bims-conane Biomed News
on Congenital anemias
Issue of 2026–06–14
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion-Dependent β-Thalassemia.
  2. A novel heterozygous mutation in ANK1 solves a mystery of a patient with hyperbilirubinemia and splenomegaly.
  3. Successful Management of Transfusion-Dependent Unstable Hemoglobin Perth with Splenectomy: First Report from Iran and Literature Review.
  4. Exa-cel in Children with Transfusion-Dependent β-Thalassemia or Sickle Cell Disease.
  5. Altered translation efficiency of specific mRNAs in a zebrafish model of Diamond-Blackfan anemia syndrome.
  6. Luspatercept in Transfusion-Dependent Thalassemia With Red Blood Cell Antibodies: A Case Series.
  7. EHA Recommendations for preconceptual and antenatal screening and prenatal diagnosis for hemoglobinopathies.
  1. Am J Hematol. 2026 Jun 07.
    Correction of Ineffective Erythropoiesis and Normalization of Iron Homeostasis After Exagamglogene Autotemcel in Transfusion-Dependent β-Thalassemia.
    CLIMB THAL‐111 and CLIMB‐131 Study Groups
      Exagamglogene autotemcel (exa-cel) is a one-time, ex vivo, CRISPR-Cas9 gene edited cell therapy approved for patients with transfusion dependent β-thalassemia (TDT) aged 12-35 years. In a Phase 3 study (CLIMB THAL-111), exa-cel treatment resulted in reactivation of fetal hemoglobin and increases in total hemoglobin, leading to transfusion independence in 91% of participants. Here, we report on the impact of exa-cel treatment on measures of ineffective erythropoiesis and iron homeostasis, which were secondary and exploratory endpoints in CLIMB THAL-111 and the CLIMB-131 long-term follow-up study. Prior to exa-cel infusion, all participants were receiving regular red blood cell transfusions and iron chelation therapy. At time of data cut (April 2025), 98% of participants (55 of 56) had been transfusion independent for ≥ 12 months and 38 (68%) had discontinued iron removal therapy (mean duration off iron removal therapy 19.4 months). Following transfusion independence and cessation of iron removal therapy, erythroferrone concentrations decreased and hepcidin levels normalized in all participants, indicating correction of ineffective erythropoiesis and restoration of iron homeostasis. Further supporting this finding, improvements and trends toward normalization were seen in key erythropoiesis biomarkers, including erythropoietin levels, reticulocyte counts, and soluble transferrin receptor concentrations. Iron overload biomarkers, including ferritin, liver iron concentration, and cardiac T2*, decreased and then remained stable throughout follow-up, even after cessation of iron removal therapy. These results demonstrate restoration of effective erythropoiesis and iron homeostasis after exa-cel infusion in the setting of transfusion independence following reactivation of fetal hemoglobin. (CLIMB THAL-111 and CLIMB-131; Clinical Trials.gov numbers NCT03655678 and NCT04208529).
    Keywords:  erythropoiesis; exagamglogene autotemcel; iron homeostasis; transfusion‐dependent β‐thalassemia
    DOI:  https://doi.org/10.1002/ajh.70382
  2. Pak J Med Sci. 2026 Apr;42(4): 1062-1066
    A novel heterozygous mutation in ANK1 solves a mystery of a patient with hyperbilirubinemia and splenomegaly.
    Yixian Shi, Yang Ou, Haicong Wu.
      Patients presented with jaundice and splenomegaly are easily diagnosed as having liver diseases. Actually, some atypical cases belong to hemolytic diseases leading to secondary hemochromatosis, which is easily misdiagnosed or never diagnosed. Here, we describe an atypical case in a 27 years old man presenting with unconjugated hyperbilirubinemia and splenomegaly since early childhood, who was hospitalized to check for any possible causes related to liver diseases. However, the probable etiology related to hemolytic diseases and liver disease was ruled out by negative traditional tests, which left a mystery to us. Fortunately, next-generation sequencing is becoming a suitable choice to determine the candidate genes responsible for rare or inherited disorders. A novel de novo mutation (c.5032delA) was firstly identified through whole exome sequencing which could induce an arginine to glycine substitution at residue 1678 (p.R1678Gfs*12), causing a premature termination codon in exon 38 of ANK1. ANK1 is involved in erythrocyte cytoskeleton formation, and contributes to one of the most common causes of hereditary spherocytosis (HS). Besides, homology-modeling analysis confirmed the loss-of-function of frameshift variant of ANK1 with bioinformatics methods. This work adds new knowledge in the etiology of hereditary spherocytosis. In addition, genetic testing can open up new perspectives for atypical and unknown diseases when traditional tests cannot be met.
    Keywords:  ANK1; Case report; Hereditary spherocytosis; Hyperbilirubinemia; Splenomegaly
    DOI:  https://doi.org/10.12669/pjms.42.4.12871
  3. Hemoglobin. 2026 Jun 09. 1-6
    Successful Management of Transfusion-Dependent Unstable Hemoglobin Perth with Splenectomy: First Report from Iran and Literature Review.
    Samin Alavi, Hossein Najmabadi, Mehdi Sarafi, Asghar Ramyar.
      Unstable hemoglobin (Hb) variants are a rare cause of congenital non-spherocytic hemolytic anemia, characterized by hemoglobin instability and Heinz body formation. Diagnosis is often challenging and requires a high index of suspicion, supported by targeted laboratory investigations. We report the first documented case of an unstable hemoglobin variant identified as hemoglobin Perth (also known as Hb Abraham Lincoln) from Iran in a patient who was transfusion-dependent since early childhood. At 10 years of age, he presented with acute cholecystitis and cholelithiasis, accompanied by profound direct hyperbilirubinemia. He underwent cholecystectomy and splenectomy, which resulted in significant clinical improvement, including transfusion independence and stabilization of hemoglobin levels. This case is particularly noteworthy for the exceptionally high levels of direct bilirubin unreported in previous cases of Hb Perth, as well as the successful therapeutic outcome achieved following splenectomy.
    Keywords:  Hb Perth; Heinz body; Hemolytic anemia; splenectomy; unstable hemoglobin
    DOI:  https://doi.org/10.1080/03630269.2026.2652612
  4. N Engl J Med. 2026 Jun 11.
    Exa-cel in Children with Transfusion-Dependent β-Thalassemia or Sickle Cell Disease.
    CLIMB THAL-141 and CLIMB SCD-151 Study Groups
       BACKGROUND: Exagamglogene autotemcel (exa-cel) is a cell therapy in which autologous CD34+ hematopoietic cells are engineered through ex vivo clustered regularly interspaced short palindromic repeats-Cas9 editing of the erythroid-specific enhancer region of BCL11 to express fetal hemoglobin. In phase 3 studies involving participants 12 to 35 years of age with sickle cell disease or transfusion-dependent β-thalassemia, exa-cel eliminated vaso-occlusive crises and the need for red-cell transfusions.
    METHODS: In two ongoing, phase 3, open-label, single-group studies, we evaluated exa-cel in children 5 to 11 years of age with transfusion-dependent β-thalassemia or sickle cell disease. Before exa-cel infusion, participants underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end points were transfusion independence for at least 12 consecutive months in children with transfusion-dependent β-thalassemia and freedom from severe vaso-occlusive crises for at least 12 consecutive months in children with sickle cell disease.
    RESULTS: A total of 15 children with transfusion-dependent β-thalassemia and 11 with sickle cell disease received exa-cel; median follow-up was 16.0 months (range, 2.2 to 32.1) and 16.9 months (range, 7.6 to 33.1), respectively. Of 8 children with transfusion-dependent β-thalassemia who were followed to at least 16 months, 8 were transfusion independent; the status of the remaining 7 was not yet evaluable. Of 8 children with sickle cell disease who were followed to at least 16 months, 8 were free of vaso-occlusive crises; the status of the remaining 3 was not yet evaluable. All the children had at least one grade 3 or 4 adverse event; 2 children with transfusion-dependent β-thalassemia had severe veno-occlusive liver disease that was assessed as being related to busulfan conditioning, 1 of whom died.
    CONCLUSIONS: Exa-cel therapy resulted in transfusion independence or freedom from severe vaso-occlusive crises in participants with transfusion-dependent β-thalassemia or sickle cell disease, respectively, who were followed for at least 16 months. All the participants had grade 3 or 4 adverse events. (Funded by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-141 ClinicalTrials.gov number, NCT05356195; CLIMB SCD-151 ClinicalTrials.gov number, NCT05329649.).
    DOI:  https://doi.org/10.1056/NEJMoa2603387
  5. Biochem Biophys Res Commun. 2026 Jun 05. pii: S0006-291X(26)00875-2. [Epub ahead of print]828 154111
    Altered translation efficiency of specific mRNAs in a zebrafish model of Diamond-Blackfan anemia syndrome.
    Tamayo Uechi, Mariko Nagatomo, Yukari Nakajima, Yutaka Suzuki, Naoya Kenmochi.
      Diamond-Blackfan anemia syndrome (DBAS) is a congenital pure red-cell aplasia that is often accompanied by physical deformities. Heterozygous mutations in more than 20 ribosomal protein (RP) genes have been linked to the disease. The most frequently mutated gene is RPS19, which accounts for 25% of the patients. Haploinsufficiency of the RP genes may affect translation of specific mRNAs that could be related to the anemia. However, the underlying mechanisms are still unclear. To evaluate the impacts of RP depletion on translation, using a zebrafish model of DBAS with knockdown of the RPS19 ortholog (rps19), we compared changes in polysomal mRNAs with those in total mRNAs in the DBAS model to examine the translation efficiency of individual transcripts. As a result, we calculated the translation efficiency of 5464 transcripts. Among them, the transcripts from 75 genes exhibited translational repression to less than half compared to the controls. Erythropoiesis-related genes were enriched among the repressed genes. Unexpectedly, some genes related to glycan biosynthesis were also translationally repressed. One of these was the pigq gene, which participates in a glycosylphosphatidylinositol-anchor biosynthesis. We injected synthesized pigq mRNA into embryos with rps19 knockdown (the DBAS model), and found that the anemia phenotype was rescued, but morphological defects were not, indicating its role in erythropoiesis in zebrafish. These results suggest that impaired translation of erythropoiesis-related and glycan biosynthesis-related genes is implicated in the pathogenesis of DBAS.
    Keywords:  Diamond-Blackfan anemia syndrome; Polysome profiling; Ribosomopathy; Translation efficiency; Zebrafish model
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154111
  6. EJHaem. 2026 Jun;7(3): e70320
    Luspatercept in Transfusion-Dependent Thalassemia With Red Blood Cell Antibodies: A Case Series.
    Nattiya Teawtrakul.
      Red blood cell (RBC) antibodies complicate transfusion support in transfusion-dependent thalassemia (TDT), and data on luspatercept in this setting remain limited. We retrospectively reviewed seven adults with TDT and RBC antibodies treated with luspatercept at Srinagarind Hospital from January 2025 to January 2026. Baseline transfusion need was six packed RBC units/12 weeks in all patients. During weeks 13-24, six patients achieved a clinically meaningful reduction, with a median decrease of three units/12 weeks (range, 2-5; median 50.0%). Responses were greatest without warm autoantibodies. No new alloantibodies or serious adverse events were observed. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
    Keywords:  alloimmunization; autoantibody; luspatercept; thalassemia; transfusion
    DOI:  https://doi.org/10.1002/jha2.70320
  7. Hemasphere. 2026 Jun;10(6): e70381
    EHA Recommendations for preconceptual and antenatal screening and prenatal diagnosis for hemoglobinopathies.
    Mariane de Montalembert, Maria D Cappellini, Achille Iolascon, Lucia de Franceschi, Eda Ömur, Michele Abi Saad, Immacolata Andolfo, Celeste Bento, Maria Berghs, Doris Bonnet, Andreas Glenthoj, Beatrice Gulbis, Tuphan K Dolai, Jorge Lima, Irene Motta, Roberta Russo, Ali Taher, Leon Tshilolo, Antonio Almeida, David Rees.
      Thalassemia and sickle cell disease (SCD) are among the most common monogenic disorders worldwide. They cause chronic hemolytic anemia, the consequences and prognosis of which vary considerably depending on the genetic characteristics of patients and the healthcare system in their country of residence. Both diseases are autosomal recessive in their transmission, with carriers generally being asymptomatic. Informing carriers of thalassemia or SCD about reproductive risks and choices, while taking into account cultural and religious considerations, is a priority within global strategies to improve outcomes for these diseases. The European Hematology Association (EHA)'s Topic In Focus (TIF) Hemoglobinopathies Group created a focus group of hematologists, patients, anthropologists, and an obstetrician from Europe, the Middle East, India, and Africa. The Group considered that preconceptual screening tests would correspond to tests conducted before pregnancy (screening for carriers before marriage/conception), antenatal screening referred to tests completed on pregnant women, and prenatal diagnosis referred to tests performed on the fetus. It proposed guidelines addressing optimal timing of screening, appropriate laboratory tests, and communication strategies, taking into account the great diversity of regions and cultures where thalassemia and SCD are present. A main discussion point was that no recommendations would be given for couples about reproductive decisions, and that the aim was to present the existing and available options in different countries. Eight questions were examined using available literature, leading to the formulation of seven recommendations, which were submitted to a vote using the Delphi method. Consensus agreement was obtained for all recommendations.
    DOI:  https://doi.org/10.1002/hem3.70381
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