bims-conane Biomed News
on Congenital anemias
Issue of 2024–08–18
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Iron metabolism in sickle cell disease patients undergoing chronic red blood cell exchange: A delicate homeostasis in balance.
  2. Hydroxyurea in the sickle cell disease modern era.
  3. A Review of Gene Therapies for Hemoglobinopathies.
  4. Exercise and training in sickle cell disease: Safety, potential benefits, and recommendations.
  5. Prevalence of Pulmonary Hypertension among Sudanese Patients with Sickle Cell Disease.
  6. Characterizing left ventricular systolic dysfunction in sickle cell disease: three contrasting case reports.
  7. Prevalence, patterns, and factors associated with abnormal lung function among children with sickle cell disease in Uganda: a cross-sectional study.
  8. Context matters: role of ATF4 in hematopoiesis.
  9. G6PD deficiency and diabetes complications.
  10. Active spread of β-thalassemia beyond the thalassemia belt: A study on a Russian population.
  11. Mutations in linker-2 of KLF1 impair expression of membrane transporters and cytoskeletal proteins causing hemolysis.
  1. Br J Haematol. 2024 Aug 11.
    Iron metabolism in sickle cell disease patients undergoing chronic red blood cell exchange: A delicate homeostasis in balance.
    Caterina Giovanna Valentini, Luciana Teofili, Eric Gehrie.
      Sickle cell disease (SCD) is an inherited haemoglobinopathy associated with significant morbidity and mortality. Automated red blood cell exchange (aRCE) plays a key role in managing SCD, eliciting both therapeutic and prophylactic effects. The ideal post-apheresis Ht target for chronic aRCE treatment is not yet unanimously recognized, as well as iron homeostasis can be different among patients. Ross et al. reported their experience on the chronic management of SCD patients undergoing aRCE with a final post-exchange Ht higher than the value commonly adopted, analysing red blood cell transfusion requirements and iron-related outcomes in the study population. Commentary on: Ross et al. Automated red blood cell exchange with a post-procedure haematocrit targeted at 34% in the chronic management of sickle cell disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19674.
    Keywords:  automated red blood cell exchange; iron metabolism; sickle cell disease
    DOI:  https://doi.org/10.1111/bjh.19703
  2. Expert Rev Clin Pharmacol. 2024 Aug 13.
    Hydroxyurea in the sickle cell disease modern era.
    Chazmyn Riley, Walter K Kraft, Robin Miller.
       INTRODUCTION: Sickle cell disease is an inherited disorder characterized by hemoglobin S polymerization leading to vaso-occlusion and hemolytic anemia. These result in a variety of pathological events, causing both acute and chronic complications. Millions around the world are affected by sickle cell disease with predominance in sub-Saharan Africa. Hydroxyurea was the first drug approved for use in sickle cell disease to reduce occurrence of painful crises and blood transfusions in patients with frequent, moderate to severe painful crises.
    AREAS COVERED: With the development of new therapeutics, the role of hydroxyurea is evolving. This narrative review aims to provide clinical data, safety information, and supplementary evidence for the role of hydroxyurea in the current era of sickle cell disease. A comprehensive literature search of databases, including PubMed and Cochrane Library, was conducted from 1963-2024.
    EXPERT OPINION: Even though new medications have been approved for sickle cell disease, hydroxyurea remains the gold standard. Hydroxyurea is not only a disease modifier, but it has additional clinical benefits, it is affordable, and its longevity has prompted expanded research in areas such as underutilization and pharmacogenomics. As the treatment landscape evolves, hydroxyurea's long-standing record of efficacy and safety continues to support its role as a key agent in disease management.
    Keywords:  Hemoglobinopathy; hydroxycarbamide; hydroxyurea; sickle cell anemia; sickle cell disease
    DOI:  https://doi.org/10.1080/17512433.2024.2390915
  3. Hemoglobin. 2024 Aug 15. 1-12
    A Review of Gene Therapies for Hemoglobinopathies.
    Boubini Jones-Wonni, Amar H Kelkar, Maureen O Achebe.
      Due to the significant morbidity and mortality of hemoglobinopathies, curative options have long been pursued. The overall goal of gene therapy is to modify a patient's own hematopoietic stem cells to overcome the deleterious effects of the underlying genetic defect by gene addition, gene editing, or gene silencing. Gene addition incorporates genes with superior function than the abnormal gene; gene editing takes advantage of molecular tools such as zinc finger proteins, Transcription Activator-Like Effector Nucleases and Clustered Regularly Interspaced Short Palindromic Repeats coupled with Cas9 proteins (CRISPR-Cas9) which allow for sequence-specific breaks in DNA that disrupt gene function; and gene silencing suppresses gene expression by interference with mRNA transcription/protein translation or epigenetic modification. The majority of gene therapy strategies for hemoglobinopathies have targeted erythroid-specific BCL11A, a major regulator of fetal hemoglobin repression at the gamma-globin locus, in the normal fetal-to-adult hemoglobin switch that occurs shortly after birth. Other goals have involved the incorporation of anti-sickling globins, such as βT87Q or βAS3. Landmark clinical trials of gene therapy in transfusion-dependent thalassemia and sickle cell disease have shown remarkable efficacy and acceptable safety and culminated in recent regulatory approvals of gene therapy for both diseases in Europe and the United States.
    Keywords:  Gene therapy; sickle cell disease; transfusion-dependent thalassemia
    DOI:  https://doi.org/10.1080/03630269.2024.2369534
  4. Am J Hematol. 2024 Aug 12.
    Exercise and training in sickle cell disease: Safety, potential benefits, and recommendations.
    Philippe Connes, Emeric Stauffer, Robert I Liem, Elie Nader.
      Sickle cell disease (SCD) is a genetic disorder characterized by complex pathophysiological mechanisms leading to vaso-occlusive crisis, chronic pain, chronic hemolytic anemia, and vascular complications, which require considerations for exercise and physical activity. This review aims to elucidate the safety, potential benefits, and recommendations regarding exercise and training in individuals with SCD. SCD patients are characterized by decreased exercise capacity and tolerance. Acute intense exercise may be accompanied by biological changes (acidosis, increased oxidative stress, and dehydration) that could increase the risk of red blood cell sickling and acute clinical complications. However, recent findings suggest that controlled exercise training is safe and well tolerated by SCD patients and could confer benefits in disease management. Regular endurance exercises of submaximal intensity or exercise interventions incorporating resistance training have been shown to improve cardiorespiratory and muscle function in SCD, which may improve quality of life. Recommendations for exercise prescription in SCD should be based on accurate clinical and functional evaluations, taking into account disease phenotype and cardiorespiratory status at rest and in response to exercise. Exercise programs should include gradual progression, incorporating adequate warm-up, cool-down, and hydration strategies. Exercise training represents promising therapeutic strategy in the management of SCD. It is now time to move through the investigation of long-term biological, physiological, and clinical effects of regular physical activity in SCD patients.
    DOI:  https://doi.org/10.1002/ajh.27454
  5. Open Respir Med J. 2024 ;18 e18743064292252
    Prevalence of Pulmonary Hypertension among Sudanese Patients with Sickle Cell Disease.
    Yousif Ahmed Elfaki, Ahmed Saadeldin Ibrahim, Tarig Hakim Merghani.
       Background: Sickle Cell Disease (SCD) is a hereditary condition characterized by aberrant red blood cell morphology, leading to persistent hemolytic anemia. The consequential impact of SCD on the pulmonary vasculature can result in pulmonary hypertension (PHT), a severe complication that detrimentally affects the well-being and survival of individuals with SCD. The prevalence and risk determinants of PHT in SCD patients exhibit variations across diverse geographical regions and populations. This study aims to ascertain the prevalence of PHT among Sudanese SCD patients and identify associated factors.
    Methods: A cohort of thirty-one adult sickle cell disease (SCD) patients, as confirmed by hemoglobin electrophoresis, were recruited for participation in this cross-sectional study. Comprehensive data encompassing demographic, clinical, and laboratory parameters were collected. Doppler echocardiography was employed to quantify pulmonary arterial systolic pressure (PASP) and evaluate right ventricular size and function.
    Results: Within our cohort, the prevalence of PHT was 29%. Active cigarette smoking demonstrated a significant association with PHT (P=0.042), while hydroxyurea therapy exhibited no noticeable impact on PHT (P=0.612).
    Conclusion: Our investigation revealed a PHT prevalence of less than one-third in our SCD patient population, aligning with prior studies. Notably, independent of other factors, cigarette smoking emerged as a distinct risk factor for PHT in SCD patients. This highlights the potential utility of smoking cessation as an intervention to delay the onset of this condition. However, further research is imperative to elucidate the mechanisms through which smoking contributes to PHT development in individuals with SCD.
    Keywords:  Cigarette smoking; Electrophoresis; Hydroxyurea; Pulmonary hypertension; Sickle cell disease; Sudanese
    DOI:  https://doi.org/10.2174/0118743064292252240422100911
  6. Eur Heart J Case Rep. 2024 Aug;8(8): ytae383
    Characterizing left ventricular systolic dysfunction in sickle cell disease: three contrasting case reports.
    George Katis, Sridhar Srinivasan, Perla Eleftheriou, Malcolm Walker, Polyvios Demetriades.
       Background: Left ventricular systolic dysfunction (LVSD) is an uncommon but life-threatening complication of sickle cell disease (SCD), with poorly characterized aetiology. We present three SCD patients with LVSD due to different underlying mechanisms.
    Case summary: The first case describes rapid deterioration in LV function secondary to severe cardiac iron overload in a 37-year-old female with poor chelation compliance after 10 years of top-up transfusions for SCD. The second case is a severe non-ischaemic dilated cardiomyopathy (DCM) in a 42-year-old SCD patient with longstanding sickle nephropathy and hypertension. The final case demonstrates severe LVSD with large transmural infarcts (ischaemic DCM) in the absence of epicardial coronary disease in a 52-year-old SCD patient.
    Discussion: This case series presents the first attempt to characterize the aetiology of LVSD in SCD. We identified three phenotypes: iron-overload cardiomyopathy, non-ischaemic DCM, and ischaemic DCM. These contrasting cases highlight the significance of understanding the underlying pathology in determining individualized treatment plans for these high-risk patients. We discuss the role of cardiac MRI (CMR) in characterizing LV dysfunction, and we believe that this case series will form the basis of prospective studies to further delineate the pathophysiology of LVSD in SCD.
    Keywords:  Cardiac MRI; Case report; Heart failure; Left ventricular systolic dysfunction; Sickle cell disease
    DOI:  https://doi.org/10.1093/ehjcr/ytae383
  7. BMC Pediatr. 2024 Aug 10. 24(1): 516
    Prevalence, patterns, and factors associated with abnormal lung function among children with sickle cell disease in Uganda: a cross-sectional study.
    Pamella Mwa Aol, Geriga Fahdil, Felix Bongomin, Bonny Okello, Charles Batte, Bruce J Kirenga, Rebecca Nantanda, Hellen Tukamuhebwa Aanyu.
       BACKGROUND: Pulmonary complications are common among children with sickle cell disease (SCD). However, there is little literature on associated lung function abnormalities in Uganda. We aimed to determine the prevalence, patterns, and factors associated with abnormal lung function among children with SCD in a tertiary care hospital in Uganda.
    METHOD: A cross-sectional study was conducted among children aged 6 to 18 years at the SCD clinic (SCC) of Mulago National Super-Specialized Hospital between January 2020 and April 2021. Data on sociodemographic and clinical characteristics was collected using a standardized questionnaire. Laboratory investigations, including a complete blood count and serum lactate dehydrogenase (LDH), were done. Spirometry was performed following the ATS/ERS standards. Multivariable modified Poisson regression analysis was performed to determine factors associated with abnormal lung function.
    RESULTS: A total of 332 participants were enrolled. The mean age was 11.7 ± 3.4 years, and 184 (55.4%) were female. Overall, 126 (37.9%) participants had abnormal lung function: 67/126 (53.2%) restrictive, 57/126 (45.2%) obstructive, and 2/126 (1.6%) mixed-ventilatory patterns. Factors associated with abnormal lung function were; serum LDH level > 600UL (aIRR: 1.89 95% CI: 1.2 - 7.4, p = 0.049), a history of acute chest syndrome (aIRR: 1.55, 95% CI: 1.06-2.25, p = 0.024), wasting (aIRR: 1.33, 95%CI: 1.02 - 1.72, p = 0.032), and use of charcoal for household cooking (aIRR: 1.49, 95% CI: 1.03-2.15, p = 0.035).
    CONCLUSION: More than one-third of children with SCD in Uganda have lung function abnormalities. Strategies to improve nutrition, reduce exposure to charcoal smoke, and monitoring serum LDH levels may be important in preventing or managing abnormal lung function in this population. The identification of reversible and irreversible airway obstruction in children with sickle cell disease also highlights the need for targeted interventions to address these specific patterns of abnormal lung function.
    Keywords:  Children; Lung function; Sickle cell disease; Uganda
    DOI:  https://doi.org/10.1186/s12887-024-04988-5
  8. Blood. 2024 Aug 15. 144(7): 684-686
    Context matters: role of ATF4 in hematopoiesis.
    Junhua Lyu, Jian Xu.
      
    DOI:  https://doi.org/10.1182/blood.2024025066
  9. Nat Genet. 2024 Aug;56(8): 1541
    G6PD deficiency and diabetes complications.
    Kyle Vogan.
      
    DOI:  https://doi.org/10.1038/s41588-024-01881-w
  10. Clin Genet. 2024 Aug 14.
    Active spread of β-thalassemia beyond the thalassemia belt: A study on a Russian population.
    Ekaterina Shchemeleva, Valentina V Salomashkina, Daria Selivanova, Nina Tsvetaeva, Anait Melikyan, Liliya Doronina, Vadim L Surin.
      β-Thalassemia is a disease traditionally associated with thalassemia belt countries. Nonetheless, as global migration intensifies, β-thalassemia-causing variants spread far from their origin. We investigated this process to detect some patterns underlying its course. We analyzed β-thalassemia-causing variants and the origin of 676 unrelated participants in Moscow, the largest city of Russia, far away from the thalassemia belt. Our analyses revealed that modern Russia has one of the broadest spectra of thalassemia-causing variants: 46 different variants, including two novel β0 variants. Only a small proportion of the reported pathogenic variants likely originated in the resident subpopulation. Almost half of the variants that supposedly had emerged outside the Russian borders have already been assimilated by (were found in) the resident subpopulation. The primary modern source of immigration transferring thalassemia to a nonthalassemic part of Russia is the Caucasus region. We also found traces of ancient migration flows from non-Caucasus countries. Our data indicate that β-thalassemia-causing variants are actively spilling over into resident populations of countries outside thalassemia belt regions. Therefore, viewing thalassemia as a disease exclusive to specific ethnic groups creates a mind trap that can complicate the diagnosis.
    Keywords:  Caucasus; migration; mutation spectrum; novel mutation; thalassemia belt; β‐thalassemia
    DOI:  https://doi.org/10.1111/cge.14606
  11. Nat Commun. 2024 Aug 15. 15(1): 7019
    Mutations in linker-2 of KLF1 impair expression of membrane transporters and cytoskeletal proteins causing hemolysis.
    Stephen Huang, Casie Reed, Melissa Ilsley, Graham Magor, Michael Tallack, Michael Landsberg, Helen Mitchell, Kevin Gillinder, Andrew Perkins.
      The SP/KLF family of transcription factors harbour three C-terminal C2H2 zinc fingers interspersed by two linkers which confers DNA-binding to a 9-10 bp motif. Mutations in KLF1, the founding member of the family, are common. Missense mutations in linker two result in a mild phenotype. However, when co-inherited with loss-of-function mutations, they result in severe non-spherocytic hemolytic anemia. We generate a mouse model of this disease by crossing Klf1+/- mice with Klf1H350R/+ mice that harbour a missense mutation in linker-2. Klf1H350R/- mice exhibit severe hemolysis without thalassemia. RNA-seq demonstrate loss of expression of genes encoding transmembrane and cytoskeletal proteins, but not globins. ChIP-seq show no change in DNA-binding specificity, but a global reduction in affinity, which is confirmed using recombinant proteins and in vitro binding assays. This study provides new insights into how linker mutations in zinc finger transcription factors result in different phenotypes to those caused by loss-of-function mutations.
    DOI:  https://doi.org/10.1038/s41467-024-50579-4
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