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British Journal of Haematology Nov 2019Sickle cell disease (SCD) and thalassaemia are genetic disorders that are caused by errors in the genes for haemoglobin and are some of the most common significant... (Review)
Review
Sickle cell disease (SCD) and thalassaemia are genetic disorders that are caused by errors in the genes for haemoglobin and are some of the most common significant genetic disorders in the world, resulting in significant morbidity and mortality. Great disparities exist in the outcome of these conditions between resource- rich and resource-poor nations. Antenatal screening for these disorders aims to provide couples with information about their reproductive risk and enable them to make informed reproductive choices; ultimately reducing the likelihood of children being born with these conditions. This review provides an overview of the current status of antenatal, pre-marital and population screening of SCD and thalassaemia in countries with both high-and low prevalence of these conditions, methods of screening in use, and discusses some of the pitfalls, ethical issues and controversies surrounding antenatal screening. It also discusses outcomes of some screening programmes and recognises the need for the establishment of antenatal screening in areas where their prevalence is highest; namely sub-Saharan Africa and India.
Topics: Anemia, Sickle Cell; Female; Hemoglobinopathies; Humans; Pregnancy; Prenatal Diagnosis; Thalassemia
PubMed: 31509241
DOI: 10.1111/bjh.16188 -
Archives of Gynecology and Obstetrics Nov 2021To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait.
PURPOSE
To determine the risk of adverse maternal and neonatal outcomes in pregnant women with a hemoglobinopathy trait.
MATERIALS AND METHODS
Retrospective cohort study was conducted to compare adverse maternal and neonatal outcomes between pregnant women with a hemoglobinopathy trait (study group; n = 172), and without a hemoglobinopathy trait (control group; n = 360). The medical data were extracted from clinical records of pregnant women attending antenatal care and delivering at the University Hospital Basel or University Hospital Zurich between 2015 and 2018.
RESULTS
A total of 172 pregnant women with a hemoglobinopathy trait and 360 controls were recruited. Apart from fetal acidosis, the groups did not differ significantly in any variables of adverse neonatal outcomes. Whereas, among the maternal outcomes the rate of abortion, gestational diabetes mellitus, bacteriuria or urinary tract infection, intrahepatic cholestasis, abnormal placentation and anemia postpartum were significantly increased in women with a hemoglobinopathy trait.
CONCLUSION
In our study, a hemoglobinopathy trait increased the risk of adverse maternal outcomes but did not increase adverse neonatal outcomes.
Topics: Acidosis; Adolescent; Adult; Bacteriuria; Case-Control Studies; Female; Hemoglobinopathies; Humans; Infant, Newborn; Middle Aged; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Retrospective Studies; Young Adult
PubMed: 33842991
DOI: 10.1007/s00404-021-06058-y -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Mar 2020Alpha-thalassemia is an autosomal recessive genetic disease as well as a relatively common hemoglobinopathy. Severe alpha-thalassemia (also known as Hb Bart's Hydrops...
Alpha-thalassemia is an autosomal recessive genetic disease as well as a relatively common hemoglobinopathy. Severe alpha-thalassemia (also known as Hb Bart's Hydrops fetalis syndrome) and intermediate alpha-thalassemia (also known as Hb H disease) are among the most common birth defects in southern China. To implement carrier screening and large population prevention program in high incidence areas can significantly reduce the incidence of alpha-thalassemia. This guideline was established by combining the discoveries of basic research, clinical research and guidelines from other countries and the actual data of Chinese population. It has summarized the medical genetics knowledge and key points in the clinical treatment for alpha-thalassemia, and provided suggestions for the clinical diagnosis and standard management of patients.
Topics: China; Genetics, Medical; Hemoglobins, Abnormal; Humans; Hydrops Fetalis; Practice Guidelines as Topic; alpha-Thalassemia
PubMed: 32128738
DOI: 10.3760/cma.j.issn.1003-9406.2020.03.003 -
Blood Oct 2019β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the... (Review)
Review
β-Thalassemia and sickle cell disease (SCD) are the most prevalent monogenic diseases. These disorders are caused by quantitative or qualitative defects in the production of adult hemoglobin. Gene therapy is a potential treatment option for patients lacking an allogenic compatible hematopoietic stem cell (HSC) donor. New-generation lentiviral vectors (LVs) carrying a β-globin-like gene have revolutionized this field by allowing effective HSC transduction, with no evidence of genotoxicity to date. Several clinical trials with different types of vector are underway worldwide; the initial results are encouraging with regard to the sustained production of therapeutic hemoglobin, improved biological parameters, a lower transfusion requirement, and better quality of life. Long-term follow-up studies will confirm the safety of LV-based gene therapy. The optimization of patient conditioning, HSC harvesting, and HSC transduction has further improved the therapeutic potential of this approach. Novel LV-based strategies for reactivating endogenous fetal hemoglobin (HbF) are also promising, because elevated HbF levels can reduce the severity of both β-thalassemia and SCD. Lastly, genome-editing approaches designed to correct the disease-causing mutation or reactivate HbF are currently under investigation. Here, we discuss the clinical outcomes of current LV-based gene addition trials and the promising advantages of novel alternative therapeutic strategies.
Topics: Anemia, Sickle Cell; Animals; Clinical Trials as Topic; Fetal Hemoglobin; Gene Editing; Genetic Therapy; Genetic Vectors; Hemoglobinopathies; Humans; Lentivirus; beta-Globins; beta-Thalassemia
PubMed: 31467062
DOI: 10.1182/blood.2019000949 -
British Journal of Clinical Pharmacology Aug 2022Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have... (Review)
Review
Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have migrated there owing to demographic migration, β-thalassaemia can now be detected in areas other than malaria-endemic areas. Every year, an estimated 300 000-500 000 infants, the vast majority of whom are from developing countries, are born with a severe haemoglobin anomaly. Currently, some basic techniques, which include iron chelation therapy, hydroxyurea, blood transfusion, splenectomy and haematopoietic stem cell transplantation, are being used to manage thalassaemia patients. Despite being the backbone of treatment, traditional techniques have several drawbacks and limitations. Ineffective erythropoiesis, correction of globin chain imbalance and adjustment of iron metabolism are some of the innovative treatment methods that have been developed in the care of thalassaemia patients in recent years. Moreover, regulating the expression of B-cell lymphoma/leukaemia 11A and sex-determining region Y-box through the enhanced expression of micro RNAs can also be considered putative targets for managing haemoglobinopathies. This review focuses on the biological basis of β-globin gene production, the pathophysiology of β-thalassaemia and the treatment options that have recently been introduced.
Topics: Blood Transfusion; Humans; Infant; Iron; Iron Chelating Agents; Thalassemia; beta-Thalassemia
PubMed: 35373382
DOI: 10.1111/bcp.15343 -
The Journal of Maternal-fetal &... Dec 2022To evaluate the studies which have reported the prevalence of maternal complications and outcomes for women with SCA/SCD. Healthy populations make a healthy community... (Review)
Review
To evaluate the studies which have reported the prevalence of maternal complications and outcomes for women with SCA/SCD. Healthy populations make a healthy community and improve the future for mankind. Pregnant women are an essential segment of humanity as they bear the fetus and supply nutrition for their development throughout the gestational period. Their health status and disease conditions also play a vital role in deciding the future of the offspring. The Mesh terms: "Haemoglobinopathies" + "Sickle cell anemia" + "Sickle cell disease" + "Ethnic tribes" + "Pregnancy outcomes" + "India" were used to search the literature available from public databases such as "PubMed", "PubMed Central" "Google Scholar", "Science Direct" and "Scopus" and the same is checked for removing repetitions. The data was extracted and collected literature was thoroughly analysed. SCD/SCA is a commonly prevalent hereditary hemoglobinopathy disease and is related to augmented risk factors and premature mortality. SCD severely affects pregnancy, which leads to the elevated occurrence of perinatal and maternal outcomes such as pre-eclampsia, eclampsia, abortions, intrauterine growth retardation (IUGR), etc., and sufficient care during the pregnancy guarantees an improved outcome. Due to the best health care conveniences, availability of drugs such as hydroxyurea, antibiotic prophylaxis, and vaccination, the life expectancy of SCD patients has greatly improved in recent times though directly related to the access and services available at the healthcare facilities for the needy and poor. Moreover, the latest innovations in the fields of prenatal screening and preimplantation genetic diagnosis (PGD), facilitate partners suffering from SCA/SCD to have a healthy child. There are no available studies on the prevalence of SCA/SCD in pregnant women among ethnic tribal populations from India. This review article is focused on the effects of SCA/SCD on pregnancy outcomes, the consistent follow-up, routine check-ups and successful management of complications throughout pregnancy, the various diagnostic methods toward preventive methods, curative and management therapeutic strategies and also defines the perinatal and maternal outcomes in the ethnic tribal populations of India.
Topics: Female; Humans; Pregnancy; Anemia, Sickle Cell; Ethnicity; India; Pregnancy Complications, Hematologic; Pregnancy Outcome
PubMed: 33563075
DOI: 10.1080/14767058.2021.1872536 -
Frontiers in Immunology 2020Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow... (Review)
Review
Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow failure syndromes, and primary immunodeficiencies. Early establishment of donor-derived innate and adaptive immunity following HCT is associated with improved overall survival, lower risk of infections and decreased incidence of graft failure. Immune reconstitution (IR) is impacted by numerous clinical variables including primary disease, donor characteristics, conditioning regimen, and graft versus host disease (GVHD). Recent advancements in HCT have been directed at reducing toxicity of conditioning therapy, expanding donor availability through use of alternative donor sources, and addressing morbidity from GVHD with novel graft manipulation. These novel transplant approaches impact the kinetics of immune recovery, which influence post-transplant outcomes. Here we review immune reconstitution in pediatric patients undergoing HCT for non-malignant disorders. We explore the transplant-associated factors that influence immunologic recovery and the disease-specific associations between IR and transplant outcomes.
Topics: Age Factors; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hemoglobinopathies; Humans; Immune Reconstitution; Primary Immunodeficiency Diseases; Risk Factors; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome
PubMed: 33013851
DOI: 10.3389/fimmu.2020.01988 -
Clinical Chemistry Sep 2023Oxford Nanopore Technology (ONT) third-generation sequencing (TGS) is a versatile genetic diagnostic platform. However, it is nonetheless challenging to prepare...
BACKGROUND
Oxford Nanopore Technology (ONT) third-generation sequencing (TGS) is a versatile genetic diagnostic platform. However, it is nonetheless challenging to prepare long-template libraries for long-read TGS, particularly the ONT method for analysis of hemoglobinopathy variants involving complex structures and occurring in GC-rich and/or homologous regions.
METHODS
A multiplex long PCR was designed to prepare library templates, including the whole-gene amplicons for HBA2/1, HBG2/1, HBD, and HBB, as well as the allelic amplicons for targeted deletions and special structural variations. Library construction was performed using long-PCR products, and sequencing was conducted on an Oxford Nanopore MinION instrument. Genotypes were identified based on integrative genomics viewer (IGV) plots.
RESULTS
This novel long-read TGS method distinguished all single nucleotide variants and structural variants within HBA2/1, HBG2/1, HBD, and HBB based on the whole-gene sequence reads. Targeted deletions and special structural variations were also identified according to the specific allelic reads. The result of 158 α-/β-thalassemia samples showed 100% concordance with previously known genotypes.
CONCLUSIONS
This ONT TGS method is high-throughput, which can be used for molecular screening and genetic diagnosis of hemoglobinopathies. The strategy of multiplex long PCR is an efficient strategy for library preparation, providing a practical reference for TGS assay development.
Topics: Humans; Sequence Analysis, DNA; Nanopores; Genomics; Hemoglobinopathies; Gene Library; High-Throughput Nucleotide Sequencing
PubMed: 37311260
DOI: 10.1093/clinchem/hvad073 -
Biosensors Feb 2024Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the...
Hemoglobin (Hb) disorders are among the most common monogenic diseases affecting nearly 7% of the world population. Among various Hb disorders, approximately 1.5% of the world population carries -thalassemia (-Thal), affecting 40,000 newborns every year. Early screening and a timely diagnosis are essential for -thalassemia patients for the prevention and management of later clinical complications. However, in Africa, Southern Europe, the Middle East, and Southeast Asia, where -thalassemia is most prevalent, the diagnosis and screening for -thalassemia are still challenging due to the cost and logistical burden of laboratory diagnostic tests. Here, we present Gazelle, which is a paper-based microchip electrophoresis platform that enables the first point-of-care diagnostic test for -thalassemia. We evaluated the accuracy of Gazelle for the -Thal screening across 372 subjects in the age range of 4-63 years at Apple Diagnostics lab in Mumbai, India. Additionally, 30 blood samples were prepared to mimic -Thal intermediate and -Thal major samples. Gazelle-detected levels of Hb A, Hb F, and Hb A demonstrated high levels of correlation with the results reported through laboratory gold standard high-performance liquid chromatography (HPLC), yielding a Pearson correlation coefficient = 0.99. This ability to obtain rapid and accurate results suggests that Gazelle may be suitable for the large-scale screening and diagnosis of -Thal.
Topics: Infant, Newborn; Humans; Animals; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; beta-Thalassemia; Antelopes; Hemoglobinopathies; Chromatography, High Pressure Liquid
PubMed: 38392002
DOI: 10.3390/bios14020083 -
Genes Feb 2023Beta-like globin gene expression is developmentally regulated during life by transcription factors, chromatin looping and epigenome modifications of the β-globin locus.... (Review)
Review
Beta-like globin gene expression is developmentally regulated during life by transcription factors, chromatin looping and epigenome modifications of the β-globin locus. Epigenome modifications, such as histone methylation/demethylation and acetylation/deacetylation and DNA methylation, are associated with up- or down-regulation of gene expression. The understanding of these mechanisms and their outcome in gene expression has paved the way to the development of new therapeutic strategies for treating various diseases, such as β-hemoglobinopathies. Histone deacetylase and DNA methyl-transferase inhibitors are currently being tested in clinical trials for hemoglobinopathies patients. However, these approaches are often uncertain, non-specific and their global effect poses serious safety concerns. Epigenome editing is a recently developed and promising tool that consists of a DNA recognition domain (zinc finger, transcription activator-like effector or dead clustered regularly interspaced short palindromic repeats Cas9) fused to the catalytic domain of a chromatin-modifying enzyme. It offers a more specific targeting of disease-related genes (e.g., the ability to reactivate the fetal γ-globin genes and improve the hemoglobinopathy phenotype) and it facilitates the development of scarless gene therapy approaches. Here, we summarize the mechanisms of epigenome regulation of the β-globin locus, and we discuss the application of epigenome editing for the treatment of hemoglobinopathies.
Topics: Humans; Epigenesis, Genetic; Epigenome; Hemoglobinopathies; beta-Globins; Chromatin; DNA
PubMed: 36980849
DOI: 10.3390/genes14030577