bims-conane Biomed News
on Congenital anemias
Issue of 2024–09–22
fourteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Investing in Sickle Cell Disease : Global attention on and funding of disease research would benefit millions.
  2. New Treatments for Sickle Cell Disease: After years of little progress, new therapies to treat or even cure the disease are reaching patients.
  3. Newer Modalities and Updates in the Management of Sickle Cell Disease: A Systematic Review.
  4. Genetic variants associated with white blood cell count amongst individuals with sickle cell disease.
  5. UM171 enhances fitness and engraftment of gene modified hematopoietic stem cells from sickle cells disease patients.
  6. Respiratory management of acute chest syndrome in children with sickle cell disease.
  7. Detection of Hemoglobin Constant Spring: A Comparison of Capillary Electrophoresis Versus High-Performance Liquid Chromatography.
  8. A novel and apparent de novo ALAS2 missense variant associated with congenital sideroblastic anemia.
  9. Management of iron overload: lessons from transfusion-dependent hemoglobinopathies.
  10. Recent advances and clinical applications of red blood cell lifespan measurement.
  11. Rates of Strokes in Californians with Sickle Cell Disease in the Post-STOP Era.
  12. Roxadustat, an hypoxia-inducible factor-prolyl hydroxylase inhibitor induce sickle cell crisis: A case report.
  13. Pathogenic G6PD variants: Different clinical pictures arise from different missense mutations in the same codon.
  14. Lipoprotein metabolism mediates hematopoietic stem cell responses under acute anemic conditions.
  1. Sci Am. 2024 Oct 01. 331(3): 98
    Investing in Sickle Cell Disease : Global attention on and funding of disease research would benefit millions.
    Ambroise Wonkam.
      
    DOI:  https://doi.org/10.1038/scientificamerican102024-3T3xOzF7gg8EvmQvNcMZfq
  2. Sci Am. 2024 Oct 01. 331(3): 85
    New Treatments for Sickle Cell Disease: After years of little progress, new therapies to treat or even cure the disease are reaching patients.
    Sara Reardon.
      
    DOI:  https://doi.org/10.1038/scientificamerican102024-bhc7mJocNIdIEkxD7Z0ie
  3. J Blood Med. 2024 ;15 435-447
    Newer Modalities and Updates in the Management of Sickle Cell Disease: A Systematic Review.
    Zeel Vishnubhai Patel, Priyadarshi Prajjwal, Lakshmi Deepak Bethineedi, Divyakshi J Patel, Kaarvi Khullar, Hinal Patel, Kanishka Khatri, Mohammed Dheyaa Marsool Marsool, Srikanth Gadam, Soumya Aleti, Omniat Amir.
      Sickle cell disease (SCD), the most common autosomal recessive genetic disorder, affects the hemoglobin (Hb) chains in human red blood cells. It is caused by mutations in the β-globin genes, leading to the production of hemoglobin S, which results in the formation of sickle-shaped red blood cells (RBCs). These abnormal cells cause hemolysis, endothelial damage, and small vessel occlusion, leading to both acute and long-term complications. According to the World Health Organization's 2008 estimates, SCD affects approximately 2.28 per 1000 individuals globally. Despite this high prevalence, therapeutic advancements have been slow. For many years, the only FDA-approved medications for managing SCD complications were hydroxyurea and deferiprone. However, recent years have seen the approval of several new therapies, including L-glutamine (2017), voxelotor and crizanlizumab (2019), as well as exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) (2023). These treatments have proven effective in managing both the acute and chronic effects of SCD, including hemolytic anemia, chronic pain, stroke, vaso-occlusive crises, and multiple organ damage syndromes. This review explores the mechanisms of action, practical considerations, and side effects of these emerging therapies, drawing from a comprehensive search of databases such as PubMed, Medline, and Cochrane.
    Keywords:  Casgevy; Crizanlizumab; L-Glutamine; Lyfgenia; Voxelotor; sickle cell disease
    DOI:  https://doi.org/10.2147/JBM.S477507
  4. Br J Haematol. 2024 Sep 15.
    Genetic variants associated with white blood cell count amongst individuals with sickle cell disease.
    International Component of the NHLBI Recipient Epidemiology and Donor Evaluation Study (REDS‐III) and for the TOPMed (NHLBI TransOmics for Precision Medicine) SCD working
       BACKGROUND: Sickle cell disease (SCD) is a Mendelian disorder characterized by a point mutation in the β-globin gene that leads to sickling of erythrocytes. Several studies have shown that absolute neutrophil count is strongly associated with clinical severity of SCD, suggesting an apparent role of white blood cells (WBC) in SCD pathology. However, the mechanism by which genetic variants lead to WBC count differences in SCD patients remains unclear.
    METHODS: Genome-wide association (GWA) analyses were carried out amongst a cohort of 2409 Brazil SCD participants. Association of WBC count and genetic markers were investigated in homozygous sickle cell anaemia participants and compound heterozygous sickle cell haemoglobin C participants.
    RESULTS: GWA analysis showed that variants in genes TERT, ACKR1, and FAM3C are associated with WBC count variation. The well-studied association between WBC count and Duffy null phenotype (variant in ACKR1) in healthy populations was replicated, reinforcing the influence of the SNP rs2814778 (T>C) in WBC count.
    CONCLUSION: Genetics plays an important role in regulating WBC count in patients with SCD. Our results point to possible mechanisms involved in WBC count variation and as increased WBC count is associated with more severe SCD, these results could suggest potential therapeutic targets for individuals with SCD.
    Keywords:  GWAS; WBC; sickle cell disease
    DOI:  https://doi.org/10.1111/bjh.19758
  5. Blood Adv. 2024 Sep 18. pii: bloodadvances.2024013932. [Epub ahead of print]
    UM171 enhances fitness and engraftment of gene modified hematopoietic stem cells from sickle cells disease patients.
    Boya Liu, Denise Klatt, Yu Zhou, John P Manis, Guy Sauvageau, Danilo Pellin, Christian Brendel, David A Williams.
      Hematopoietic stem cell transplantation with lentiviral vector (LVV) transduced autologous cells has proven an effective therapeutic strategy for sickle cell disease (SCD). However, ex vivo culture or proliferative stress associated with in vivo reconstitution may amplify any underlying genetic risk of leukemia. We aimed to minimize culture-induced stress and reduce genomic damage during ex vivo culture, enhance stem cell fitness and reconstitution of SCD CD34+ cells transduced with BCL11A shmiR-encoding LVV currently in clinical trials (NCT NCT03282656). UM171, a pyrimidoindole derivative can expand normal hematopoietic stem cells (HSCs) during in vitro culture and has been shown to be safe and effective in clinical trials using umbilical cord blood (NCT02668315). We examined the effect of UM171 during ex vivo LVV transduction of SCD HSCs. Culture of SCD CD34+ HSCs with UM171 during transduction reduced DNA damage and reactive oxygen species (ROS), decreased apoptosis, and was associated with increased numbers of immunophenotypically defined long-term HSCs. UM171 increased the engraftment of LVV transduced human HSCs in immunodeficient mice and barcode tracing revealed increased clonal diversity of engrafting cells. In competitive transplantation assays, analysis of BM showed that cells transduced in the presence of UM171 consistently outcompeted those transduced under control conditions. In summary, exposure of SCD peripheral blood CD34+ cells to UM171 during LVV transduction enhances stem cell fitness. These findings suggest manufacturing of genetically modified HSCs in the presence of UM171 may improve efficacy, safety and sustainability of gene therapy utilizing ex vivo approaches.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013932
  6. Eur Respir Rev. 2024 Jul;pii: 240005. [Epub ahead of print]33(173):
    Respiratory management of acute chest syndrome in children with sickle cell disease.
    Bushra Ahmed, Michele Arigliani, Atul Gupta.
      Acute chest syndrome (ACS) is a leading cause of respiratory distress and hospitalisation in children with sickle cell disease (SCD). The aetiology is multifactorial and includes fat embolism, venous thromboembolism, alveolar hypoventilation and respiratory infections, with the latter being particularly common in children. These triggers contribute to a vicious cycle of erythrocyte sickling, adhesion to the endothelium, haemolysis, vaso-occlusion and ventilation-perfusion mismatch in the lungs, resulting in the clinical manifestations of ACS. The clinical presentation includes fever, chest pain, dyspnoea, cough, wheeze and hypoxia, accompanied by a new pulmonary infiltrate on chest radiography. Respiratory symptoms may overlap with those of acute asthma, which may be difficult to distinguish. Patients with ACS may deteriorate rapidly; thus prevention, early recognition and aggressive, multidisciplinary team management is essential. In this narrative review, we highlight the current evidence regarding the epidemiology, pathophysiology, treatment and preventative strategies for ACS, focusing on the aspects of major interest for the paediatric pulmonologist and multidisciplinary team who manage children with SCD.
    DOI:  https://doi.org/10.1183/16000617.0005-2024
  7. Cureus. 2024 Aug;16(8): e67228
    Detection of Hemoglobin Constant Spring: A Comparison of Capillary Electrophoresis Versus High-Performance Liquid Chromatography.
    Sharifatul Fatma Embong, Adibah Daud, Mohammad Hudzaifah Nordin, Sumaiyah Adzahar.
       INTRODUCTION: In Malaysia, Hemoglobin Constant Spring (Hb CS) is the most common non-deletional α-thalassemia, caused by a mutation at the termination codon of the α2-globin gene (TAA>CAA). Detection typically involves identifying an abnormal peak at zone 2 on capillary electrophoresis (CE) or a small peak at the C-window on high-performance liquid chromatography (HPLC), indicative of Hb CS.
    OBJECTIVE: This study aimed to investigate the correlation between HPLC and CE in detecting Hb CS, evaluating their respective diagnostic accuracies and limitations.
    METHODS: A cross-sectional study was conducted at Hospital Sultanah Nur Zahirah involving secondary school students (Form 4) from Terengganu who participated in a thalassemia screening program conducted by the Ministry of Health (MOH) from January 2019 to December 2022. Blood samples from subjects showing a positive peak in zone 2 of CE and a small peak at the C-window of HPLC were selected. Molecular studies of these samples were performed to confirm the presence of Hb CS. For the statistical analysis, the Pearson correlation coefficient was employed to assess the relationship between CE and HPLC results.
    RESULTS: Hb CS was confirmed in all samples by molecular studies, revealing 92.3% heterozygous, 7.2% compound heterozygous, and 0.5% homozygous cases. CE detected 92.3% of heterozygous Hb CS cases, while HPLC detected only 48.2%. For compound heterozygous Hb CS, CE detected 100%, whereas HPLC detected 89.3%. Both homozygous cases were detected by CE and HPLC. The Pearson correlation coefficient test showed a significant linear relationship (p<0.001) between CE's zone 2 peak values and HPLC's C-window peaks (n=389).  Conclusion: These findings highlight the efficacy of CE as a reliable method for Hb CS detection, suggesting its potential superiority over traditional HPLC in clinical settings.
    Keywords:  alpha-thalassemia; capillary electrophoresis; hemoglobin constant spring; high-performance liquid chromatography (hplc); non-deletional α-thalassemia
    DOI:  https://doi.org/10.7759/cureus.67228
  8. Front Pediatr. 2024 ;12 1411676
    A novel and apparent de novo ALAS2 missense variant associated with congenital sideroblastic anemia.
    Jianling Cai, Tianming Liu, Yuxuan Huang, Hongxing Chen, Meidie Yu, Dongqing Zhang, Zhanqin Huang.
       Background: Congenital sideroblastic anemia (CSA) constitutes a group of inherited erythropoietic disorders. Some affect mainly or exclusively erythroid cells; other syndromic forms occur within multisystem disorders with extensive nonhematopoietic manifestations. In this study, we have performed clinical and molecular investigations on a 10-year-old boy suspected of having CSA.
    Methods: Routine blood examination, peripheral blood and bone marrow smears, and serum iron tests were performed. Gene mutation analysis was conducted using whole-exome sequencing (WES) and the results were confirmed using Sanger sequencing. Furthermore, the functional impact of the identified variant was assessed/predicted with bioinformatics methods.
    Results: The patient presented with severe microcytic anemia (hemoglobin, 50 g/L), iron overload and ring sideroblasts in the bone marrow. Moreover, WES revealed the presence of a hemizygous missense variant in ALAS2 (c.1102C > T), changing an encoded arginine to tryptophan (p. Arg368Trp). This variant was verified via Sanger sequencing, and neither of the parents carried this variant, which was suspected to be a de novo variant. Using in silico analysis with four different software programs, the variant was predicted to be harmful. PyMol and LigPlot software showed that the p. Arg368Trp variant may result in changes in hydrogen bonds. The patient was treated with vitamin B6 combined with deferasirox. After 6 months, the hemoglobin increased to 99 g/L and the serum ferritin decreased significantly.
    Conclusion: We report a novel pathogenic variant in the ALAS2 gene (c.1102C > T:p. Arg368Trp), which caused CSA in a 10-year-old boy. Mutational analysis is important in patients with CSA when family history data are unavailable. Anemia due to the ALAS2 Arg368Trp variant responds to pyridoxine supplements.
    Keywords:  ALAS2; congenital; in silico analysis; pyridoxine; sideroblastic anemia
    DOI:  https://doi.org/10.3389/fped.2024.1411676
  9. Blood. 2024 Sep 18. pii: blood.2023022502. [Epub ahead of print]
    Management of iron overload: lessons from transfusion-dependent hemoglobinopathies.
    Thomas D Coates.
      Prior to the advent of effective iron chelation, death from iron-induced cardiomyopathy and endocrine failure occurred in the second decade in patients with thalassemia major and this experience has driven expectation of poor outcomes and caused anxiety in all disorders associated with iron loading to this day. To be clear, severe iron overload still causes significant morbidity and mortality in many parts of the world, but current understanding of iron metabolism, non-invasive monitoring of organ specific iron loading in humans and effective iron chelators have dramatically reduced morbidity of iron overload. Furthermore, clinical experience in hemoglobinopathies supports iron biology learned from animal studies and identifies common concepts in the biology of iron toxicity that inform the management of iron toxicity in several human disorders. The resultant significant increase in survival uncovers new complications due to much longer exposure to anemia and to iron which must be considered in long-term therapeutic strategies. This review will discuss the management of iron toxicity in patients with hemoglobinopathies and transfusion-dependent anemias and how iron biology informs the clinical approach to treatment.
    DOI:  https://doi.org/10.1182/blood.2023022502
  10. Heliyon. 2024 Sep 15. 10(17): e36507
    Recent advances and clinical applications of red blood cell lifespan measurement.
    Dan Ji, Yu Peng, Yakun Zhang, Xinyi Tang, Mingyu Zhao, Longrong Ran, Xuelian Wu, Xin Luo, Shuang Chen, Tingting Jiang, Jun Li, Zailin Yang, Yao Liu.
      The red blood cell (RBC) lifespan is a crucial indicator used in clinical diagnostics, treatment, and disease monitoring. This biomarker quantifies the duration that red blood cells (RBCs) circulate within the bloodstream after being released from the bone marrow, serving as a sensitive and direct indicator of red blood cell turnover. Conventional techniques for RBC lifespan measurement, including differential agglutination, 51Cr labeling, and 15N glycine labeling, each present their own set of challenges, such as complexity, radioactive exposure, and potential allergic reaction. The carbon monoxide (CO) breath test has emerged as an advanced and non-invasive alternative, indirectly assessing RBC lifespan through hemoglobin (Hb) renewal rates. This method is convenient, rapid, and lacks the drawbacks of traditional approaches. The CO breath test for RBC lifespan is widely utilized in benign anemia, malignant hematological disorders, neonatal hyperbilirubinemia, and diabetes mellitus, offering valuable insights into disease mechanisms, progression, and treatment outcomes.
    Keywords:  Anemia; CO breath test; Hemolysis; RBC lifespan
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e36507
  11. Blood. 2024 Sep 20. pii: blood.2023023031. [Epub ahead of print]
    Rates of Strokes in Californians with Sickle Cell Disease in the Post-STOP Era.
    Olubusola B Oluwole, Ann Brunson, Oyebimpe Oluyemisi Adesina, Shaina Willen, Theresa Hm Keegan, Kleber Yotsumoto Fertrin, Ted Wun.
      Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The STOP trial (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke. Using statewide emergency department and hospitalization data from the California Department of Health Care Access and Innovation (1991-2019), we determined the cumulative incidence and rates for primary and recurrent strokes and TIAs in people with SCD pre- and post-STOP. For the 7,636 patients included in our SCD cohort, cumulative incidence for first ischemic stroke was 2.1% (95% CI: 1.8%, 2.4%) by age 20 years and 13.5% (95% CI: 12.3%, 14.7%) by age 60 years. Cumulative incidence for first intracranial hemorrhage (ICH) was 0.5% (95% CI: 0.4%, 0.7%) by age 20 years and 6.8% (95%CI: 5.9%, 7.7%) by age 60 years. Ischemic stroke rates increased in children (age <18 years, 234.9 vs 165.1 per 100,000PY, P=0.012) and adults (ages 31-50 years, 431.1 vs 303.2 per 100,000PY, P=0.031) in 2010-2019, compared to the preceding decade. There was an increase in rates of ICH in ages 18-30 and TIA in children <18 years from 2010-2019 when compared to the prior decade. Risk factors for stroke and TIA included increasing age, hypertension, and hyperlipidemia. These findings underscore the need for prevention of strokes in adults with SCD and suggest an emphasis on the management of modifiable cerebrovascular risk factors that have been demonstrated to be effective in the general population.
    DOI:  https://doi.org/10.1182/blood.2023023031
  12. Br J Haematol. 2024 Sep 18.
    Roxadustat, an hypoxia-inducible factor-prolyl hydroxylase inhibitor induce sickle cell crisis: A case report.
    Melchior Chabannes, Antonin Vagnet, Lise Benjemia, Jean Seibel, Maxime Tristant, Marie-Blanche Rabier, Thomas Crepin, Didier Ducloux.
      
    DOI:  https://doi.org/10.1111/bjh.19783
  13. Br J Haematol. 2024 Sep 18.
    Pathogenic G6PD variants: Different clinical pictures arise from different missense mutations in the same codon.
    Simonetta Costa, Angelo Minucci, Amit Kumawat, Maria De Bonis, Giorgia Prontera, Mariannita Gelsomino, Milena Tana, Eloisa Tiberi, Alberto Romano, Antonio Ruggiero, Stefano Mastrangelo, Giuseppe Palumbo, Valentina Giorgio, Maria Elisabetta Onori, Martino Bolognesi, Carlo Camilloni, Lucio Luzzatto, Giovanni Vento.
      G6PD deficiency results from mutations in the X-linked G6PD gene. More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype-phenotype correlations are subtle. We report a rare G6PD variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: G6PD Union, p.(Arg454Cys), and G6PD Andalus, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild-type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant-specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.
    Keywords:   G6PD ; G6PD deficiency; chronic haemolytic disorder; class A variant; molecular dynamics simulations
    DOI:  https://doi.org/10.1111/bjh.19775
  14. Nat Commun. 2024 Sep 16. 15(1): 8131
    Lipoprotein metabolism mediates hematopoietic stem cell responses under acute anemic conditions.
    Kiyoka Saito, Mark van der Garde, Terumasa Umemoto, Natsumi Miharada, Julia Sjöberg, Valgardur Sigurdsson, Haruki Shirozu, Shunsuke Kamei, Visnja Radulovic, Mitsuyoshi Suzuki, Satoshi Nakano, Stefan Lang, Jenny Hansson, Martin L Olsson, Takashi Minami, Gunnar Gouras, Johan Flygare, Kenichi Miharada.
      Hematopoietic stem cells (HSCs) react to various stress conditions. However, it is unclear whether and how HSCs respond to severe anemia. Here, we demonstrate that upon induction of acute anemia, HSCs rapidly proliferate and enhance their erythroid differentiation potential. In severe anemia, lipoprotein profiles largely change and the concentration of ApoE increases. In HSCs, transcription levels of lipid metabolism-related genes, such as very low-density lipoprotein receptor (Vldlr), are upregulated. Stimulation of HSCs with ApoE enhances their erythroid potential, whereas HSCs in Apoe knockout mice do not respond to anemia induction. VldlrhighHSCs show higher erythroid potential, which is enhanced after acute anemia induction. VldlrhighHSCs are epigenetically distinct because of their low chromatin accessibility, and more chromatin regions are closed upon acute anemia induction. Chromatin regions closed upon acute anemia induction are mainly binding sites of Erg. Inhibition of Erg enhanced the erythroid differentiation potential of HSCs. Our findings indicate that lipoprotein metabolism plays an important role in HSC regulation under severe anemic conditions.
    DOI:  https://doi.org/10.1038/s41467-024-52509-w
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