bims-conane 2024-12-08 papers

Br J Biomed Sci. 2024 ;81 13663

Homozygous Delta-Beta Thalassaemia With Alpha Thalassaemia and Erythrocytosis- a Rare Case Report.

Hala Shokr, Mandeep Kaur Marwah, Hisam Siddiqi, Christine Wright, Sukhjinder Marwah.

In this report, we describe a case of homozygous delta-beta (δβ) thalassaemia, a rare genetic disorder characterized by severe deficiency in delta (δ) and beta (β)-globin chain production, leading to ineffective erythropoiesis and chronic haemolytic anaemia. The patient, a 26-year-old female with δβ-thalassaemia, experienced a miscarriage. High-performance liquid chromatography revealed 89.5% foetal haemoglobin (HbF) and 14.4% glycated HbF. Sebia capillary electrophoresis showed haemoglobin peak of 97.2% and 2.8%. Kleihauer Bekte test indicated a pancellular pattern of foetal cells, while morphology analysis demonstrated microcytic, hypochromic red cells and target cells. Gene analysis confirmed compound heterozygosity for two large deletions in the β-globin gene cluster.

Keywords: RBC indices; delta-beta thalassemia; foetal haemoglobin; inherited blood disorders; thalassemia

DOI: https://doi.org/10.3389/bjbs.2024.13663

Expert Rev Hematol. 2024 Dec;17(12): 977-983

Quantitative MRI evaluation of iron deposition in patients with transfusion-dependent thalassemia: clinical management insights.

Xiaojing Ning, Fei Peng, Siyu Tan, Cheng Tang, Chaotian Luo, Fangyan Xiao, Chen Zhao, Peng Peng.

BACKGROUND: In patients with thalassemia, different organs are affected differently by iron overload. Nevertheless, the reasons for this could be the same key transporters. This study investigated the iron deposition in different organs of transfusion-dependent thalassemia (TDT) patients and its correlation.
RESEARCH DESIGN AND METHODS: This cross-sectional study involved 54 TDT patients who underwent MRI T2* examinations of the heart, liver, pancreas, spleen, kidneys, and pituitary. The study analyzed the iron deposition in each organ and evaluated the correlation of iron deposition using Spearman's test.
RESULTS: Among the 54 patients with TDT, liver iron overload was found in 49/54 (90.7%) cases, pancreas iron overload in 43/54 (79.6%) cases, spleen iron overload in 18/26 (69.2%) patients, heart iron overload in 20/54 (37.0%) cases, and kidney iron overload in 8/54 (14.8%) patients. Most patients (66.7%) with iron overload in the liver but not in the heart exhibited spleen iron abnormalities. Pituitary T2* and pancreas T2* (r = 0.790), pituitary T2* and kidney T2* (r = 0.692), kidney T2* and pancreas T2* (r = 0.672) showed positive correlation (all p < 0.05).
CONCLUSIONS: Patients with TDT exhibited significant organ-specific iron overload. These findings highlight the importance of routine MRI screening for monitoring and managing iron overload in patients with TDT. Pituitary, pancreas, and kidney may have similar iron-loading mechanisms.

Keywords: Iron overload; MRI; kidney; pituitary; thalassemia

DOI: https://doi.org/10.1080/17474086.2024.2435353

Br J Haematol. 2024 Dec 04.

Iron overload in hereditary spherocytosis: Are genetic factors the cause?

Lucie Donaty, Muriel Giansily-Blaizot, Ivan Bertchansky, Séverine Cunat, Vincent Azoury, Perrine Mahe, Patricia Aguilar Martinez.

Non-transfusional iron overload (IOL) in hereditary spherocytosis (HS) is poorly documented compared with other red blood cell disorders. We studied 13 HS adults with confirmed IOL to identify potential genetic factors. Using a next-generation sequencing panel of 46 genes related to HS, anaemia and iron metabolism, we found no association between IOL and the genes involved in HS nor the HFE:p.(Cys282Tyr) variant responsible for hereditary haemochromatosis. However, potential genetic factors contributing to IOL were identified in some patients, including variants in HJV (haemojuvelin), SLC40A1 (ferroportin), PKLR (pyruvate kinase), ABCG5 and ABCB8, highlighting the need for larger studies.

Keywords: genetic modifiers; hereditary spherocytosis; hyperferritinaemia; iron overload

DOI: https://doi.org/10.1111/bjh.19941

Zhonghua Yi Xue Za Zhi. 2024 Dec 03. 104(45): 4118-4124

[Expert consensus on the diagnosis and treatment of pyruvate kinase deficiency].

Red Blood Cell Disease (Anemia) Group, Chinese Society of Hematology, Chinese Medical Association

Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder caused by mutations in the PKLR gene, encoding erythrocyte pyruvate kinase, which affects erythrocyte energy production, and then in turn affects erythrocyte function and longevity. PKD is characterized by chronic hemolytic anemia, and other features include chronic hemolytic complications, such as iron overload, decreased bone mineral density, and cardiopulmonary complications. The treatment of PKD requires individualized approach based on the patient's condition, including red blood cell transfusions, pyruvate kinase activators, and treatment for complications. This consensus focuses on the pathogenesis, clinical characteristics, diagnosis and treatment of PKD, and aims to provide better medical service for clinicians, such as diagnosis, treatment, monitoring, and prevention of complications for PKD patients.

DOI: https://doi.org/10.3760/cma.j.cn112137-20240430-01012

Front Immunol. 2024 ;15 1493398

Case report: Modified transplantation for pediatric patients with pyruvate kinase deficiency.

Yuhui Pang, Xiaoyu Qi, Jiayue Qin, Xiaoran Zhai, Rongxiao Wang, Jianzhu Cao, Na Zhang, Jinxia Liu, Jianying Li, Weihai Wu, Shanshan Wei, Jingjing Zhang, Shaofei Zhang, Yaochen Zhang, Yan Yue.

Pyruvate kinase deficiency (PKD) is an autosomal recessive genetic disease caused by mutations in the PKLR gene. To date, the clinical manifestations of PKD are heterogeneous, ranging from fetal anemia, neonatal jaundice, and severe chronic hemolytic anemia to fully compensated hemolytic anemia. Successful cases of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for PKD have been reported, however, the number of cases is very small, and experiences are very limited. Here, we report two successful cases involving our modified conditioning regimen. This approach is suitable for patients with severe transfusion dependence. In conclusion, for PKD patients with severe transfusion dependence, allo-HSCT is an option and is currently a safe and effective way to completely eliminate the need for transfusions of drugs, such as Mitapivat, or genetic therapies and allow the patient to return to normal life.

Keywords: allogeneic hematopoietic stem cell transplantation; case report; modified conditioning regimen; pyruvate kinase deficiency; severe transfusion dependence

DOI: https://doi.org/10.3389/fimmu.2024.1493398

Mol Ther Nucleic Acids. 2024 Dec 10. 35(4): 102371

Efficient and in situ correction of hemoglobin Constant Spring mutation by prime editing in human hematopoietic cells.

Congwen Shao, Qing Liu, Jinchao Xu, Jianxiang Zhang, Chengpeng Zhang, Ye Xin, Yuhua Ye, Bin Lin, Xinhua Zhang, Li Cheng, Xiangmin Xu, Peng Xu.

Hemoglobin Constant Spring (Hb CS) is the most common non-deletional and clinically significant α-thalassemic mutation, and it is caused by an anti-termination mutation at the α2-globin gene stop codon. We developed a prime editing strategy for the creation and correction of Hb CS. We showed that prime editing could efficiently introduce Hb CS mutations in both human erythroblast cell lines (an average frequency of 32%) and primary hematopoietic stem and progenitor cells (HSPCs) from healthy donors (an average frequency of 27%). By targeting the established Hb CS homozygous erythroblasts, we achieved an average frequency of 32% in situ correction without selection. Notably, prime editing corrected the Hb CS mutation to wild type at an average frequency of 21% in HSPCs from three patients with hemoglobin H Constant Spring (HCS). Erythrocytes that differentiated from prime-edited erythroblasts or HSPCs exhibited a significant reduction in the amount of αCS-globin chains. Insertions and deletions on HBA2 locus and Cas9-dependent DNA off-target editing were detected with relatively low frequency after prime editing. Our findings showed that prime editing can successfully correct Hb CS in erythroblasts and patient HSPCs, which provides proof of principle for its therapeutic potential in HCS.

Keywords: Constant Spring mutation; HSPCs; MT: RNA/DNA Editing; prime editing; α-thalassemia

DOI: https://doi.org/10.1016/j.omtn.2024.102371

Front Pharmacol. 2024 ;15 1438611

Comparison of the effects of deferasirox film-coated tablets (Jadenu®) and deferasirox dispersible tablets (Exjade®) in patients with beta thalassemia major: a preliminary report of the effects on the satisfaction, convenience, cardiac/liver MRI T2*, serum ferritin level, and biochemical profiles.

Mahya Mobinikhaledi, Vahid Falahati, Amin Tajerian, Amir Almasi Hashiani, Kazem Ghaffari, Ali Ghasemi.

Background: Deferasirox (DFX) is a once-daily oral iron chelator with proven dose-dependent efficacy in patients with thalassemia major (TM). The reason for switching from DFX dispersible tablets (Exjade®) to DFX film-coated tablets (Jadenu®) was intolerance. Many patients also reported that deferasirox® did not taste good. In this study, we compared the effect of Jadenu® and Exjade® on satisfaction, convenience, cardiac/liver MRI T2*, serum ferritin levels, and biochemical profiles in patients with thalassemia major.
Method: Sixty-two patients with thalassemia over 2 years of age, who had iron overload indicated by chelation therapy, were randomly divided into two groups. The first group (n = 32) is treated with Exjade®, and the second group (n = 30) is treated with Jadenu®. Laboratory investigations included alkaline phosphatase (ALK), alanine transferase (ALT), aspartate transferase (AST), and serum ferritin levels. Cardiac/liver MRI T2* levels and patient satisfaction and convenience, were assessed before and 1 year after starting therapy.
Results: The study found that 53.3% of Jadenu® patients were satisfied with the taste of the medication compared to only 12.5% of Exjade® patients, which was statistically significant (p = 0.001). Additionally, 40% of Jadenu® patients were satisfied with the ease of taking the medication compared to 28.1% of Exjade® patients, and again, the difference was statistically significant (p = 0.047). A comparison of the cardiac MRI T2* levels between the two studied groups showed no significant difference (p = 0.851).
Conclusion: Jadenu® offers patients an improved formulation that can be taken on an empty stomach, has a better taste, and presents fewer gastrointestinal tolerability concerns. Overall, patient satisfaction is higher with Jadenu®, which may improve adherence and reduce the frequency and severity of complications associated with iron overload. This, in turn, may help mitigate cardiovascular and hepatic complications from iron overload in the long term.
Clinical Trial Registration: https://irct.behdasht.gov.ir/search/result?query=IRCT20210830052346N1.

Keywords: convenience; deferasirox; heart; iron overload; liver; satisfaction; thalassemia major

DOI: https://doi.org/10.3389/fphar.2024.1438611