bims-conane Biomed News
on Congenital anemias
Issue of 2024–08–11
thirteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Genome editing in K562 cells suggests a functional role for the XmnI Gg polymorphism: a widely used genetic marker in β-thalassemia and sickle cell disease patients.
  2. Could oxygen gradient ektacytometry help to detect sickle cell trait carriers at risk for kidney disorders or exercise-related complications?
  3. The Double-Edged Sword of Extremely High Prices for Gene Therapies in Sickle Cell Disease.
  4. Comment on: Severe β-thalassemia (Hb Zunyi) mimicking congenital dyserythropoietic anemia-The deceivingly normal mean corpuscular volume and hemoglobin electrophoresis in dominantly inherited β-thalassemia: Hb Little Venice.
  5. Influence of Hemoglobin Strasbourg, a Rare High Oxygen Affinity Hemoglobin Variant, on Different Methods of HbA1c Measurement.
  6. Long-term quality of life after hematopoietic cell transplant for sickle cell disease in childhood: A STELLAR interim analysis.
  7. A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds.
  8. Correlation of Electrocardiographic and Echocardiographic Changes with Serum Ferritin Level in Multi-Transfused β-Thalassemia Major Patients.
  9. A Novel Frameshift Mutation of HBB Causing Dominant β-Thalassemia in a Chinese Individual.
  10. Comorbidities and complications in adult and paediatric patients with pyruvate kinase deficiency: Analysis from the Peak Registry.
  11. Curative therapies raise the bar for the heart.
  12. A Rare Case of Iron Overload in Hereditary Spherocytosis: A Case Report.
  13. Next-generation CRISPR-based gene-editing therapies tested in clinical trials.
  1. Cell Mol Biol (Noisy-le-grand). 2024 Jul 28. 70(7): 230-236
    Genome editing in K562 cells suggests a functional role for the XmnI Gg polymorphism: a widely used genetic marker in β-thalassemia and sickle cell disease patients.
    Azadeh Ahmadifard, Nahal Maroofi, Maryam Maleki Tehrani, Tahere Dabestani, Masoumeh Sadat Mousavi Maleki, Sepideh Bayrami, Mehdi Banan.
      The XmnI Gg -158 C/T polymorphism has been widely associated with fetal hemoglobin (HbF) levels, the severity of disease, and the response to the drug hydroxyurea (HU) in both β-thalassemia (β-thal) and sickle cell disease (SCD) patients. However, the functional significance of this single nucleotide polymorphism (SNP) remains unclear. To gain insight, green fluorescence protein (GFP) cassettes harboring the XmnI C or T alleles in their left homology arms (i.e. Gg promoters) were knocked into the Gg gene(s) of K562 cells via CRISPR/Cas9. Subsequently, the GFP fluorescence levels were compared in the ensuing cell populations and isolated clones. In both instances, median fluorescence intensities (MFI) of the knockin cells having the inserted XmnI T allele were higher than those having the XmnI C allele. Our results suggest that the XmnI T allele can increase Gg expression in K562 cells. The possible functional significance of the XmnI Gg -158 C/T polymorphism provides a rationale for the aforementioned associations. Furthermore, the XmnI polymorphism as a functional SNP substantiates its importance as a prognostic marker.
    DOI:  https://doi.org/10.14715/cmb/2024.70.7.33
  2. Br J Haematol. 2024 Aug 08.
    Could oxygen gradient ektacytometry help to detect sickle cell trait carriers at risk for kidney disorders or exercise-related complications?
    Philippe Connes, Elie Nader.
      The study of Ellsworth et al. (Br J Haematol, 2024) demonstrated the usefulness of oxygen gradient ektacytometry technique to better identify the physiological parameters that could increase the risk of sickling of red blood cells (RBCs) from sickle cell trait (SCT) carriers. Oxygen gradient ektacytometry combined with pH and osmolality modulations could help in identifying SCT carriers at risk for kidney disorders or exercise-related complications. Other factors than the percentages of haemoglobin S are probably involved in the propensity of RBCs from SCT carriers to sickle during deoxygenation. Commentary on: Ellsworth et al. Hypertonicity and/or acidosis induce marked rheological changes under hypoxic conditions in sickle trait red blood cells. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19669.
    Keywords:  oxygen gradient ektacytometry; red blood cells; sickle cell
    DOI:  https://doi.org/10.1111/bjh.19704
  3. JAMA. 2024 Aug 05.
    The Double-Edged Sword of Extremely High Prices for Gene Therapies in Sickle Cell Disease.
    Edward R Scheffer Cliff, Frazer A Tessema.
      
    DOI:  https://doi.org/10.1001/jama.2024.11703
  4. Pediatr Blood Cancer. 2024 Aug 08. e31266
    Comment on: Severe β-thalassemia (Hb Zunyi) mimicking congenital dyserythropoietic anemia-The deceivingly normal mean corpuscular volume and hemoglobin electrophoresis in dominantly inherited β-thalassemia: Hb Little Venice.
    Anselm Chi-Wai Lee, Hai Yang Law.
      
    DOI:  https://doi.org/10.1002/pbc.31266
  5. Hemoglobin. 2024 Aug 05. 1-3
    Influence of Hemoglobin Strasbourg, a Rare High Oxygen Affinity Hemoglobin Variant, on Different Methods of HbA1c Measurement.
    Marcus Wagner, Birgit Stoffel-Wagner, Berndt Zur.
      Hemoglobin Strasbourg is a rare high oxygen affinity hemoglobin variant which leads to secondary erythrocytosis. This variant is caused by a HBB gene mutation c.71T > A resulting in an amino acid exchange on position 23 of the β globin chain (p.Val23Asp.). The influence of Hb Strasbourg on HbA1c measurement has not been studied to date. For patients with hemoglobin variants it is important to know whether possible interferences exist with the measurement of HbA1c. We therefore investigated the influence of Hb Strasbourg on HbA1c measurement with two different HPLC (high-performance liquid chromatography) systems and one turbidimetric immunoassay in two non-diabetic brothers who are heterozygous carriers of Hb Strasbourg. The examined tests are all used in routine diagnostics. In the case of Hb Strasbourg, the HbA1c measured by HPLC showed lower results than those obtained by the immunoassay. We conclude that HbA1c is underestimated when measured with these methods as glycated Hb Strasbourg is most likely not co-eluting with HbA1c in HPLC.
    Keywords:  Hb Strasbourg; HbA1c; beta-globin variant; hemoglobinopathy
    DOI:  https://doi.org/10.1080/03630269.2024.2360450
  6. Am J Hematol. 2024 Aug 06.
    Long-term quality of life after hematopoietic cell transplant for sickle cell disease in childhood: A STELLAR interim analysis.
    Staci D Arnold, Nitya Bakshi, Diana Ross, Crystal Smith, Cynthia Sinha, Anirudh Veludhandi, Valerie Dutreuil, Shasha Bai, Lillian R Meacham, Greg Guilcher, Monica Bhatia, Allistair Abraham, Kimberly A Kasow, Ann Haight, Fuad El Rassi, Elizabeth Stenger, Joseph Lipscomb, Lakshmanan Krishnamurti.
      We prospectively collected PROMIS©25 and PROMIS©29 surveys in the Sickle Cell Transplant Evaluation of Long Term and Late Effects Registry (STELLAR). Mobility and social participation T-scores were decreased; all other domains were within the norm.
    DOI:  https://doi.org/10.1002/ajh.27436
  7. Hemasphere. 2024 Aug;8(8): e139
    A cellular reporter system to evaluate endogenous fetal hemoglobin induction and screen for therapeutic compounds.
    Thijs C J Verheul, Nynke Gillemans, Kerstin Putzker, Rezin Majied, Tingyue Li, Memnia Vasiliou, Bert Eussen, Annelies de Klein, Wilfred F J van IJcken, Emile van den Akker, Marieke von Lindern, Joe Lewis, Ulrike Uhrig, Yukio Nakamura, Thamar van Dijk, Sjaak Philipsen.
      Reactivation of fetal hemoglobin expression alleviates the symptoms associated with β-globinopathies, severe hereditary diseases with significant global health implications due to their high morbidity and mortality rates. The symptoms emerge following the postnatal transition from fetal-to-adult hemoglobin expression. Extensive research has focused on inducing the expression of the fetal γ-globin subunit to reverse this switch and ameliorate these symptoms. Despite decades of research, only one compound, hydroxyurea, found its way to the clinic as an inducer of fetal hemoglobin. Unfortunately, its efficacy varies among patients, highlighting the need for more effective treatments. Erythroid cell lines have been instrumental in the pursuit of both pharmacological and genetic ways to reverse the postnatal hemoglobin switch. Here, we describe the first endogenously tagged fetal hemoglobin reporter cell line based on the adult erythroid progenitor cell line HUDEP2. Utilizing CRISPR-Cas9-mediated knock-in, a bioluminescent tag was integrated at the HBG1 gene. Subsequent extensive characterization confirmed that the resulting reporter cell line closely mirrors the HUDEP2 characteristics and that the cells report fetal hemoglobin induction with high sensitivity and specificity. This novel reporter cell line is therefore highly suitable for evaluating genetic and pharmacologic strategies to induce fetal hemoglobin. Furthermore, it provides an assay compatible with high-throughput drug screening, exemplified by the identification of a cluster of known fetal hemoglobin inducers in a pilot study. This new tool is made available to the research community, with the aspiration that it will accelerate the search for safer and more effective strategies to reverse the hemoglobin switch.
    DOI:  https://doi.org/10.1002/hem3.139
  8. Indian J Pediatr. 2024 Aug 09.
    Correlation of Electrocardiographic and Echocardiographic Changes with Serum Ferritin Level in Multi-Transfused β-Thalassemia Major Patients.
    Komal S Chaudhari, Siddhant Singhal, Ritu Chawla, Kumari Pratima.
      
    DOI:  https://doi.org/10.1007/s12098-024-05213-y
  9. Hemoglobin. 2024 Aug 05. 1-4
    A Novel Frameshift Mutation of HBB Causing Dominant β-Thalassemia in a Chinese Individual.
    Cuili Yao, Long Chen, Jingting Ma, Na Li, Jiang Lin, Lina Huang, Yani Lin, Jun Xue.
      We reported a rare β-thalassemia patient, a 41-year-old Chinese male with small cell hypopigmentation anemia, jaundice and splenomegaly as the main clinical symptoms. By using Next-Generation Sequencing (NGS), we identified a novel de novo HBB mutation(c.358_365dup, p.Phe123Alafs*39) which resulted in an abnormally prolonged β-globin chain comprising 159 amino acid residues. The secondary and three-dimensional structures of the β-globin predicted that the novel prolonged β-globin chain has a considerable risk of instability in the hemoglobin, and leads to clinical phenotype. This study contributes to the enrichment of the genetic pathogenic mutation database for thalassemia and underscores the significance of NGS in the screening of mutations for thalassemia families.
    Keywords:  Dominant β-thalassemia; HBB; frameshift mutation; next-generation sequencing (NGS); prolonged β-globin chain
    DOI:  https://doi.org/10.1080/03630269.2024.2376588
  10. Br J Haematol. 2024 Aug;205(2): 613-623
    Comorbidities and complications in adult and paediatric patients with pyruvate kinase deficiency: Analysis from the Peak Registry.
    Andreas Glenthøj, Rachael F Grace, Carl Lander, Eduard J van Beers, Bertil Glader, Kevin H M Kuo, Yan Yan, Bryan McGee, Audra N Boscoe, Junlong Li, Paola Bianchi.
      Pyruvate kinase (PK) deficiency, a rare, congenital haemolytic anaemia caused by mutations in the PKLR gene, is associated with many clinical manifestations, but the full disease burden has yet to be characterised. The Peak Registry (NCT03481738) is an observational, longitudinal registry of adult and paediatric patients with PK deficiency. Here, we described comorbidities and complications in these patients by age at most recent visit and PKLR genotype. As of 13 May 2022, 241 patients were included in the analysis. In total, 48.3% had undergone splenectomy and 50.5% had received chelation therapy. History of iron overload (before enrolment/during follow-up) was common (52.5%), even in never-transfused patients (20.7%). Neonatal complications and symptoms included jaundice, splenomegaly and hepatomegaly, with treatment interventions required in 41.5%. Among adults, osteopenia/osteoporosis occurred in 19.0% and pulmonary hypertension in 6.7%, with median onset ages of 37, 33 and 22 years, respectively. Biliary events and bone health problems were common across PKLR genotypes. Among 11 patients who had thromboembolic events, eight had undergone prior splenectomy. Patients with PK deficiency may have many complications, which can occur early in and throughout life. Awareness of their high disease burden may help clinicians better provide appropriate monitoring and management of these patients.
    Keywords:  adult and paediatric haematology; haemolytic anaemia; iron–clinical iron overload; pyruvate kinase deficiency; red cells–enzyme disorders
    DOI:  https://doi.org/10.1111/bjh.19601
  11. Blood. 2024 Aug 08. 144(6): 597-599
    Curative therapies raise the bar for the heart.
    John C Wood.
      
    DOI:  https://doi.org/10.1182/blood.2024025187
  12. Cureus. 2024 Jul;16(7): e63934
    A Rare Case of Iron Overload in Hereditary Spherocytosis: A Case Report.
    Audrey Bui, Avani P Shah, Min Y Chae, Peyton Popard, Bijoy Telivala.
      Hereditary spherocytosis (HS) is a hereditary hematologic disorder characterized by fragile spherical red blood cells that are susceptible to hemolysis. HS patients are often asymptomatic or present with anemia; however, serious complications of chronic hemolysis can include cholelithiasis and aplastic crisis. Splenectomy is considered the standard surgical treatment in moderate and severe forms of HS, with the main complication being a life-long risk of infection. Interestingly, our case suggests a possibility of secondary hemochromatosis as a complication of chronic hemolysis seen in HS. A vast majority of hemochromatosis patients possess a genetic predisposition, which increases their serum iron level and iron storage within the reticuloendothelial system. However, we present a case in which the genetic panel for common mutations associated with hemochromatosis resulted as negative. This case emphasizes the need for increased awareness regarding the potential development of idiopathic hemochromatosis in patients with long-standing HS, allowing for prompt intervention and preventing the associated complications.
    Keywords:  anemia; hemochromatosis; hereditary spherocytosis; iron overload; splenectomy
    DOI:  https://doi.org/10.7759/cureus.63934
  13. Nat Med. 2024 Aug 05.
    Next-generation CRISPR-based gene-editing therapies tested in clinical trials.
    Natalie Healey.
      
    DOI:  https://doi.org/10.1038/d41591-024-00056-8
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