One-step genetic correction of hemoglobin E/beta-thalassemia patient-derived iPSCs by the CRISPR/Cas9 system

Thalassemia is a quantitative abnormality of the hemoglobin marked by inadequate hemoglobin synthesis due to the lack orabsence of synthesis of one or more globin polypeptide chains. Hemoglobin variant is a qualitative abnormality due to the presence ofthe abnormal amino acid sequence of one or more globin polypeptide chains. HbE β thalassemia is a disorder of hemoglobin that resultsfrom the fusion between the gene β-thalassemia allele from one parent with a gene HbE allele from another parent. In this case, HbEβ-Thalassemia patient was a 4.8 year girl diagnosed with hemoglobin E-beta thalassemia based on history and clinical manifestations;pale, the presence of splenomegaly and hepatomegaly. Laboratory tests were Hb: 7.7 g/dL, MCV: 52.9 fl, MCH: 17.7 pg, MCHC: 33.5g/dL and ferritin: 1012 ng/mL. Peripheral blood smear evaluation showed a microcytic hypochromic anemia with hemolytic signs andinfected features of leukocytes. Hb electrophoresis using HPLC showed a Hb F: 37.7% and HbA2 52.4%, indicating that HbA2 was falsehigh due to coeluating with HbE. The patient was treated by blood transfusion and received additional therapy such as folic acid, ironchelation and vitamin E.

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Genetic Mutation of Hb E/beta Thalassemia Patient in Bangladesh and Its Relation With Clinical Severity

10.21203/rs.3.rs-927268/v1 ◽

2021 ◽

Author(s):

Nishat Mahzabin ◽

Md. Abdul Aziz ◽

Md. Akhlak-Ul Islam ◽

Nusrat Jahan ◽

Md. Kamrul Hasan Sajib ◽

...

Keyword(s):

High Performance ◽

Mutational Analysis ◽

Severe Disease ◽

Genetic Mutation ◽

Clinical Severity ◽

Beta Thalassemia ◽

Thalassemia Patient ◽

Cross Sectional ◽

Hemoglobin E ◽

Hb E

Abstract Background: Hemoglobin E/β-thalassemia is a common inherited hemoglobin disorder among South Asian countries. The phenotypically diverse presentation of the disease is often attributed to coinheritance of β-globin (HBB) gene mutations. The current study described the phenotype and genetic basis of Hb E/β-thalassemia patients and assessed its relation with clinical severity.Methods: A total of 32 patients were included in this cross-sectional study. Cases were confirmed by using capillary hemoglobin electrophoresis or high-performance liquid chromatography. Those with positive findings were further analyzed with clinical information and ancestral data either from the interview or medical records. Data collection was confined to May 2019 and July 2020. Gene sequencing was performed using Sanger’s sequencing method for mutational analysis, and Mahidol scoring was used to grade clinical severity.Result: A total of 13 heterozygous mutations were identified in the HBB gene. Of all, IVS-1-5 (G>C) (n=17, 53.1%) was the most common, and codon 30 (G>C) (n=4, 12.5%) was the second most common mutations. According to the Mahidol scoring system, 37.5% (n=12) were classified as phenotypically mild, 43.8% (n=14) as moderate and 18.8% (n=6) as severe. The IVS-1-5(G>C) mutation was found to be frequently associated with severe disease and showed no mild form.Conclusion: The present study described the clinical severity and its association with genetic mutations in hemoglobin E/β-thalassemia patients. This finding could guide individually tailored management strategies for this particular group of patients.

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Hemarthrosis in hemoglobin E beta thalassemia: a rare clinical scenario

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20204077 ◽

2020 ◽

Vol 7 (10) ◽

pp. 1582

Author(s):

Malini Garg ◽

Prakas K. Mandal ◽

Prakash S. Shekhawat ◽

Tuphan K. Dolai

Keyword(s):

Hip Joint ◽

Rare Case ◽

Beta Thalassemia ◽

Clinical Scenario ◽

Thalassemia Patient ◽

Hemoglobin E ◽

Beta Thalassaemia ◽

Bilateral Knee ◽

Joint Effusions

Hemorrhagic joint effusions are rarely seen in patients with haemoglobinopathies. Joint effusions often develop in association with deferiprone-related arthropathy in beta thalassaemia patients. Here we report a very rare case of bilateral knee and hip joint effusions in a case of hemoglobin E (HbE) beta thalassemia patient.

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TALASEMIA BETA HEMOGLOBIN E

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v22i1.746 ◽

2016 ◽

Vol 22 (1) ◽

pp. 309

Author(s):

Viviyanti Zainuddin ◽

Agus Alim Abdullah ◽

Mansyur Arif

Keyword(s):

Clinical Manifestations ◽

Iron Chelation ◽

Hypochromic Anemia ◽

Peripheral Blood Smear ◽

Beta Thalassemia ◽

Hemoglobin Variant ◽

Thalassemia Patient ◽

Hemoglobin E ◽

Polypeptide Chains ◽

Additional Therapy

Thalassemia is a quantitative abnormality of the hemoglobin marked by inadequate hemoglobin synthesis due to the lack or absence of synthesis of one or more globin polypeptide chains. Hemoglobin variant is a qualitative abnormality due to the presence of the abnormal amino acid sequence of one or more globin polypeptide chains. HbE β thalassemia is a disorder of hemoglobin that results from the fusion between the gene β-thalassemia allele from one parent with a gene HbE allele from another parent. In this case, HbE β-Thalassemia patient was a 4.8 year girl diagnosed with hemoglobin E-beta thalassemia based on history and clinical manifestations; pale, the presence of splenomegaly and hepatomegaly. Laboratory tests were Hb: 7.7 g/dL, MCV: 52.9 fl, MCH: 17.7 pg, MCHC: 33.5 g/dL and ferritin: 1012 ng/mL. Peripheral blood smear evaluation showed a microcytic hypochromic anemia with hemolytic signs andinfected features of leukocytes. Hb electrophoresis using HPLC showed a Hb F: 37.7% and HbA2 52.4%, indicating that HbA2 was false high due to coeluating with HbE. The patient was treated by blood transfusion and received additional therapy such as folic acid, iron chelation and vitamin E

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Benefits of chronic blood transfusion in hemoglobin E/β thalassemia with pulmonary arterial hypertension

International Journal of General Medicine ◽

10.2147/ijgm.s66610 ◽

2014 ◽

pp. 411 ◽

Cited By ~ 7

Author(s):

Nonlawan Chueamuangphan ◽

Jayanton Patumanond ◽

Wattana Wongtheptien ◽

Weerasak Nawarawong ◽

Apichard Sukornthasarn ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Blood Transfusion ◽

Arterial Hypertension ◽

Beta Thalassemia ◽

Hemoglobin E ◽

Pulmonary Arterial

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Gingival enlargement in thalassemia patient – A Conjectural Association

UNIVERSITY JOURNAL OF DENTAL SCIENCES ◽

10.21276/ujds.2020.6.3.15 ◽

2020 ◽

Vol 6 (3) ◽

pp. 74-77

Author(s):

CS BAIJU ◽

Gunjan Gupta ◽

Karuna Joshi ◽

Shagufta ◽

N.D Gupta

Keyword(s):

Single Gene ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Thalassemia Patient ◽

Anterior Maxilla ◽

Facial Region ◽

Periodontal Tissues ◽

Beta Thalassemia Major ◽

Gingival Enlargement ◽

Maxilla And Mandible

Thalassemia is a single gene inherited blood disease. Beta thalassemia major is life threating. It causes abnormality in various organs and oral-facial region. Thalassemia patients are immune-deficient because of iron-overload. Immune system abnormality includes neutrophilic dysfunction and impairment of phagocytosis by the monocyte-macrophage system. Iron accumulation also affects periodontal tissues, which seems to increase the level of cytokines and thus have an enhancing effect on gingival inflammation. This article highlights a peculiar case of gingival enlargement in anterior maxilla and mandible. The patient was known case of a beta-thalassemia major. Blood investigation revealed a lower level of hemoglobin. The patient underwent non-surgical periodontal therapy. Proper periodontal care improves the quality of life in these patients. This case report reinforces the significance of proper history taking with all minor details and the role of patient education in phase I therapy

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Molecular analysis of the beta-thalassemia phenotype associated with inheritance of hemoglobin E (alpha 2 beta2(26)Glu leads to Lys).

Journal of Clinical Investigation ◽

10.1172/jci110226 ◽

1981 ◽

Vol 68 (1) ◽

pp. 118-126 ◽

Cited By ~ 20

Author(s):

E J Benz ◽

B W Berman ◽

B L Tonkonow ◽

E Coupal ◽

T Coates ◽

...

Keyword(s):

Molecular Analysis ◽

Beta Thalassemia ◽

Hemoglobin E

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Correlation of BACH1 and Hemoglobin E/Beta-Thalassemia Globin Expression

Turkish Journal of Hematology ◽

10.4274/tjh.2014.0197 ◽

2016 ◽

Vol 33 (1) ◽

pp. 15-20 ◽

Cited By ~ 1

Author(s):

Tze Yan Lee ◽

Logeswaran Muniandy ◽

Lai Kuan Teh ◽

Maha Abdullah ◽

Elizabeth George ◽

...

Keyword(s):

Beta Thalassemia ◽

Hemoglobin E

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Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency

Blood ◽

10.1182/blood.v88.7.2761.bloodjournal8872761 ◽

1996 ◽

Vol 88 (7) ◽

pp. 2761-2767 ◽

Cited By ~ 26

Author(s):

DC Rees ◽

J Duley ◽

HA Simmonds ◽

B Wonke ◽

SL Thein ◽

...

Keyword(s):

Hemolytic Anemia ◽

Beta Thalassemia ◽

Hemoglobin E ◽

Oxidant Damage ◽

Hb E ◽

Hb Variant ◽

Chain Synthesis ◽

The Stability ◽

Enzyme Deficient ◽

Globin Chain Synthesis

A Bangladeshi family is described in which the genes for both hemoglobin E (Hb E) and pyrimidine 5′ nucleotidase deficiency are segregating. An individual homozygous for both these conditions has a severe hemolytic anemia, whereas family members who are homozygous for Hb E are asymptomatic and those homozygous for pyrimidine 5′ nucleotidase deficiency have the mild hemolytic anemia that is characteristic of this disorder. Globin-chain synthesis experiments have shown that the mechanism underlying the interaction between these two genotypes is a marked decrease in the stability of Hb E in pyrimidine 5′ nucleotidase-deficient red blood cells (RBCs). It has also been found that in the enzyme-deficient RBCs in which Hb E is highly unstable, free alpha-chains, though not beta E-chains, acoumulate on the membrane. In view of the increasing evidence that the hemolysis associated with pyrimidine 5′ nucleotidase deficiency results not only from an increase in the level of erythrocyte pyrimidines, but also from inhibition of the hexose monophosphate shunt activity in young erythrocytes, it is likely that the marked instability of Hb E in the enzyme-deficient cells results from oxidant damage acting on a mildly unstable Hb variant. These observations may have important implications for the better understanding of the pathophysiology of Hb E/beta-thalassemia, globally the commonest important form of thalassemia.

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MOLECULAR ANALYSIS OF NON-TRANSFUSION DEPENDENT THALASSEMIA ASSOCIATED WITH HEMOGLOBIN E-β-THALASSEMIA DISEASE WITHOUT α--THALASSEMIA

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2019.038 ◽

2019 ◽

Vol 11 (1) ◽

pp. e2019038 ◽

Cited By ~ 4

Author(s):

Paramee Phanrahan ◽

Supawadee Yamsri ◽

Nattiya Teawtrakul ◽

Goonnapa Fucharoen ◽

Kanokwan Sanchaisuriya ◽

...

Keyword(s):

Dna Analysis ◽

Globin Gene ◽

Phenotypic Expression ◽

Nucleotide Polymorphisms ◽

Thalassemia Patient ◽

Hemoglobin E ◽

Modifying Factors ◽

Myb Gene ◽

Hb E ◽

Klf1 Gene

Background: The finding of many Thai Hb E-β0-thalassemia patients with non-transfusion dependent thalassemia (NTDT) phenotype without co-inheritance of α-thalassemia has prompted us to investigate the existence of other genetic modifying factors. Methods: Study was done on 146 adult Thai patients with NTDT Hb E-β0-thalassemia and a homozygous β-thalassemia patient without co-inheritance of α-thalassemia. Multiple single-nucleotide polymorphisms (SNPs) associated with γ-globin gene expression including the Gγ-XmnI of HBG2 gene, rs2297339, rs4895441, and rs9399137 of the HBS1L-MYB gene, rs4671393 in the BCL11A gene, and G176AfsX179, T334R, R238H and -154 (C-T) in the KLF1 gene were investigated using PCR-and related techniques. Results: Heterozygous and homozygous for Gg-XmnI of HBG2 gene were detected at 68.0% and 6.1%, respectively. Further DNA analysis identified the rs2297339 (C-T), rs4895441 (A-G), and rs9399137 (T-C) of HBS1L-MYB gene in 86.4%, 22.5% and 20.4%, respectively. The rs4671393 (G-A) of the BCL11A gene was found at 31.3%. For the KLF1 gene, the T334R and G176AfsX179 (+/-) were detected at 8.2% and 1.4%, respectively. Conclusion: It was found that these SNPs when analyzed in combination could explain the mild phenotypic expression of all cases. These results underline the importance of these informative SNPs on phenotypic expression of Hb E-β-thalassemia patients.

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