri, Attawut Chaibunruang, Hataichanok Srivorakun, Anupong Pansuwan, Kanokwan Sanchaisuriya, Goonnapa Fucharoen, Supan Fucharoen.
       OBJECTIVES: This study reported a large cohort of fetal blood analysis of various hemoglobinopathies.
    METHODS: A total of 371 fetal blood specimens were recruited. Complete blood count and hemoglobin (Hb) analysis using capillary electrophoresis were performed. Genotypes were defined by DNA analysis.
    RESULTS: Among 371 fetuses, 36 were non-thalassemic and 29 thalassemia genotypes were identified in the remaining 335 fetuses. Fetuses with β-thalassemia and Hb E traits, homozygous Hb E, and Hb E-β0-thalassemia had similar hematological parameters as those of non-thalassemic. However, the levels of Hb A in β-thalassemia and Hb E traits were approximately half of that observed in the non-thalassemic fetuses. As for Hb E, fetuses with a single copy of the βE-globin gene in the Hb E trait and Hb E-β0-thalassemia had lower Hb E levels as compared to that of the homozygous Hb E. For α-thalassemia, fetuses with one or two α-globin gene defects had small changes in hematological parameters, but variable Hb Bart's levels were observed. Fetuses with Hb H and Hb H-CS diseases had moderate anemia, whereas those with homozygous Hb CS and Hb Bart's hydrops fetalis had severe anemia. Identification of the fetuses with Hb Bart's hydrops fetalis with various genetic interactions allows the exact re-location of electrophoretic mobilities of various embryonic Hbs.
    CONCLUSIONS: This study confirmed the genetic heterogeneity of hemoglobinopathies among the fetuses and fetal blood analysis are useful for presumptive diagnosis of hemoglobinopathies. The results should facilitate a prevention and control program of hemoglobinopathies in the region.
    Keywords:  Hb analysis; fetal blood; hemoglobinopathies; prenatal diagnosis; thalassemia
    DOI:  https://doi.org/10.1515/dx-2024-0190
  5. Molecules. 2025 Jan 17. pii: 385. [Epub ahead of print]30(2):
    Hemoglobin Variants as Targets for Stabilizing Drugs.
    Miroslava Žoldáková, Michal Novotný, Krishna P Khakurel, Gabriel Žoldák.
      Hemoglobin is an oxygen-transport protein in red blood cells that interacts with multiple ligands, e.g., oxygen, carbon dioxide, carbon monoxide, and nitric oxide. Genetic variations in hemoglobin chains, such as those underlying sickle cell disease and thalassemias, present substantial clinical challenges. Here, we review the progress in research, including the use of allosteric modulators, pharmacological chaperones, and antioxidant treatments, which has begun to improve hemoglobin stability and oxygen affinity. According to UniProt (as of 7 August 2024), 819 variants of the α-hemoglobin subunit and 771 variants of the β-hemoglobin subunit have been documented, with over 116 classified as unstable. These data demonstrate the urgent need to develop variant-specific stabilizing options. Beyond small-molecule drugs/binders, novel protein-based strategies-such as engineered hemoglobin-binding proteins (including falcilysin, llama-derived nanobodies, and α-hemoglobin-stabilizing proteins)-offer promising new options. As our understanding of hemoglobin's structural and functional diversity grows, so does the potential for genotype-driven approaches. Continued research into hemoglobin stabilization and ligand-binding modification may yield more precise, effective treatments and pave the way toward effective strategies for hemoglobinopathies.
    Keywords:  2,3-bisphosphoglycerate (2,3-BPG); Bohr effect; allosteric regulation; genetic variants; hemoglobin (Hb); oxygen affinity; oxygen-binding properties; protein engineering; sickle cell disease (SCD); thalassemia
    DOI:  https://doi.org/10.3390/molecules30020385
  6. Am J Hematol. 2025 Jan 30.
    Non-Transfusion-Dependent Thalassemia: An Image Gallery Worth a Thousand Words.
    Khaled M Musallam, Sujit Sheth, Thomas D Coates, Hanny Al-Samkari, Maria Domenica Cappellini, Kevin H M Kuo, Vip Viprakasit, Ali T Taher.
      
    DOI:  https://doi.org/10.1002/ajh.27621
  7. J Exp Med. 2025 Mar 03. pii: e20241248. [Epub ahead of print]222(3):
    Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia.
    Zhe Chen, Feng Wu, Yan Li, Lei Li, Yufei Lei, Siwei Gao, Tao Chen, Yuxin Xie, Jianwen Xiao, Hanqing Zeng, Jianchuan Deng, Xueya Zhao, Yu Hou.
      Hematopoietic stem cells (HSCs) are susceptible to replication stress, which is a major contributor to HSC defects in Fanconi anemia (FA). Here, we report that HSCs relax the global chromatin by downregulating the expression of a chromatin architectural protein, DEK, in response to replication stress. DEK is abnormally accumulated in bone marrow (BM) CD34+ cells from patients with FA and in Fancd2-deficient HSCs. DEK haploinsufficiency promotes chromatin relaxation, replication stress relief, and function recovery of Fancd2-deficient HSCs. Furthermore, inhibition of DEK restores the proliferation of FA CD34+ cells in vitro and enhances their engraftment in vivo. Mechanistically, the activating transcription factor 2 (ATF2), specifically phosphorylated ATF2 at Thr69/71, was identified as a promoter of DEK transcription. Fancd2 deficiency results in p38 hyperphosphorylation, which in turn phosphorylates ATF2 at Thr69/71, leading to DEK accumulation in HSCs. In conclusion, our findings establish a functional link between chromatin relaxation and replication stress tolerance in HSCs and highlight DEK as a target for FA.
    DOI:  https://doi.org/10.1084/jem.20241248
  8. Genes (Basel). 2024 Dec 27. pii: 28. [Epub ahead of print]16(1):
    Relevance of Next-Generation Sequencing in the Diagnosis of Thalassemia and Hemoglobinopathies: The Experience of Four Italian Diagnostic Hubs.
    Rita Selvatici, Valentina Guida, Massimo Maffei, Milena Agata Irrera, Alice Margutti, Paola Bisceglia, Massimo Mogni, Erica Melchionda, Giuseppina Stoico, Nicoletta Grifone, Laura Bocciardo, Simone Salerio, Vittoria Nagliati, Angela Alberico, Giusy Tringali, Cristina Melles, Alessandro De Luca, Alessandra Ferlini, Domenico Coviello, Cristina Curcio.
      Thalassemias and hemoglobinopathies are among the most common genetic diseases worldwide and have a significant impact on public health. The decreasing cost of next-generation sequencing (NGS) has quickly enabled the development of new assays that allow for the simultaneous analysis of small nucleotide variants (SNVs) and copy number variants (CNVs) as deletions/duplications of α- and β-globin genes.
    BACKGROUND/OBJECTIVES: This study highlighted the efficacy and rapid identification of all types of mutations in the α- and β-globin genes, including silent variants, using the Devyser Thalassemia NGS kit. Furthermore, we report the frequency of mutations identified in a total population of 2649 individuals recruited from four Italian Medical Genetics Laboratories.
    METHODS: All samples were first hematologically characterized, and sequence analysis was conducted by using the Devyser Thalassemia NGS kit. All variants were also validated in an independent sample by a conventional molecular test.
    RESULTS: A total of 1789 subjects were identified with genetic variants in the globin genes, of which 966 (53.9%) had variations in the β-gene, 480 (26.8%) had variations in the α-gene; and 307 (17.1%) had variations in both α- and β-genes. Variant analysis evidenced a heterogeneous mutation spectrum enriched with variants not usually observed in the Italian population.
    CONCLUSIONS: This study showed the high effectiveness and the rapid identification of all mutation types in both α- and β-globin genes, including silent variants. It should be emphasized that the NGS approach greatly shortens turnaround reporting times, overcoming the classic diagnostic flowchart which envisages multistep, subsequent, diagnostic approaches, often requiring long resolution times.
    Keywords:  hemoglobinopathies; next-generation sequencing approach; thalassemias
    DOI:  https://doi.org/10.3390/genes16010028
  9. Front Med (Lausanne). 2024 ;11 1480831
    Efficacy and safety of hydroxyurea therapy on patients with β-thalassemia: a systematic review and meta-analysis.
    Tianmin Huang, Huixian Jiang, Ganling Tang, Jingyi Li, Xiaoman Huang, Zhenguang Huang, Hongliang Zhang.
       Objective: Our aim is to review the safety and efficacy of hydroxyurea (HU) on β-thalassemia patients.
    Methods: Studies that evaluated the safety and efficacy of HU on β-thalassemia patients were searched in Pub-Med, Cochrane Databases, Web of Science, China-Biology-Medicine, CNKI, Embase, VIP, and WanFang data. The proportions of response rate (RR) (50% fall in transfusion need in transfusion-dependent β-thalassemia patients, or 1 g/dL elevate in hemoglobin (Hb) levels in transfusion-independent β-thalassemia patients) and good RR (transfusion-free in transfusion-dependent β-thalassemia patients or 2 g/dL elevate in Hb levels in transfusion-independent β-thalassemia patients) were utilized to evaluate the effect size (ES). The secondary outcomes were the adverse events incidence rates of HU in β-thalassemia patients.
    Results: Two randomized controlled trials (RCTs) and 25 single-armed observational studies with typically 1,748 individuals were involved in our analysis. All 27 clinical trials were reported with fair quality. HU, in transfusion-dependent β-thalassemia patients, was related to a significant decrease in transfusion requirements [a pooled RR of 0.37 and a pooled good RR of 0.65 (95% CI, 0.53-0.76)]; in transfusion-independent β-thalassemia patients, it was correlated to an excellent raise in Hb levels [a pooled RR of 0.20 (95% CI, 0.08-0.35) and a pooled good RR of 0.53 (95% CI, 0.41-0.65)]. Neutropenia and leucopenia were the most prevalent adverse events in β-thalassemia patients treated with HU, while the incidence rates of other side effects were relatively lower.
    Conclusion: Our findings demonstrated that β-thalassemia patients tolerated and responded well to HU. Due to the control arms absence in the involved studies, more double-masked RCTs are essential for proving the safety and efficacy of HU in β-thalassemia patients.
    Keywords:  efficacy; hydroxyurea; meta-analysis; safety; β-thalassemia
    DOI:  https://doi.org/10.3389/fmed.2024.1480831
  10. Nat Commun. 2025 Jan 29. 16(1): 1140
    Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis.
    Aadit P Shah, Kiran R Majeti, Freja K Ekman, Sridhar Selvaraj, Devesh Sharma, Roshani Sinha, Eric Soupene, Prathamesh Chati, Sofia E Luna, Carsten T Charlesworth, Travis McCreary, Benjamin J Lesch, Tammy Tran, Simon N Chu, Matthew H Porteus, M Kyle Cromer.
      Blood transfusion plays a vital role in modern medicine, but frequent shortages occur. Ex vivo manufacturing of red blood cells (RBCs) from universal donor cells offers a potential solution, yet the high cost of recombinant cytokines remains a barrier. Erythropoietin (EPO) signaling is crucial for RBC development, and EPO is among the most expensive media components. To address this challenge, we develop highly optimized small molecule-inducible synthetic EPO receptors (synEPORs) using design-build-test cycles and genome editing. By integrating synEPOR at the endogenous EPOR locus in O-negative induced pluripotent stem cells, we achieve equivalent erythroid differentiation, transcriptomic changes, and hemoglobin production using small molecules compared to EPO-supplemented cultures. This approach dramatically reduces culture media costs. Our strategy not only addresses RBC production challenges but also demonstrates how protein and genome engineering can introduce precisely regulated cellular behaviors, potentially improving scalable manufacturing of a wide range of clinically relevant cell types.
    DOI:  https://doi.org/10.1038/s41467-025-56239-5
  11. Expert Opin Emerg Drugs. 2025 Jan 29. 1-3
    Mitapivat: a step forward across different hemolytic diseases.
    Mohammad Hassan Hodroj, Joseph Klim, Nicole Charbel, Ali Taher.
      
    Keywords:  Mitapivat; Pyruvate Kinase activator; Sickle Cell Disease; Thalassemia
    DOI:  https://doi.org/10.1080/14728214.2025.2458063
  12. Life Med. 2023 Apr;2(2): lnad009
    Waking up the silenced beauty: CRISPR/Cas9 mediated reactivation of fetal hemoglobin genes to treat severe beta-thalassemia in young patients.
    Liren Wang, Stefan Siwko, Dali Li.
      
    DOI:  https://doi.org/10.1093/lifemedi/lnad009
  13. Mol Med. 2025 Jan 29. 31(1): 29
    Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis.
    Judith Giroud-Gerbetant, Fernando Sotillo, Gonzalo Hernández, Irene Ruano, David Sebastián, Joana Fort, Mayka Sánchez, Günter Weiss, Neus Prats, Antonio Zorzano, Manuel Palacín, Susanna Bodoy.
       BACKGROUND: Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency.
    METHODS: We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA.
    RESULTS: Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload.
    CONCLUSIONS: The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance.
    Keywords:  Amino acids; Erythropoiesis; Kidney disease; Rare disease
    DOI:  https://doi.org/10.1186/s10020-025-01100-0
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