bims-conane Biomed News
on Congenital anemias
Issue of 2024‒09‒29
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Interactions of electrophoretically silent hemoglobin Hekinan II [HBA1:c.84G>T] with various forms of α-thalassemias and other hemoglobinopathies: novel insights into the molecular and hematological characteristics and genetic origins.
  2. Characterization of Hemoglobin Malay Phenotypes in Tertiary Hospitals.
  3. Fanconi anemia: realizing hematopoietic cure.
  4. Trans-acting genetic modifiers of clinical severity in heterozygous β-Thalassemia trait.
  5. Hemoglobin J-Auckland: a clinically silent low oxygen affinity variant presenting with persistent asymptomatic hypoxemia at high altitude.
  6. How We Treat Hemolytic Anemia Due to Pyruvate Kinase Deficiency.
  7. Transplant outcome in pediatric Fanconi anemia.
  8. Expression of microRNA-155 in thalassemic erythropoiesis.
  1. Libyan J Med. 2024 Dec 31. 19(1): 2406620
    Interactions of electrophoretically silent hemoglobin Hekinan II [HBA1:c.84G>T] with various forms of α-thalassemias and other hemoglobinopathies: novel insights into the molecular and hematological characteristics and genetic origins.
    Sitthichai Panyasai, Prasert Chantanaskulwong, Nopphadol Permsripong, Thippawal Mokmued.
      To determine the molecular basis, genotype - phenotype relationship, and genetic origin of Hemoglobin (Hb) Hekinan associated with several forms of α-thalassemia and other hemoglobinopathies for a better understanding of its diverse clinical phenotypes. Seventeen participants with suspected abnormal Hb were studied. Hb analysis was performed using high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Mutational and α-haplotypic and structural analyses were conducted, and the effects of mutations on globin-chain stability were determined. All participants harbored Hb Hekinan II (HBA1:c.84 G>T) co-inherited with another α-globin gene anomaly. Three novel genotypes, (ααHekinan/αCSα), (ααHekinan/αCSα,βA/βE), and (ααHekinan/αCSα,βE/βE), were characterized. Despite being co-inherited with both α- and β-Hb variants Hb Hekinan II led to minimal changes in erythrocyte parameters, suggesting a non-pathological nature. HPLC but not CE revealed a distinct small shoulder-like Hb pattern. Thai Hb Hekinan II was strongly associated with haplotype [+ - S + - - -] and the possibility of four different haplotypes, while two Burmese Hb Hekinan II were associated with haplotypes [± - S + - + -] and [± - S + - - -]. The novel genotypes identified provide a fresh perspective on Hb Hekinan II diversity. HPLC has superior identification capabilities for samples of Hb Hekinan II co-inherited with α-thalassemia. Thai and Burmese Hb Hekinan II have diverse origins.
    Keywords:  Hemoglobin hekinan II; capillary electrophoresis; high-performance liquid chromatography; α-globin haplotype; α-hemoglobin variant
    DOI:  https://doi.org/10.1080/19932820.2024.2406620
  2. Hemoglobin. 2024 May;48(3): 153-160
    Characterization of Hemoglobin Malay Phenotypes in Tertiary Hospitals.
    Alia Suzana Asri, Muhammad Hafiz Samsuddin, Norunaluwar Jalil, Norlida Mohamad Tahir, Hafizah Hashim, Raja Zahratul Azma, Ezalia Esa, Rinie Awai Albert, Hafiza Alauddin.
      Hemoglobin (Hb) Malay is a common β hemoglobinopathy in Malaysia caused by A > G mutation in codon 19 leading to β+-thalassemia phenotype. However, screening for Hb Malay is challenging as it is undetectable by routine capillary electrophoresis (CE) or high-performance liquid chromatograpy (HPLC) methods. This study aimed to determine the Hb Malay phenotypes. The study was done on 521 cases with presumed β thalassemia from UKMMC and Hospital Selayang as well as confirmed Hb Malay cases from Hospital Sultanah Bahiyah, Kedah in over a 5-year period. Hb analysis using CE or HPLC followed by multiplex amplification refractory mutation system polymerase chain reaction and DNA sequencing were performed. Significant differences in mean values of haematological parameters among Hb Malay carriers against β thalassemia carriers were determined using one-way ANOVA and ROC analysis. A total of 482/521 cases of β globin mutations were identified. Among these, 54 Hb Malay cases were identified whereby 21 Hb Malay cases were from UKMMC and Hospital Selayang whilst 33 Hb Malay cases were from Hospital Sultanah Bahiyah, Kedah. Fifty-two were Hb Malay carriers whereas two cases were compound heterozygotes. The mean hemoglobin, mean cell volume, mean cell hemoglobin, and HbA of Hb Malay carriers were significantly higher than β° thalassemia carriers. The HbA2 range of Hb Malay carriers was wider (3.5-5.5%) with median value of 3.9%. A new HbA2 cutoff value ≤4.6% (AUC 0.717, p < 0.001) was proposed. Compound heterozygous Hb Malay/IVS1-5(G > C) showed transfusion-dependent thalassemia phenotype. Hb Malay carriers have different red cell and electrophoretic parameters than classical β° thalassemia carriers with wider HbA2 range. HbA2 of ≤4.6% should prompt a molecular confirmation for Hb Malay carrier status.
    Keywords:  DNA analysis; Hb Malay; hemoglobinopathy; thalassemia
    DOI:  https://doi.org/10.1080/03630269.2024.2380873
  3. Blood. 2024 Sep 19. 144(12): 1245-1246
    Fanconi anemia: realizing hematopoietic cure.
    Alexandra M Satty.
      
    DOI:  https://doi.org/10.1182/blood.2024025541
  4. Ann Hematol. 2024 Sep 24.
    Trans-acting genetic modifiers of clinical severity in heterozygous β-Thalassemia trait.
    Joanna B Loh, Jules M Ross, Khaled M Musallam, Kevin H M Kuo.
      There is a group of beta (β)-thalassemia trait 'carriers' (with heterozygous mutations) who should be asymptomatic with minor abnormalities in their hematological parameters, but experience more severe disease manifestations than predicted based solely on their β-globin genotype. This review focuses on literature describing trans-acting genetic modifiers outside of the α- and β-globin gene clusters that could cause this phenomenon. These genetic modifiers are categorized into: mutations affecting the quantity of alpha-globin products, non-globin mutations affecting erythropoiesis, membranopathies, enzymopathies and erythrocyte-independent modifiers of complications relating to β-thalassemia. Although some genetic determinants seem to correlate more directly with β-thalassemia trait severity, such as mutations in SUPT5H, PIEZO1 and hereditary elliptocytosis, the difficulties of linking the contribution of other modulating factors are elucidated in this review. Targeted next generation sequencing of hemolytic anemias can be helpful but also raises another quandary in interpreting variants of uncertain significance. The accrual of knowledge, along with the increased availability of genetic testing for genetic modifiers has considerable potential for clinical applications such as genetic counselling, decision-making for clinical interventions and prognostication, and perhaps generating new therapeutic targets.
    Keywords:  Anemia; Mutations; Phenotype; Thalassemia
    DOI:  https://doi.org/10.1007/s00277-024-06007-0
  5. Hematology. 2024 Dec;29(1): 2405751
    Hemoglobin J-Auckland: a clinically silent low oxygen affinity variant presenting with persistent asymptomatic hypoxemia at high altitude.
    Ali Alsuheel Asseri, Ibrahim Tawhari, Afaf Haif Qahtani, Ibrahim A Asiri, Husain Alkhaldy.
      BACKGROUND: Inherited hemoglobin disorders are common in clinical practice. While qualitative (i.e. sickle cell disease) and quantitative (thalassemia) hemoglobinopathies are usually diagnosed clinically and confirmed through simple laboratory assessments, hemoglobin variants with altered oxygen affinity often go undetected due to their typically silent clinical presentation. Hemoglobin (Hb) J-Auckland, a low oxygen affinity hemoglobin variant first described in 1987 in Auckland, New Zealand, is one such silent disorder.CASE PRESENTATION: We report for the first time a clinically evident case of previously undiagnosed Hb J-Auckland in an 8-year-old girl who presented with unexplained hypoxemia at high altitude. Her oxygen level was corrected with supplemental oxygen and when assessed at low altitude. A brief discussion of the diagnostic approach and clinical implications is provided.
    CONCLUSION: Standard hemoglobin analysis is essential for the evaluation of suspected altered affinity hemoglobinopathy, and genetic testing is often required for definitive diagnosis. Early recognition and diagnosis of these variants can prevent mismanagement and improve patient outcomes.
    Keywords:  Low-affinity; Saudi Arabia; altitude; hemoglobin J-Auckland; hemoglobinopathy; hypoxemia; oxygen; partial pressure
    DOI:  https://doi.org/10.1080/16078454.2024.2405751
  6. Hematol Rep. 2024 Aug 31. 16(3): 559-567
    How We Treat Hemolytic Anemia Due to Pyruvate Kinase Deficiency.
    Sara Tama-Shekan, Valeria Moreno, Ludovic Saba, Chakra P Chaulagain.
      BACKGROUND: Pyruvate kinase (PK) deficiency is an inherited red blood cell (RBC) enzyme disorder that results in non-immune chronic hemolytic anemia. Characteristic symptoms of PK deficiency include anemia, fatigue, splenomegaly, jaundice, gallstones, thrombosis, and transfusional iron overload. Previously, treatments aimed at symptomatic management with RBC transfusions, phototherapy, folic acid supplementation, splenectomy, and iron chelation therapy when iron overload was documented. Mitapivat, a recently approved medication for treatment of PK-deficiency hemolytic anemia, is an oral allosteric activator of wild-type and mutant RBC PK enzymes. In this paper, we describe three cases of PK-deficiency anemia treated with mitapivat and describe modern management of this rare hemolytic disorder.METHODS: A retrospective healthcare database analysis was conducted to extract relevant information. Both quantitative and qualitative methods were integrated to provide a more comprehensive understanding of the cases.
    RESULTS: Two patients responded well to treatment with mitapivat, noted by an increase in hemoglobin levels, improvements in hemolytic markers, less frequent or no RBC transfusion requirements, and improvements in fatigue. One patient carrying two non-missense mutations of the PKLR gene did not respond to treatment with mitapivat. As variations in patient-specific factors (including genotype) can lead to different clinical manifestations and responses to treatment, we recommend considering both the phenotype (clinical symptoms and signs) and the genotype of the PKLR gene when making therapeutic decisions about starting a patient on mitapivat.
    CONCLUSIONS: While mitapivat addresses the previously unmet needs of most patients with PK deficiency as the first and only disease-modifying medication to receive approval for this condition, not all patients with PK deficiency are amenable to treatment with mitapivat.
    Keywords:  hemolytic anemia; mitapivat; pyruvate kinase deficiency; transfusional iron overload
    DOI:  https://doi.org/10.3390/hematolrep16030054
  7. Blood. 2024 Sep 19. 144(12): 1350
    Transplant outcome in pediatric Fanconi anemia.
      
    DOI:  https://doi.org/10.1182/blood.2024026318
  8. PeerJ. 2024 ;12 e18054
    Expression of microRNA-155 in thalassemic erythropoiesis.
    Tipparat Penglong, Nuttanan Pholngam, Nasra Tehyoh, Natta Tansila, Hansuk Buncherd, Supinya Thanapongpichat, Kanitta Srinoun.
      Background: Ineffective erythropoiesis (IE) is the primary cause of anemia and associated pathologies in β-thalassemia. The characterization of IE is imbalance of erythroid proliferation and differentiation, resulting in increased erythroblast proliferation that fails to differentiate and gives rise to enucleate RBCs. MicroRNAs (miRs) are known to play important roles in hematopoiesis. miR-155 is a multifunctional molecule involved in both normal and pathological hematopoiesis, and its upregulation is observed in patients with β-thalassemia/HbE. However, the expression and function of miR-155, especially in β-thalassemia, have not yet been explored.Methods: To study miR-155 expression in thalassemia, erythroblast subpopulations, CD45-CD71+Ter-119+ and CD45-CD71-Ter-119+ were collected from β IVSII-654 thalassemic bone marrow. Additionally, a two-phase culture of mouse bone marrow erythroid progenitor cells was performed. Expression of miR-155 and predicted mRNA target genes, c-myc, bach-1 and pu-1, were determined by quantitative reverse transcription (qRT)-polymerase chain reaction (PCR) and normalized to small nucleolar RNA (snoRNA) 202 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively. To investigate the effect of miR-155 expression, erythroblasts were transfected with miR-inhibitor and -mimic in order to elevate and eliminate miR-155 expression, respectively. Erythroid cell differentiation was evaluated by Wright-Giemsa staining and flow cytometry.
    Results: miR-155 was upregulated, both in vivo and in vitro, during erythropoiesis in β-thalassemic mice. Our study revealed that gain- and loss of function of miR-155 were involved in erythroid proliferation and differentiation, and augmented proliferation and differentiation of thalassemic mouse erythroblasts may be associated with miR-155 upregulation. miR-155 upregulation in β-thalassemic mice significantly increased the percentage of basophilic and polychromatic erythroblasts. Conversely, a significant decrease in percentage of basophilic and polychromatic erythroblasts was observed in β-thalassemic mice transfected with anti-miR-155 inhibitor. We also examined the mRNA targets (c-myc, bach-1 and pu-1) of miR-155, which indicated that c-myc is a valid target gene of miR-155 that regulates erythroid differentiation.
    Conclusion: miR-155 regulates IE in β-thalassemia via c-myc expression controlling erythroblast proliferation and differentiation.
    Keywords:  Ineffective erythropoiesis; Thalassemic mice; c-myc; miR-155
    DOI:  https://doi.org/10.7717/peerj.18054
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