Pub Date : 2024-09-23DOI: 10.1080/03630269.2024.2403405
Hyeon Jun Jung, Boram Kim, Hee-Jin Kim, Mee Jeong Lee
Hemoglobin (Hb) Chile, a variant of Hb M, is produced by a point mutation of CTG→ATG on codon 29 (legacy codon 28) of the Hb β locus gene, which results in an amino acid substitution of Leu→Met. It has been identified in two families worldwide and is inherited in an autosomal dominant manner. Here, we report a case of Hb Chile in which a de novo mutation was detected in the proband. A 17-year-old male presented to the outpatient clinic with a pale appearance. There was cyanosis on his lips and fingers. Blood tests indicated the existence of hemolysis, but complete blood counts revealed no anemia. Peripheral arterial oxygen saturation on pulse oximetry was 80% on room air and did not improve with oxygen supplementation. The level of methemoglobin was 15.4%. Targeted next-generation sequencing identified a heterozygous NM_000518.4(HBB):c.85C > A mutation, indicating Hb Chile. The Hb Chile mutation, on the other hand, was not discovered in his parents, implying that it arose as a result of a de novo mutation. This case highlights the necessity of suspecting Hb gene mutations in patients with unexplained chronic methemoglobinemia, even if there is no family history.
{"title":"De Novo Occurrence of Hb Chile [β28(B10) Leu→Met] in a Korean Boy with Methemoglobinemia.","authors":"Hyeon Jun Jung, Boram Kim, Hee-Jin Kim, Mee Jeong Lee","doi":"10.1080/03630269.2024.2403405","DOIUrl":"https://doi.org/10.1080/03630269.2024.2403405","url":null,"abstract":"<p><p>Hemoglobin (Hb) Chile, a variant of Hb M, is produced by a point mutation of <i><u>C</u></i>TG→<i><u>A</u></i>TG on codon 29 (legacy codon 28) of the Hb β locus gene, which results in an amino acid substitution of Leu→Met. It has been identified in two families worldwide and is inherited in an autosomal dominant manner. Here, we report a case of Hb Chile in which a <i>de novo</i> mutation was detected in the proband. A 17-year-old male presented to the outpatient clinic with a pale appearance. There was cyanosis on his lips and fingers. Blood tests indicated the existence of hemolysis, but complete blood counts revealed no anemia. Peripheral arterial oxygen saturation on pulse oximetry was 80% on room air and did not improve with oxygen supplementation. The level of methemoglobin was 15.4%. Targeted next-generation sequencing identified a heterozygous NM_000518.4(<i>HBB</i>):c.85C > A mutation, indicating Hb Chile. The Hb Chile mutation, on the other hand, was not discovered in his parents, implying that it arose as a result of a <i>de novo</i> mutation. This case highlights the necessity of suspecting Hb gene mutations in patients with unexplained chronic methemoglobinemia, even if there is no family history.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142285970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1080/03630269.2024.2380873
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.
{"title":"Characterization of Hemoglobin Malay Phenotypes in Tertiary Hospitals.","authors":"Alia Suzana Asri, Muhammad Hafiz Samsuddin, Norunaluwar Jalil, Norlida Mohamad Tahir, Hafizah Hashim, Raja Zahratul Azma, Ezalia Esa, Rinie Awai Albert, Hafiza Alauddin","doi":"10.1080/03630269.2024.2380873","DOIUrl":"https://doi.org/10.1080/03630269.2024.2380873","url":null,"abstract":"<p><p>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 HbA<sub>2</sub> range of Hb Malay carriers was wider (3.5-5.5%) with median value of 3.9%. A new HbA<sub>2</sub> cutoff value ≤4.6% (AUC 0.717, <i>p</i> < 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 HbA<sub>2</sub> range. HbA<sub>2</sub> of ≤4.6% should prompt a molecular confirmation for Hb Malay carrier status.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142285969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1080/03630269.2024.2407633
Beryl Elizabeth Serjeant, Karlene Mason, Marvin Reid, Ian Hambleton, Graham Roger Serjeant
In order to document the prevalence, clinical features, hematology and outcome of the aplastic crisis in homozygous sickle cell disease (HbSS), a cohort study has been conducted from birth. Newborn screening of 100 000 deliveries at the main government maternity hospital, Kingston, Jamaica between 1973 and 1981 detected 311 cases of HbSS who have been followed at the Medical Research Council Laboratories at the University of the West Indies, Kingston, Jamaica. Clinically defined aplastic crises occurred in 118 (38%) patients at a median age of 7.5 years (range 0.5-23.0 years). All but one event seroconverted to parvovirus B19, the exception being a 9.3 year male with classic aplasia but subsequent IgG did not exceed 3 IU. Defined by zero reticulocyte counts, 94 patients presented with a median hemoglobin of 3.7 g/dL (range 18-87 g/L) representing a median fall from steady state levels of 3.8 g/dL. Clear epidemic peaks occurred at 1979-1980, 1984-1986, and 1990-1993 and the admission rate and use of blood cultures fell with each epidemic, reflecting increased familiarity with the complication. Symptoms were usually nonspecific and all but 7 were transfused. No patient had a recurrence and two died from aplasia (one with remote rural residence and the other following an incorrect diagnosis). Of those seroconverting to parvovirus B19, 68% manifested aplasia and 24% had no hematologic change. Correctly diagnosed and managed, the aplastic crisis is essentially benign. (230 words).
{"title":"The Aplastic Crisis in HbSS: Observations from the Jamaican Birth Cohort.","authors":"Beryl Elizabeth Serjeant, Karlene Mason, Marvin Reid, Ian Hambleton, Graham Roger Serjeant","doi":"10.1080/03630269.2024.2407633","DOIUrl":"https://doi.org/10.1080/03630269.2024.2407633","url":null,"abstract":"<p><p>In order to document the prevalence, clinical features, hematology and outcome of the aplastic crisis in homozygous sickle cell disease (HbSS), a cohort study has been conducted from birth. Newborn screening of 100 000 deliveries at the main government maternity hospital, Kingston, Jamaica between 1973 and 1981 detected 311 cases of HbSS who have been followed at the Medical Research Council Laboratories at the University of the West Indies, Kingston, Jamaica. Clinically defined aplastic crises occurred in 118 (38%) patients at a median age of 7.5 years (range 0.5-23.0 years). All but one event seroconverted to parvovirus B19, the exception being a 9.3 year male with classic aplasia but subsequent IgG did not exceed 3 IU. Defined by zero reticulocyte counts, 94 patients presented with a median hemoglobin of 3.7 g/dL (range 18-87 g/L) representing a median fall from steady state levels of 3.8 g/dL. Clear epidemic peaks occurred at 1979-1980, 1984-1986, and 1990-1993 and the admission rate and use of blood cultures fell with each epidemic, reflecting increased familiarity with the complication. Symptoms were usually nonspecific and all but 7 were transfused. No patient had a recurrence and two died from aplasia (one with remote rural residence and the other following an incorrect diagnosis). Of those seroconverting to parvovirus B19, 68% manifested aplasia and 24% had no hematologic change. Correctly diagnosed and managed, the aplastic crisis is essentially benign. (230 words).</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142285971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Graft rejection and Graft-versus-host disease (GVHD) are some of the significant factors resulting in morbidity and mortality following allogeneic hematopoietic cell transplantation. Prophylaxis for GVHD using T-cell depleting agents is helpful in reducing the transplant-related mortality and graft rejection. Both tATG and fATG exhibit varied amounts of antibody specificities and perform distinct immunomodulatory effects, regardless of their capacity to deplete T-lymphocytes. We conducted this single-center, retrospective study at our center to compare both formulations. Twenty-six patients were included in the study, 13 in each cohort. The median age at diagnosis of β-thalassemia was 5 months (range, 3-12 months) in the tATG group and 6 months (range, 3-9 months) in the f-ATG group, respectively. Acute GVHD was observed in 1 (7.7) and 2(15.4) in the tATG and fATG group, respectively. No cases of chronic GVHD were observed in either group. There was no difference in the mixed chimerism observed at 6 months in both groups, tATG (n = 5, 38.5%) and fATG (n = 6, 46.15). There was 1 (7.6) rejection at day +72 observed in the tATG group, whereas no rejection was observed in the fATG group. At a mean follow-up duration of 288 days since transplant, there were no deaths in either of the groups. In conclusion, both ATG preparations showed equivalent effectiveness in preventing rejections and GVHD. However, further larger studies are required to establish the long-term efficacy and safety of both formulations in ASCT.
{"title":"ATG-Thymoglobulin Versus ATG-Fresenius for Conditioning in Thalassemia Patients Who Underwent Allogenic Stem Cell Transplantation from Matched-Sibling Donor: A Tertiary Cancer Care Center Short-Term Experience.","authors":"Reema Singh, Rohan Halder, Vinayak Hemant Gupta, Sujay Rainchwar, Niharika Bhatia, Varsha Mishra, Tribikram Panda, Pritish Chandra Patra, Narendra Agrawal, Dinesh Bhurani","doi":"10.1080/03630269.2024.2398244","DOIUrl":"https://doi.org/10.1080/03630269.2024.2398244","url":null,"abstract":"<p><p>Graft rejection and Graft-versus-host disease (GVHD) are some of the significant factors resulting in morbidity and mortality following allogeneic hematopoietic cell transplantation. Prophylaxis for GVHD using T-cell depleting agents is helpful in reducing the transplant-related mortality and graft rejection. Both tATG and fATG exhibit varied amounts of antibody specificities and perform distinct immunomodulatory effects, regardless of their capacity to deplete T-lymphocytes. We conducted this single-center, retrospective study at our center to compare both formulations. Twenty-six patients were included in the study, 13 in each cohort. The median age at diagnosis of β-thalassemia was 5 months (range, 3-12 months) in the tATG group and 6 months (range, 3-9 months) in the f-ATG group, respectively. Acute GVHD was observed in 1 (7.7) and 2(15.4) in the tATG and fATG group, respectively. No cases of chronic GVHD were observed in either group. There was no difference in the mixed chimerism observed at 6 months in both groups, tATG (<i>n</i> = 5, 38.5%) and fATG (<i>n</i> = 6, 46.15). There was 1 (7.6) rejection at day +72 observed in the tATG group, whereas no rejection was observed in the fATG group. At a mean follow-up duration of 288 days since transplant, there were no deaths in either of the groups. In conclusion, both ATG preparations showed equivalent effectiveness in preventing rejections and GVHD. However, further larger studies are required to establish the long-term efficacy and safety of both formulations in ASCT.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-03DOI: 10.1080/03630269.2024.2398236
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.
Youngstown 血红蛋白[HBB:c.305A > C]是一种罕见的不稳定血红蛋白,由 Beta 球蛋白链第 101 个密码子上的谷氨酸被丙氨酸取代引起。在杂合状态下,它会导致溶血性贫血。本病例是一名六岁的中国-爪哇女孩,她患有杂合子 Youngstown 血红蛋白,临床特征为慢性溶血和铁超载。在高效液相色谱(HPLC)上,Hb Youngstown 出现在接近 4.6 分钟的 S 窗口,在碱性凝胶电泳上可形成混合四聚体,表现为两条不同的条带,分别位于 A 的阴极和 F 的附近。这种杂合型血红蛋白 Youngstown 的临床表现和血红蛋白分析结果与杂合型血红蛋白 Rush 重叠。只有通过β球蛋白基因测序或完整的质谱分析才能在分子水平上将它们区分开来。
{"title":"First Report of Hb Youngstown in Capillary Electrophoresis and Overlapping Hb Analysis Findings with Hb Rush.","authors":"Kim Yan Poh, Ping Chong Bee","doi":"10.1080/03630269.2024.2398236","DOIUrl":"https://doi.org/10.1080/03630269.2024.2398236","url":null,"abstract":"<p><p>Hb Youngstown [<i>HBB:</i>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.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hemoglobin (Hb) H disease presents a wide range of clinical phenotypes, from asymptomatic to severe forms, depending on significant genetic heterogeneity. This is the first report of clinical and hematological features of the nondeletional HbH disease caused by --CR/αCSα. A baby was born to a father and a mother with --CR and αCSα carriers, respectively. She had severe symptomatic hypochromic microcytic anemia at 2 months of age with Hb 7.8 g/dL, packed cell volume (PCV) 0.27 L/L, mean corpuscular volume (MCV) 64.3 fL, and mean corpuscular Hb (MCH) 18.3 pg. The Hb analysis using capillary electrophoresis (CE) showed Hb Bart's, HbH, and Hb CS peaks at 17.1%, 2.2%, and 1.6%, respectively. A better understanding of a patient's clinical and hematological features with --CR/αCSα is useful for hemoglobinopathy counseling for the national thalassemia controlling program.
{"title":"The First Thai Case of Nondeletional HbH Disease Caused by Compound Heterozygosity for α-Thalassemia-1 Chiang Rai (--<sup>CR</sup>) Type Deletion with Hb Constant Spring.","authors":"Duantida Songdej, Praguywan Kadegasem, Nongnuch Sirachainan, Chedtapak Ruengdit, Manoo Punyamung, Sakorn Pornprasert","doi":"10.1080/03630269.2024.2388661","DOIUrl":"https://doi.org/10.1080/03630269.2024.2388661","url":null,"abstract":"<p><p>Hemoglobin (Hb) H disease presents a wide range of clinical phenotypes, from asymptomatic to severe forms, depending on significant genetic heterogeneity. This is the first report of clinical and hematological features of the nondeletional HbH disease caused by --<sup>CR</sup>/α<sup>CS</sup>α. A baby was born to a father and a mother with --<sup>CR</sup> and α<sup>CS</sup>α carriers, respectively. She had severe symptomatic hypochromic microcytic anemia at 2 months of age with Hb 7.8 g/dL, packed cell volume (PCV) 0.27 L/L, mean corpuscular volume (MCV) 64.3 fL, and mean corpuscular Hb (MCH) 18.3 pg. The Hb analysis using capillary electrophoresis (CE) showed Hb Bart's, HbH, and Hb CS peaks at 17.1%, 2.2%, and 1.6%, respectively. A better understanding of a patient's clinical and hematological features with --<sup>CR</sup>/α<sup>CS</sup>α is useful for hemoglobinopathy counseling for the national thalassemia controlling program.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1080/03630269.2024.2390934
Xi-Gui Long, Xi He, Li-Hong Zheng, Liang Liang, Ting Qin, You-Qiong Li
We report the molecular and hematological identifications of two novel δ-globin gene mutations found in Guangxi Zhuang Autonomous Region, China. Capillary electrophoresis of the proband showed 1.3% Hb A2, accompanied by a minor unknown peak (0.7%) within the Z1 zone. High-performance liquid chromatography also revealed the presence of 1.5% Hb A2 and a 0.6% unknown peak. Routine genetic testing (Gap-PCR and reverse dot-blot hybridization) for common α-thalassemia was performed, and no mutations were observed. Sanger sequencing identified a heterozygous mutation for GAC > AAC at codon 79 (HBD:c.238G > A) and G > A at polyA + 70 (HBD:c.*200G > A) of the δ-globin gene. This variant was named Hb A2-Guangxi [δ79 (EF3) Asp→Asn, HBD:c.238G > A] after the geographic origin of the proband.
{"title":"Hb A<sub>2</sub>-Guangxi [δ79 (EF3) Asp→Asn, <i>HBD</i>: C.238G > A] and polyA + 70 (<i>HBD</i>: C.*200G > A): Two Novel δ-Globin Gene Mutations Identified in a Chinese Family.","authors":"Xi-Gui Long, Xi He, Li-Hong Zheng, Liang Liang, Ting Qin, You-Qiong Li","doi":"10.1080/03630269.2024.2390934","DOIUrl":"https://doi.org/10.1080/03630269.2024.2390934","url":null,"abstract":"<p><p>We report the molecular and hematological identifications of two novel δ-globin gene mutations found in Guangxi Zhuang Autonomous Region, China. Capillary electrophoresis of the proband showed 1.3% Hb A<sub>2</sub>, accompanied by a minor unknown peak (0.7%) within the Z1 zone. High-performance liquid chromatography also revealed the presence of 1.5% Hb A<sub>2</sub> and a 0.6% unknown peak. Routine genetic testing (Gap-PCR and reverse dot-blot hybridization) for common α-thalassemia was performed, and no mutations were observed. Sanger sequencing identified a heterozygous mutation for GAC > AAC at codon 79 (<i>HBD</i>:c.238G > A) and G > A at polyA + 70 (<i>HBD</i>:c.*200G > A) of the δ-globin gene. This variant was named Hb A<sub>2</sub>-Guangxi [δ79 (EF3) Asp→Asn, <i>HBD</i>:c.238G > A] after the geographic origin of the proband.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1080/03630269.2024.2369534
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.
由于血红蛋白病的发病率和死亡率都很高,人们长期以来一直在寻求治疗方案。基因治疗的总体目标是通过基因添加、基因编辑或基因沉默,改变患者自身的造血干细胞,以克服潜在基因缺陷的有害影响。基因添加是将功能优于异常基因的基因整合在一起;基因编辑是利用分子工具,如锌指蛋白、转录激活剂样效应核酸酶和Cas9蛋白(CRISPR-Cas9)偶联的簇状规则间隔短链色重复序列(Clustered Regularly Interspaced Short Palindromic Repeats coupled with Cas9 proteins),使DNA序列发生特异性断裂,从而破坏基因功能;基因沉默则是通过干扰mRNA转录/蛋白质翻译或表观遗传修饰来抑制基因表达。针对血红蛋白病的大多数基因治疗策略都以红细胞特异性 BCL11A 为靶点,BCL11A 是γ-球蛋白基因座上胎儿血红蛋白抑制的主要调节因子,在出生后不久就会发生胎儿到成人血红蛋白的正常转换。其他目标还包括加入抗镰状球蛋白,如βT87Q或βAS3。对输血依赖型地中海贫血症和镰状细胞病的基因疗法进行了具有里程碑意义的临床试验,结果表明疗效显著,安全性可接受,最近欧洲和美国的监管机构批准了这两种疾病的基因疗法。
{"title":"A Review of Gene Therapies for Hemoglobinopathies.","authors":"Boubini Jones-Wonni, Amar H Kelkar, Maureen O Achebe","doi":"10.1080/03630269.2024.2369534","DOIUrl":"https://doi.org/10.1080/03630269.2024.2369534","url":null,"abstract":"<p><p>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 <i>BCL11A</i>, 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 β<sup>T87Q</sup> 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.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1080/03630269.2024.2360450
Marcus Wagner, Birgit Stoffel-Wagner, Berndt Zur
Hemoglobin Strasbourg is a rare high oxygen affinity hemoglobin variant which leads to secondary erythrocytosis. This variant is caused by a HBB gene mutation c.71T > A resulting in an amino acid exchange on position 23 of the β globin chain (p.Val23Asp.). The influence of Hb Strasbourg on HbA1c measurement has not been studied to date. For patients with hemoglobin variants it is important to know whether possible interferences exist with the measurement of HbA1c. We therefore investigated the influence of Hb Strasbourg on HbA1c measurement with two different HPLC (high-performance liquid chromatography) systems and one turbidimetric immunoassay in two non-diabetic brothers who are heterozygous carriers of Hb Strasbourg. The examined tests are all used in routine diagnostics. In the case of Hb Strasbourg, the HbA1c measured by HPLC showed lower results than those obtained by the immunoassay. We conclude that HbA1c is underestimated when measured with these methods as glycated Hb Strasbourg is most likely not co-eluting with HbA1c in HPLC.
{"title":"Influence of Hemoglobin Strasbourg, a Rare High Oxygen Affinity Hemoglobin Variant, on Different Methods of HbA1c Measurement.","authors":"Marcus Wagner, Birgit Stoffel-Wagner, Berndt Zur","doi":"10.1080/03630269.2024.2360450","DOIUrl":"https://doi.org/10.1080/03630269.2024.2360450","url":null,"abstract":"<p><p>Hemoglobin Strasbourg is a rare high oxygen affinity hemoglobin variant which leads to secondary erythrocytosis. This variant is caused by a <i>HBB</i> gene mutation c.71T > A resulting in an amino acid exchange on position 23 of the β globin chain (p.Val23Asp.). The influence of Hb Strasbourg on HbA1c measurement has not been studied to date. For patients with hemoglobin variants it is important to know whether possible interferences exist with the measurement of HbA1c. We therefore investigated the influence of Hb Strasbourg on HbA1c measurement with two different HPLC (high-performance liquid chromatography) systems and one turbidimetric immunoassay in two non-diabetic brothers who are heterozygous carriers of Hb Strasbourg. The examined tests are all used in routine diagnostics. In the case of Hb Strasbourg, the HbA1c measured by HPLC showed lower results than those obtained by the immunoassay. We conclude that HbA1c is underestimated when measured with these methods as glycated Hb Strasbourg is most likely not co-eluting with HbA1c in HPLC.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1080/03630269.2024.2376588
Cuili Yao, Long Chen, Jingting Ma, Na Li, Jiang Lin, Lina Huang, Yani Lin, Jun Xue
We reported a rare β-thalassemia patient, a 41-year-old Chinese male with small cell hypopigmentation anemia, jaundice and splenomegaly as the main clinical symptoms. By using Next-Generation Sequencing (NGS), we identified a novel de novo HBB mutation(c.358_365dup, p.Phe123Alafs*39) which resulted in an abnormally prolonged β-globin chain comprising 159 amino acid residues. The secondary and three-dimensional structures of the β-globin predicted that the novel prolonged β-globin chain has a considerable risk of instability in the hemoglobin, and leads to clinical phenotype. This study contributes to the enrichment of the genetic pathogenic mutation database for thalassemia and underscores the significance of NGS in the screening of mutations for thalassemia families.
{"title":"A Novel Frameshift Mutation of <i>HBB</i> Causing Dominant β-Thalassemia in a Chinese Individual.","authors":"Cuili Yao, Long Chen, Jingting Ma, Na Li, Jiang Lin, Lina Huang, Yani Lin, Jun Xue","doi":"10.1080/03630269.2024.2376588","DOIUrl":"https://doi.org/10.1080/03630269.2024.2376588","url":null,"abstract":"<p><p>We reported a rare β-thalassemia patient, a 41-year-old Chinese male with small cell hypopigmentation anemia, jaundice and splenomegaly as the main clinical symptoms. By using Next-Generation Sequencing (NGS), we identified a novel <i>de novo HBB</i> mutation(c.358_365dup, p.Phe123Alafs*39) which resulted in an abnormally prolonged β-globin chain comprising 159 amino acid residues. The secondary and three-dimensional structures of the β-globin predicted that the novel prolonged β-globin chain has a considerable risk of instability in the hemoglobin, and leads to clinical phenotype. This study contributes to the enrichment of the genetic pathogenic mutation database for thalassemia and underscores the significance of NGS in the screening of mutations for thalassemia families.</p>","PeriodicalId":12997,"journal":{"name":"Hemoglobin","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}