bims-conane Biomed News
on Congenital anemias
Issue of 2024–09–08
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Transcriptional regulators of fetal hemoglobin.
  2. Identification of genetic variants associated with clinical features of sickle cell disease.
  3. Eosinophilic dialogues: a molecular exploration of sickle cell anemia severity.
  4. Sickle Cell Anemia Screening in Newborns and Analysis of Haplotypes in Patients from Santiago Island, Cape Verde.
  5. First Report of Hb Youngstown in Capillary Electrophoresis and Overlapping Hb Analysis Findings with Hb Rush.
  6. Understanding Exercise (in)tolerance in Sickle Cell Disease: Impacts of Hemolysis and Exercise Training on Skeletal Muscle Oxygen Delivery.
  7. Family study of haemoglobin Arya in a Malaysian family.
  1. Hematol Transfus Cell Ther. 2024 Aug 17. pii: S2531-1379(24)00296-7. [Epub ahead of print]
    Transcriptional regulators of fetal hemoglobin.
    Gabriela Pereira Dos Santos, Larissa Teodoro Rabi, André Alves Bezerra, Marcelo Rodrigues da Cunha, Amilton Iatecola, Victor Augusto Ramos Fernandes.
      Sickle cell anemia is a hereditary disease caused by sickle-shaped red blood cells that can lead to vaso-occlusive crises. Treatment options are currently limited, highlighting the need to develop new clinical approaches. Studies demonstrated that elevated levels of fetal hemoglobin (Hb F) are associated with a reduction of mortality and morbidity in sickle cell anemia patients. In light of this, researchers have been trying to elucidate the transcriptional regulation of Hb F to develop new therapeutic interventions. The present study aimed to present the main transcription factors of Hb F and discuss the clinical feasibility of these molecular targets. Two search strategies were used in the PubMed, SciELO, and LILACS databases between July and August 2023 to conduct this review. Manual searches were also conducted by checking references of potentially eligible studies. Eligibility criteria consisted of clinical trials and cohort studies from the last five years that investigated transcription factors associated with Hb F. The transcription factors investigated in at least four eligible studies were included in this review. As a result, 56 eligible studies provided data on the BCL11A, LRF, NF-Y, GATA1, KLF1, HRI, ATF4, and MYB factors. The studies demonstrated that Hb F is cooperatively regulated by transcription factors with the BCL11A factor appearing to be the most specific target gene for γ-globin induction. Although these data are promising, there are still significant gaps and intervention limitations due to the adverse functions of the target genes. New studies that clarify the aspects and functionalities of Hb F regulators may enable new clinical approaches for sickle cell anemia patients.
    Keywords:  Fetal hemoglobin; Gamma-globin; Gene therapy; Sickle cell anemia; Transcription factors
    DOI:  https://doi.org/10.1016/j.htct.2024.06.001
  2. Sci Rep. 2024 08 29. 14(1): 20070
    Identification of genetic variants associated with clinical features of sickle cell disease.
    Katharine Tsukahara, Xiao Chang, Frank Mentch, Kim Smith-Whitley, Anita Bhandari, Cindy Norris, Joseph T Glessner, Hakon Hakonarson.
      Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the β-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10-10) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10-8) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10-8) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10-8), 15q26.1 (rs62020555, P = 2.04 × 10-9) and 15q26.3 (rs117797325, P = 4.63 × 10-8). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD.
    Keywords:  Fetal hemoglobin; Genome-wide association study; Hemoglobinopathies; Sickle cell anemia
    DOI:  https://doi.org/10.1038/s41598-024-70922-5
  3. Ann Med Surg (Lond). 2024 Sep;86(9): 5252-5255
    Eosinophilic dialogues: a molecular exploration of sickle cell anemia severity.
    Emmanuel Ifeanyi Obeagu.
      Sickle cell anemia (SCA) is a genetically inherited hemoglobinopathy characterized by the abnormal morphology of red blood cells, resulting in vaso-occlusive events and diverse clinical complications. Recent investigations have unveiled a novel dimension in understanding SCA severity through the lens of eosinophilic dialogues. This review article synthesizes current knowledge on the molecular intricacies of eosinophils in the context of SCA, exploring their biology, molecular markers, and interactions with other cellular components. Eosinophil-mediated inflammation and oxidative stress are dissected to elucidate their impact on the disease course. Furthermore, the review evaluates potential therapeutic interventions and outlines future directions in this burgeoning field. The term "Eosinophilic Dialogues" encapsulates the multifaceted molecular exchanges that influence SCA severity, presenting a promising avenue for targeted interventions and improved clinical outcomes. This review serves as a comprehensive resource for researchers, clinicians, and healthcare practitioners engaged in unraveling the complex pathophysiology of SCA and exploring novel therapeutic avenues.
    Keywords:  eosinophils; inflammation; molecular pathways; oxidative stress; sickle cell anemia
    DOI:  https://doi.org/10.1097/MS9.0000000000002152
  4. Anemia. 2024 ;2024 1687917
    Sickle Cell Anemia Screening in Newborns and Analysis of Haplotypes in Patients from Santiago Island, Cape Verde.
    Ariana Freire, Laura Charola-Ramos, Elisa González-Guerra, João Gonçalves, Vanusa Rocha, Vera Afreixo, Enrique Martínez-Carretero, José M Raya.
      Sickle cell anemia (SCA) results from a mutation in the β-globin gene, leading to the production of mutant hemoglobin, known as hemoglobin S (HbS). Despite being a genetic disorder, the phenotype of SCA can be influenced by the level of fetal hemoglobin (HbF), which is associated with beta S-globin haplotypes. In this study, we conducted newborn screening (NBS) using samples collected from umbilical cord blood in two hospitals on Santiago Island, Cape Verde. In newborns, HbS was detected using high-performance liquid chromatography (HPLC) on dried blood spot, with confirmation through polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). In addition, we assessed the hematological and clinical characteristics of a second population group consisting of patients diagnosed with SCA. Haplotype determination was performed on both newborns with HbS and patients with SCA. Beta S-globin haplotypes were determined using PCR-RFLP. Hematological values were analyzed using standard methods. Out of 346 newborns, 21 (6%) were carriers of the sickle cell trait (HbAS) while none were identified as homozygous for sickle cell disease (HbSS). Among both groups of individuals, four haplotypes were identified: Senegal, Arabi-Indian, Bantu, and Benin. The Senegal haplotype was the most prevalent, possibly reflecting the ethnic origin of the mutations observed. Hematological values did not differ significantly among haplotypes. However, higher levels of HbF were associated with better hematological values. These findings suggest a positive impact of elevated HbF levels on reducing the severity of SCA. Finally, we demonstrated how the combination of technics, HPLC and molecular analysis, provided a consistent and reproducible results that can be used for NBS for SCA.
    DOI:  https://doi.org/10.1155/2024/1687917
  5. Hemoglobin. 2024 Sep 03. 1-4
    First Report of Hb Youngstown in Capillary Electrophoresis and Overlapping Hb Analysis Findings with Hb Rush.
    Kim Yan Poh, Ping Chong Bee.
      Hb Youngstown [HBB:c.305A > C] is a rare unstable hemoglobin caused by the substitution of glutamic acid with alanine at codon 101 of the Beta globin chain. It causes hemolytic anemia in the heterozygous state. This is a case of a six-year-old Chinese-Javanese girl with heterozygous Hb Youngstown and clinical features of chronic hemolysis and iron overload. Hb Youngstown appears at the S window near to 4.6 minutes on high-performance liquid chromatography (HPLC) and can form a hybrid tetramer on alkaline gel electrophoresis seen as two distinct bands cathodal to A and close to F. For the first time, Hb Youngstown is captured with capillary electrophoresis (CE) and shown to be eluted at zone 8. Clinical presentation and Hb analysis results of this heterozygous Hb Youngstown overlap with heterozygous Hb Rush. They can only be differentiated at molecular level by Beta globin gene sequencing or intact mass spectrometry.
    Keywords:  Hb Rush; Hb Youngstown; hybrid tetramer; unstable hemoglobin
    DOI:  https://doi.org/10.1080/03630269.2024.2398236
  6. J Appl Physiol (1985). 2024 Aug 29.
    Understanding Exercise (in)tolerance in Sickle Cell Disease: Impacts of Hemolysis and Exercise Training on Skeletal Muscle Oxygen Delivery.
    David C Irwin, Edward T N Calvo, Michael D Belbis, Sabrina K C Ehrenfort, Mathilde Noguer, Laurent A Messonnier, Paul W Buehler, Daniel M Hirai, Scott K Ferguson.
      Sickle cell disease (SCD) is characterized by central (cardiac) and peripheral vascular dysfunctions, significantly diminishing exercise capacity and quality of life. While central cardiopulmonary abnormalities in SCD are known to reduce exercise capacity and quality of life; the impact of hemolysis and subsequent cell-free hemoglobin (Hb)-mediated peripheral vascular abnormalities on those outcomes are not fully understood. Despite the recognized benefits of exercise training for cardiovascular health and clinical management in chronic diseases like heart failure, there remains substantial debate on the advisability of regular physical activity for SCD patients. This is primarily due to concerns that prolonged and/or high-intensity exercise might trigger metabolic shifts leading to vaso-occlusive crises. As a result, exercise recommendations for SCD patients are often vague or nonexistent, reflecting a gap in knowledge about the mechanisms of exercise intolerance and the impact of exercise training on SCD-related health issues. This mini-review sheds light on recent developments in understanding how SCD affects exercise tolerance, with a special focus on the roles of hemolysis and the release of cell-free hemoglobin in altering cardiovascular and skeletal muscle function. Also highlighted here is the emerging research on the therapeutic effects and safety of exercise training in SCD patients. Additionally, the review identifies future research opportunities to fill existing gaps in our understanding of exercise (in)tolerance in SCD.
    Keywords:  Sickle cell anemia; VO2 max; hemoglobin; nitric oxide; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00390.2024
  7. Malays J Pathol. 2024 Aug;46(2): 315-320
    Family study of haemoglobin Arya in a Malaysian family.
    S Nahanthiran, N H Nik Mustapha, N Yasin, F B Idris, S B Md Noor.
       INTRODUCTION: Thalassemia and haemoglobinopathies are relatively common among Malaysians. One of the rare haemoglobinopathies reported is Haemoglobin (Hb) Arya, which occurs due to substitution of aspartic acid at residue 47 of the alpha chain by asparagine. Here, we report the detection of Hb Arya in a Malaysian family, which was detected incidentally during family screening.
    CASE REPORT: A 16 years-old girl, clinically asymptomatic was noted to have low mean corpuscular haemoglobin (MCV) with normal Hb level. Hb analysis using capillary electrophoresis (CE) showed reduced Hb A of 76.5%, Hb A2 of 1.6% with presence of small peak at Zone 1 likely A2'. There was also a small peak noted at Hb D zone and Hb S zones which quantified as 1.5% and 20% respectively. Supplementary test by high performance liquid chromatography (HPLC) showed a prominent peak at D-window (19.6%) and a small peak at S-window (0.6%). DNA analysis revealed a heterozygous state of α2 codon 47 Hb Arya mutation. Subsequent family study showed a similar mutation in the father and sister of the index case.
    CONCLUSION: Very few reports are available up to date regarding Hb Arya. This report highlights the rare haemoglobinopathy in a Malay family in Malaysia that contributes to the growing literature of this rare haemoglobin variant.
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:14.