bims-conane 2025-08-31 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–08–31
six papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease.
Challenging diagnosis of spherocytosis in early infancy.
An Unusual Cause of Hexokinase 1 Deficiency-Case Report.
Efficacy of combination chelation with deferasirox and deferiprone in children with beta-thalassemia major: an audit from a unit in the developing world.
Not-So-Rare Defects of RBC Lipidic Composition: Four New Cases of Flippase Deficiency Due to ATP11C Mutations.
Piezo1 Channel Activators Yoda1 and Yoda2 in the Context of Red Blood Cells.

Blood. 2025 Aug 26. pii: blood.2024028166. [Epub ahead of print]

A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease.

Anne Chalumeau, Maria Bou Dames, Letizia Fontana, Simone Amistadi, Panagiotis Antoniou, Priyanka Loganathan, Margaux Mombled, Guillaume Corre, Martin Peterka, Mario Amendola, Carine Giovannangeli, Marcello Maresca, Annarita Miccio, Mégane Brusson.

Fetal hemoglobin (HbF) reactivation is a promising therapy for β-hemoglobinopathies. We developed a prime-editing strategy that introduces multiple mutations in the fetal γ-globin promoters that are expected to increase their activity. We tested multiple targets and optimized a variety of parameters to achieve ~50% of precise edits in a hematopoietic cell line, with minimal off-targets effects. This work improved our understanding of the complex DNA repair mechanisms involved in prime editing. We tested this strategy in patients' hematopoietic stem/progenitor cells (HSPCs). Although the editing efficiency was variable amongst donors, erythroid clones carrying multiple mutations express a significantly higher γ-globin level compared to cells carrying individual mutations, confirming the potential therapeutic benefit of our combined strategy for patients with β-hemoglobinopathies.

DOI: https://doi.org/10.1182/blood.2024028166
BMJ Case Rep. 2025 Aug 25. pii: e267506. [Epub ahead of print]18(8):

Challenging diagnosis of spherocytosis in early infancy.

Catarina Nunes, André Salvada, Rita Martins, Ana Ventura, Teresa Faria.

  This case report describes an infant who presented to the emergency department with rhinorrhoea and severe mucocutaneous pallor. Laboratory evaluation revealed normocytic anaemia with reticulocytosis and a peripheral blood smear suggestive of peripheral red blood cell (RBC) destruction, although without the presence of spherocytes. Despite the absence of spherocytes on the peripheral blood smear, the clinical evaluation, including family history, led to the consideration of hereditary spherocytosis (HS). The diagnosis was confirmed through genetic testing, revealing a heterozygous pathogenic variant in the ANK1 gene, associated with HS. This case underscores the diagnostic challenges of HS, particularly in the early infancy, and highlights the importance of genetic panels in cases of unexplained haemolytic anaemia.

Keywords:  Haematology (incl blood transfusion); Neonatal health; Pediatrics

DOI:  https://doi.org/10.1136/bcr-2025-267506
EJHaem. 2025 Aug;6(4): e70123

An Unusual Cause of Hexokinase 1 Deficiency-Case Report.

Gonench Kilich, Kelly Maurer, Tanaya Jadhav, Tejas Jammihal, Zhe Zhang, Helge Hartung, Kosuki Izumi, Kelly Hassey, Anna Raper, Erica Schindewolf, Laura Conlin, Rebecca Ganetzky, Marilyn Li, Bertil Glader, Ramakrishnan Rajagopalan, Kathleen E Sullivan.

   Introduction: Molecular analysis of red cell disorders has revolutionized diagnosis, however, there remain challenges.
Main Symptoms: This patient presented with hemolytic anemia in the newborn period. He required chronic transfusions to maintain his hemoglobin level until 6 years of age. A splenectomy was performed at 3 years of age.
Main Diagnoses: Using whole genome sequencing, we were able to identify a duplication upstream of the red cell promoter of HK1. Long-read RNA sequencing established aberrant expression off of this promoter.
Conclusions: These non-coding variants remain challenging to identify. His promoter duplication may have a founder effect in South Asia.

Keywords:  case report; hereditary hemolytic anemia; non‐coding mutation

DOI:  https://doi.org/10.1002/jha2.70123
Clin Exp Med. 2025 Aug 22. 25(1): 299

Efficacy of combination chelation with deferasirox and deferiprone in children with beta-thalassemia major: an audit from a unit in the developing world.

Vinson James, Anand Prakash.

  Effective iron chelation is crucial for preventing morbidity and mortality in transfusion-dependent beta-thalassemia major. While oral chelation is the preferred mode of administration, heavily iron-overloaded patients often require combination therapy. Although desferoxamine and deferiprone are commonly recommended, a combination of two oral chelators-deferasirox and deferiprone, offers a more convenient alternative. This study evaluates the efficacy and safety of combination oral chelation in pediatric patients with severe iron overload. Children with transfusion-dependent beta-thalassemia major and persistently high serum ferritin levels (> 2500 µg/dL) for more than six months despite maximum-dose deferasirox (40 mg/kg/day) were initiated on combination chelation with deferiprone. Serum ferritin levels were monitored at six-month intervals to assess treatment efficacy. Among 130 regularly followed patients, 27 met the criteria for combination chelation. A significant reduction in serum ferritin levels was observed, decreasing from 4277 ± 1885 µg/dL at baseline to 3242 ± 1110 µg/dL at six months (p = 0.003) and further to 2985 ± 1116 µg/dL at twelve months (p = 0.018). No significant adverse effects were noted during the study period. Combination chelation with deferasirox and deferiprone is an effective and well-tolerated strategy for managing severe iron overload in children with beta-thalassemia major. This approach provides a practical alternative to injectable therapies and may improve adherence and treatment outcomes.

Keywords:  Beta-thalassemia; Combined chelation; Iron chelation

DOI:  https://doi.org/10.1007/s10238-025-01687-y
Int J Mol Sci. 2025 Aug 10. pii: 7722. [Epub ahead of print]26(16):

Not-So-Rare Defects of RBC Lipidic Composition: Four New Cases of Flippase Deficiency Due to ATP11C Mutations.

Elisa Fermo, Elena Trombetta, Anna Paola Marcello, Cristina Vercellati, Giulia Maria Ferrari, Anna Zaninoni, Valentina Brancaleoni, Elena Di Pierro, Sara Beneventi, Marta Tornese, Bruno Fattizzo, Tommaso Casini, Paola Corti, Paola Bianchi.

  Adenosine Triphosphatase (ATPase) Phospholipid Transporting 11C gene (ATP11C), located on the X chromosome, encodes the major phosphatidylserine flippase in human erythroid cells. Only five patients have so far been reported with defective ATP11C, displaying mild hemolytic anemia and reduced flippase activity. In this study, we report four Italian male patients in three unrelated families with novel private mutations in the ATP11C gene, resulting in impaired flippase activity associated with mild/compensated hemolytic anemia. The decreased flippase activity was measured as % of phosphatidylserine internalization over time and ranged after 20 min incubation from 5% to 18.6% in all patients, regardless of the type of molecular defect. Flippase activity was also tested in healthy controls, ranging from 43% to 62% in both males and females. This measurement appears to be a useful tool for hypothesizing ATP11C abnormalities in male subjects with mild compensated hemolysis, prior to next generation sequencing (NGS) analysis. Although rare, ATP11C mutations may be underrecognized, and therefore should be suspected and investigated in male patients presenting with subtle hemolytic signs or symptoms.

Keywords:  ATP11C; flippase; hemolysis; phosphatidylserine exposure

DOI:  https://doi.org/10.3390/ijms26167722
Biomolecules. 2025 Aug 01. pii: 1110. [Epub ahead of print]15(8):

Piezo1 Channel Activators Yoda1 and Yoda2 in the Context of Red Blood Cells.

Min Qiao, Reetta Penttinen, Ariel Coli, Nicoletta Murciano, Felix M Maurer, Christian Wagner, Maria Giustina Rotordam, Lars Kaestner.

  Piezo1 is a mechanosensitive non-selective cation channel. Genetic alterations of the channel result in a hematologic phenotype named Hereditary Xerocytosis. With Yoda1 and, more recently, Yoda2, compounds to increase the activity of Piezo1 have become available. However, their concrete effect depends on the nano environment of the channel and hence on the cell type. Here we compare the potency of Yoda1 and Yoda2 in red blood cells (RBCs). We investigate the effect of the compounds on direct channel activity using automated patch clamp, as well as the secondary effects of channel activation on signalling molecules and cellular response. In terms of signalling, we investigate the temporal response of the second messenger Ca2+, and in terms of cellular response, the activity of the Gárdos channel. The opening of the Gárdos channel leads to a hyperpolarisation of the RBCs, which is measured by the Macey-Bennekou-Egée (MBE) method. Although the interpretation of the data is not straightforward, we discuss the results in a physiological context and provide recommendations for the use of Yoda1 and Yoda2 to investigate RBCs.

Keywords:  MBE-method; Piezo1; Yoda1; Yoda2; automated patch-clamp; erythrocytes; intracellular calcium; live cell imaging; mechanosensitive ion channel; membrane potential

DOI:  https://doi.org/10.3390/biom15081110