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The American Journal of Case Reports May 2024BACKGROUND Thalassemia and hemoglobin (Hb) variants are the most common hereditary red blood cell disorders worldwide. Alpha-thalassemia and alpha-globin variants are...
BACKGROUND Thalassemia and hemoglobin (Hb) variants are the most common hereditary red blood cell disorders worldwide. Alpha-thalassemia and alpha-globin variants are caused by mutations of the alpha-globin genes (HBA2 and HBA1), resulting in impaired alpha-globin production and structurally abnormal globin, respectively. Clinical severity of alpha-thalassemia correlates with the number of affected alpha-globin genes, yielding a spectrum of clinical manifestations from mild to severe anemia. Routine diagnosis involves Hb analysis and PCR-based methods, yet identifying rare variants necessitates comprehensive clinical and hematologic laboratory data. The knowledge of phenotype and genotype correlation is useful for genetic counseling and treatment planning. CASE REPORT A 59-year-old Thai woman presented with chronic anemia. Her baseline Hb level ranged between 8.0 and 9.0 g/dL, with no history of transfusion. Physical examination showed mild pallor, without enlarged liver and spleen. Laboratory investigations showed microcytic, hypochromic anemia and abnormal Hb peak by Hb analysis (retention time 4.58 min by HPLC method). Common alpha-globin gene deletions, including the Southeast-Asian/Thai 3.7 kb and 4.2 kb deletions were tested using gap-PCR, with none of these deletions detected. Direct DNA sequencing revealed a compound heterozygosity of Hb Jax (HBA2: c.44G>C) and Hb Constant Spring (HBA2: c.427T>C). CONCLUSIONS Compound heterozygosity of Hb Jax and Hb Constant Spring results in microcytic anemia. Hb Jax can be identified by Hb analysis, and diagnosis can be confirmed by direct DNA sequencing method. Coinheritance of Hb Jax and alpha-globin variants should be considered in cases with microcytic anemia and a specific Hb peak seen in Hb chromatogram.
Topics: Female; Humans; Middle Aged; alpha-Globins; alpha-Thalassemia; Anemia, Hypochromic; Hemoglobins, Abnormal
PubMed: 38725231
DOI: 10.12659/AJCR.943560 -
Anemia 2024Anemia, a global health concern, affects one-fourth of the global population, particularly women. In Indonesia, its prevalence is 23.7%, with 32.0% among 15-24...
BACKGROUND
Anemia, a global health concern, affects one-fourth of the global population, particularly women. In Indonesia, its prevalence is 23.7%, with 32.0% among 15-24 year-olds. Factors include poor nutrition, infectious diseases, chronic diseases, inherited disorders, and inadequate healthcare access. This study aimed to investigate anemia prevalence and its etiology among medical students from Jakarta.
METHODS
This study was a descriptive research with a cross-sectional approach. Undergraduate students aged 18-23 years old were selected and consented to participate by a consecutive nonrandom sampling methods. Laboratory blood data were evaluated (including Hb, MCV, MCH, HbA, and ferritin levels) and DNA was isolated to confirm the type of thalassemia carrier.
RESULTS
In total, 140 medical students, mainly female, were recruited. Anemia was found in 13.6% (11.4% had low MCV and/or MCH), and 16.5% had low MCV and/or MCH without anemia. Hb electrophoresis revealed high HbA values, suggesting the HbE variant (2.1%), and -thalassemia carrier (0.7%). DNA analysis confirmed the cd26 mutation and heterozygous IVS1nt5. Among those without anemia, 5% had , while in the group with anemia, 1.4% had (with coexistent IDA), 3.6% had , and 0.7% had .
CONCLUSION
DNA analysis can identify specific mutations associated with alpha-thalassemia, distinguishing between iron deficiency anemia and the alpha-thalassemia trait. Thalassemia screening should involve low MCV and/or MCH values as the first step (stage 1), followed by Hb analysis (stage 2) and DNA analysis (stage 3). In common areas, a combination of Hb and DNA testing is best. However, healthcare professionals must diagnose and treat thalassemia, as proper management relies on accurately identifying the underlying condition.
PubMed: 38716362
DOI: 10.1155/2024/4215439 -
Indian Journal of Hematology & Blood... Apr 2024Hemoglobinopathies are the most common monogenic disorders in the world. Traditional diagnostic algorithms generated by conventional methods for thalassemia can be...
Hemoglobinopathies are the most common monogenic disorders in the world. Traditional diagnostic algorithms generated by conventional methods for thalassemia can be labor-intensive and time-consuming due to the complexities of the genes involved and the variability in disease-causing mutations. With the advantages of next-generation sequencing (NGS) technology, molecular analysis of highly complex diseases such as hemoglobinopathies has become easier. Next-generation sequencing is a highly sensitive and effective method due to its capacity to sequence many gene regions simultaneously while allowing good read depths. In this study, single nucleotide changes, small deletions and copy number variations in and in 914 patients with suspected hemoglobinopathy were analysed with NGS. At least one or variant was detected in 483 (52.8%) patients. Ten novel variants were detected in and , three in and one in . From these variants, c.*76T > A, c.301-24 G > A, c.301-24G > C c.-41C > G, c.-37-40C > G, c.-9G > C, c. 95 + 9C > T, c.95 + 26C > A, c.95 + 38C > T and c.*18C > G variants were located in α-globin genes, c.-25T > C, c.*103T > C and c92 + 39A > G variants were located in β-globin genes, and c.-43C > A was located in . This is the first comprehensive study using NGS for the molecular diagnosis of hemoglobinopathies in Turkey. Accurate molecular diagnosis is of critical importance in hemoglobinopathies which are a public health problem due to their increased prevalence, high burden to society, and lack of curative treatment. Currently, NGS appears to be an advanced option over conventional methods to detect all variants occurring by molecular mechanisms and simultaneously analyse many genomic sequences.
PubMed: 38708170
DOI: 10.1007/s12288-023-01694-7 -
Ultrasound in Obstetrics & Gynecology :... May 2024Hemoglobin (Hb) Bart's disease is a severe manifestation of alpha thalassemia, resulting in fetal tissue hypoxia and severe anemia. There is limited research available...
OBJECTIVE
Hemoglobin (Hb) Bart's disease is a severe manifestation of alpha thalassemia, resulting in fetal tissue hypoxia and severe anemia. There is limited research available on assessing fetal speckle tracking analysis as a response to fetal anemia caused by Hb Bart's disease and its utility as a sonographic predictor for Hb Bart's disease. This study aimed to assess the diagnostic performance of fetal cardiac parameters derived from speckle tracking echocardiography for distinguishing between affected and unaffected fetuses in pregnancies at risk of Hb Bart's disease during the 17-24 gestational weeks.
METHODS
A total of 115 pregnant women at risk for fetal Hb Bart's disease, who underwent either amniocentesis or cordocentesis at Siriraj Hospital, Bangkok Thailand, were included. Speckle tracking analysis was performed on the 4-chamber view (4CV) of the fetal heart, assessing heart size, shape, ventricular contractility, and left ventricular function prior to invasive prenatal testing. Logistic regression analysis determined significant cardiac predictors and calculated the probability of a fetus having Hb Bart's disease.
RESULTS
Among the cohort, 38 fetuses (33%) were diagnosed with Hb Bart's disease, and 9 cases (7.8%) exhibited frank hydropic signs. In comparison to the control group, affected fetuses displayed a notable enlargement of the 4CV and a more globular shape specifically in the right ventricular chamber. Additionally, there were significant differences in the left global and longitudinal contractility between affected and unaffected fetuses. However, at mid-gestation, no significant distinctions were observed in terms of transverse contractility and left ventricular function between the two groups. Based on logistic regression analysis, combined cardiac parameters derived from speckle tracking analysis as a function of head circumference, could differentiate non-hydropic fetuses with Hb Bart's disease from unaffected fetuses, achieving a maximum sensitivity of 100%, specificity of 98.7%, and overall accuracy of 99.06%.
CONCLUSIONS
Speckle tracking echocardiography has the potential to accurately identify early fetal heart changes in individuals at risk of developing Bart's anemia during the second trimester. This not only offers a novel predictive marker for Hb Bart's disease but also helps address the question of the underlying mechanisms of heart failure associated with anemia. This article is protected by copyright. All rights reserved.
PubMed: 38706423
DOI: 10.1002/uog.27676 -
Molecular Biology Reports May 2024The α-Major Regulatory Element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of...
BACKGROUND
The α-Major Regulatory Element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of the α-globin gene expression. This enhancer is polymorphic and several haplotypes were identified in different populations, with haplotype D almost exclusively found in African populations. The purpose of this research was to identify the HS-40 haplotype associated with the 3.7 kb α-thalassemia deletion (-α3.7del) in the Portuguese population, and determine its ancestry and influence on patients' hematological phenotype.
METHODS AND RESULTS
We selected 111 Portuguese individuals previously analyzed by Gap-PCR to detect the presence of the -α3.7del: 50 without the -α3.7del, 34 heterozygous and 27 homozygous for the -α3.7del. The HS-40 region was amplified by PCR followed by Sanger sequencing. Four HS-40 haplotypes were found (A to D). The distribution of HS-40 haplotypes and genotypes are significantly different between individuals with and without the -α3.7del, being haplotype D and genotype AD the most prevalent in patients with this deletion in homozygosity. Furthermore, multiple correspondence analysis revealed that individuals without the -α3.7del are grouped with other European populations, while samples with the -α3.7del are separated from these and found more closely related to the African population.
CONCLUSION
This study revealed for the first time an association of the HS-40 haplotype D with the -α3.7del in the Portuguese population, and its likely African ancestry. These results may have clinical importance as in vitro analysis of haplotype D showed a decrease in its enhancer activity on α-globin gene.
Topics: Female; Humans; Male; alpha-Globins; alpha-Thalassemia; Black People; Gene Frequency; Genotype; Haplotypes; Portugal; Regulatory Sequences, Nucleic Acid; Sequence Deletion
PubMed: 38704770
DOI: 10.1007/s11033-024-09530-5 -
Cureus Mar 2024Background Hb Adana is a non-deletional alpha (α)-thalassaemia variant resulting from mutations in α1- or α2-globin codon 59 (α), leading to the production of...
Background Hb Adana is a non-deletional alpha (α)-thalassaemia variant resulting from mutations in α1- or α2-globin codon 59 (α), leading to the production of unstable α-globin. Clinical manifestations can vary from silent carrier status to dependence on blood transfusions, hepatosplenomegaly, skeletal deformities, and spinal cord compression. Despite the significance of Hb Adana inheritance, studying this variant poses challenges due to the scarcity of molecular tests and the potential for routine diagnoses to be overlooked. This study aims to investigate the prevalence of Hb Adana among local high school students and assess the hematological parameters and hemoglobin analysis of Hb Adana in Malaysia. Methodology This retrospective study analyzed 13,721 blood samples collected from high school students participating in Malaysia's National Thalassaemia Screening Program at Hospital Raja Perempuan Zainab II (HRPZ II). Deletional α-thalassaemia was detected using multiplex gap-polymerase chain reaction (PCR), while common non-deletional α-thalassaemia was identified using multiplex amplification refractory mutation system (ARMS) PCR. Data were extracted from the HRPZ II database for analysis. Results Among the participants, 2327 individuals were found to have either common deletional (n=1037, 44.6%) or non-deletional (n=1290, 55.4%) α-thalassaemia. Hb Constant Spring was the most prevalent non-deletional α-thalassaemia, accounting for 53.03% of cases. Thirty-one participants (1.33%) exhibited αα/αα, and one (0.04%) had αα/-α. Among the 32 subjects with Hb Adana, 87.5% were Malay, and 12.5% were Orang Asli. Additionally, seven cases of HbE/Hb Adana co-inheritance were identified. Hemoglobin levels in heterozygous Hb Adana individuals ranged from mild anemia to normal, between 95 g/L and 153 g/L. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were approximately 73 fL and 23 pg, respectively. Conclusion This study delineates the distribution of α-thalassaemia mutation patterns among high school students in Kelantan, Northeast Peninsular Malaysia. Our findings indicate that Hb Adana is rare in our region and co-inheritance with an α-gene deletion results in α+-thalassaemia and with HbE, α0-thalassaemia. All heterozygous Hb Adana individuals exhibited low MCVs and MCHs.
PubMed: 38694420
DOI: 10.7759/cureus.57353 -
Scientific Reports Apr 2024Hemoglobin (Hb) Lepore is a rare deletional δβ-thalassemia caused by the fusion between delta-beta genes, and cannot be identified by traditional thaltassemia gene...
Hemoglobin (Hb) Lepore is a rare deletional δβ-thalassemia caused by the fusion between delta-beta genes, and cannot be identified by traditional thaltassemia gene testing technology. The aim of this study was to conduct molecular diagnosis and clinical analysis of Hb Lepore in four unrelated Chinese families using third generation sequencing. Decreased levels of mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and an abnormal Hb band were observed in the probands of the four families. However, no common α and β-thalassemia variants were detected in the enrolled families using polymerase chain reaction-reverse dot blot hybridization based traditional thalassemia gene testing. Further third-generation sequencing revealed similar Hb Lepore-Boston-Washington variants in all the patients, which were resulted from partial coverage of the HBB and HBD globin genes, leading to the formation of a delta-beta fusion gene. Specific gap-PCR and Sanger sequencing confirmed that all the patients carried a similar Hb Lepore-Boston-Washington heterozygote. In addition, decreased levels of MCH and Hb A2 were observed in the proband's wife of family 2, an extremely rare variant of Hb Nanchang (GGT > AGT) (HBA2:c.46G > A) was identified by third-generation sequencing and further confirmed by Sanger sequencing. This present study was the first to report the similar Hb Lepore-Boston-Washington in Chinese population. By combining the utilization of Hb capillary electrophoresis and third-generation sequencing, the screening and diagnosis of Hb Lepore can be effectively enhanced.
Topics: Adult; Female; Humans; Male; Asian People; beta-Globins; beta-Thalassemia; China; East Asian People; Hemoglobins, Abnormal; High-Throughput Nucleotide Sequencing; Pedigree
PubMed: 38693200
DOI: 10.1038/s41598-024-60604-7 -
Transfusion Jun 2024Post-transfusion survival of donor red blood cells (RBCs) is important for effective chronic transfusion therapy in conditions including sickle cell disease (SCD).... (Observational Study)
Observational Study
BACKGROUND
Post-transfusion survival of donor red blood cells (RBCs) is important for effective chronic transfusion therapy in conditions including sickle cell disease (SCD). Biotin labeling RBCs allows direct in vivo measurement of multiple donor RBC units simultaneously post-transfusion.
STUDY DESIGN AND METHODS
In an observational trial of patients with SCD receiving monthly chronic transfusion therapy, aliquots of RBCs from one transfusion episode were biotin-labeled and infused along with the unlabeled RBC units. Serial blood samples were obtained to measure RBC survival. Donor units were tested for RBC indices, hemoglobin fractionation, and glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. For microcytic donor RBCs (MCV < 70 fL), HBA1 and HBA2 genetic testing was performed on whole blood.
RESULTS
We present one recipient, a pediatric patient with SCD and splenectomy who received two RBC units with aliquots from each unit labeled at distinct biotin densities (2 and 18 μg/mL biotin). One donor unit was identified to have microcytosis (MCV 68.5 fL after biotinylation); whole blood sample obtained at a subsequent donation showed 2-gene deletion alpha-thalassemia trait (ɑ-/ɑ-) and normal serum ferritin. G6PD activity was >60% of normal mean for both. The RBCs with alpha-thalassemia RBC had accelerated clearance and increased surface phosphatidylserine post-transfusion, as compared with the normocytic RBC (half life 65 vs. 86 days, respectively).
DISCUSSION
Post-transfusion RBC survival may be lower for units from donors with alpha-thalassemia trait, although the impact of thalassemia trait donors on transfusion efficacy requires further study.
Topics: Humans; Anemia, Sickle Cell; alpha-Thalassemia; Erythrocytes; Erythrocyte Transfusion; Blood Donors; Male; Cell Survival; Biotinylation; Female; Child
PubMed: 38693059
DOI: 10.1111/trf.17857 -
Hemoglobin May 2024Copy number variations (CNVs) involving the α-globin gene cluster can lead to an imbalance in the proportion of α- and β-globin chains and consequently cause clinical...
Copy number variations (CNVs) involving the α-globin gene cluster can lead to an imbalance in the proportion of α- and β-globin chains and consequently cause clinical symptoms of β-thalassemia. In our case, a 6-year-old boy, clinically diagnosed with β thalassemia intermedia, was admitted for further genetic diagnosis with his family. Targeted sequencing and third generation sequencing (TGS) were used to detect the possible variants of the thalassemia genes. Low-pass whole genome sequencing (lpWGS) was conducted to specify the exact location of relevant CNVs across the genome, which was then validated by multiplex ligation-dependent probe amplification.The results revealed that the patient had a heterozygous β mutation of Codon17 (A > T) and a full duplication of the α-globin gene cluster, inherited from his mother and father, respectively. Besides, a novel point mutation within the 5' untranslated region of β-Globin (: c. -175 (G > A) was only detected in the patient. This study suggests that lpWGS seems a powerful alternative to detect large CNVs related to thalassemia with second intention for more information of the breakpoints and a simultaneous genome-scale detection of other pathogenic CNVs.
PubMed: 38693050
DOI: 10.1080/03630269.2024.2346143 -
The Journal of Maternal-fetal &... Dec 2024Mirror syndrome (MS) is a condition characterized by the presence of maternal, fetal, and placental edema and is reversible through delivery or pregnancy termination. As... (Review)
Review
OBJECTIVES
Mirror syndrome (MS) is a condition characterized by the presence of maternal, fetal, and placental edema and is reversible through delivery or pregnancy termination. As fetal hydrops itself may be amenable to treatment, we sought to determine outcomes for MS primarily managed by fetal therapy through a narrative review of the literature and cases managed at our fetal center.
STUDY DESIGN
PubMed, Embase, Web of Science, Scopus, and Google Scholar databases were searched through January 2024 using key words: mirror syndrome, Ballantyne's syndrome, fetal hydrops, maternal hydrops, pseudotoxemia, triple edema, maternal recovery, fetal therapy, and resolution. Manuscripts describing primary management by fetal therapy that included maternal and fetal outcomes were identified. Clinical details of MS patients managed with fetal therapy at our center were also included for descriptive analysis.
RESULTS
16 of 517 manuscripts (3.1%) described fetal therapy as the primary intended treatment in 17 patients. 3 patients managed at our center were included in the analysis. Among 20 patients undergoing primary fetal therapy for management of mirror syndrome, median gestational age of presentation was 24 weeks and 5 days gestation; predominant clinical findings were maternal edema (15/20), proteinuria (10/20), pulmonary edema (8/20), and hypertension (8/20); the primary laboratory abnormalities were anemia (8/20) and elevated creatinine or transaminases (5/20). Condition-specific fetal therapies led to resolution of hydrops in 17 (85%) cases and MS in 19 (95%) cases. The median time to hydrops resolution was 7.5 days and to resolution of mirror syndrome was 10 days. Fetal therapy prolonged pregnancy by a median of 10 weeks with a median gestational age of 35 weeks and 5 days at delivery. All women delivered for indications other than mirror syndrome and 19/20 fetuses survived.
CONCLUSION
In appropriately selected cases, MS often resolves after fetal therapy of hydrops allowing for safe pregnancy prolongation with good maternal and infant outcomes.
Topics: Humans; Pregnancy; Hydrops Fetalis; Female; Fetal Therapies; Edema; Syndrome
PubMed: 38679585
DOI: 10.1080/14767058.2024.2345307