-
The Cochrane Database of Systematic... Feb 2023Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains... (Review)
Review
BACKGROUND
Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains cause membrane damage and cell death within organ systems and destruction of erythroid precursors in the bone marrow, leading to haemolytic anaemia. The life-long management of the general health effects of thalassaemia is highly challenging, and failure to deal with dental and orthodontic complications exacerbates the public health, financial and personal burden of the condition. There is a lack of evidence-based guidelines to help care seekers and providers manage such dental and orthodontic complications. This review aimed to evaluate the available evidence on methods for treating dental and orthodontic complications in people with thalassaemia to inform future recommendations. This is an update of a Cochrane Review first published in 2019.
OBJECTIVES
To assess different methods for treating dental and orthodontic complications in people with thalassaemia.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register in September 2022, and we searched nine online databases and trials registries in January 2022. We searched the reference lists of relevant articles and reviews and contacted haematologists, experts in fields of dentistry, organisations, pharmaceutical companies and researchers working in this field.
SELECTION CRITERIA
We searched for published or unpublished randomised controlled trials (RCTs) that evaluated treatment of dental and orthodontic complications in individuals diagnosed with thalassaemia, irrespective of phenotype, severity, age, sex and ethnic origin.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the 37,242 titles retrieved by the search. After deduplication, we identified two potentially relevant RCTs. On assessing their eligibility against our inclusion and exclusion criteria, we excluded one and included the other.
MAIN RESULTS
We included one parallel-design RCT conducted in Saudi Arabia and involving 29 participants (19 males, 10 females) with thalassaemia. It aimed to assess the effectiveness of photodynamic therapy as an adjuvant to conventional full-mouth ultrasonic scaling for the treatment of gingivitis. The average age of participants was around 23 years. There is very low-certainty evidence from this trial that full-mouth ultrasonic scaling plus photodynamic therapy compared to full-mouth ultrasonic scaling alone may improve gingival index score and bleeding on probing after 12 weeks in people with thalassaemia. We found no studies that assessed other interventions for the various dental or orthodontic complications of thalassaemia.
AUTHORS' CONCLUSIONS
Although the included study showed greater reduction in gingivitis in the group treated with full-mouth ultrasonic scaling plus photodynamic therapy, the evidence is of very low certainty. The study had unclear risk of bias, a short follow-up period and no data on safety or adverse effects. We cannot make definitive recommendations for clinical practice based on the limited evidence of a single trial. Future studies will very likely affect the conclusions of this review. This review highlights the need for high-quality RCTs that investigate the effectiveness of various treatment modalities for dental and orthodontic complications in people with thalassaemia. It is crucial that future trials assess adverse effects of interventions.
Topics: Male; Female; Humans; Thalassemia; Gingivitis
PubMed: 36732291
DOI: 10.1002/14651858.CD012969.pub3 -
Transfusion Clinique Et Biologique :... May 2023Thalassemia, one of the most common genetic hemoglobinopathy, is yet still an economy-depriving disorder, prevalent throughout the world. Specifically in Pakistan,...
Thalassemia, one of the most common genetic hemoglobinopathy, is yet still an economy-depriving disorder, prevalent throughout the world. Specifically in Pakistan, numerous factors have led to the ever-increasing numbers of the affected masses. Amidst its battle with other diseases, it is worthy to highlight that the country did not overlook this disorder and hence, significant work has been done to change the thalassemia status of the country. From the establishment of reforms to private philanthropic organizations, Pakistan is actively fighting against the disorder. However, some more practical working and well-devised planning can help the country, attain a thalassemic-free status.
Topics: Humans; Pakistan; Thalassemia; Hemoglobinopathies
PubMed: 36403902
DOI: 10.1016/j.tracli.2022.11.003 -
Expert Review of Hematology Mar 2021: The clinical manifestations of sickle cell disease (SCD) result from an inherited mutation in the beta-globin chain of hemoglobin (Hb) that causes Hb tetramers to... (Review)
Review
: The clinical manifestations of sickle cell disease (SCD) result from an inherited mutation in the beta-globin chain of hemoglobin (Hb) that causes Hb tetramers to polymerize when deoxygenated. The resulting erythrocyte deformation causes mechanical obstruction of blood flow by sickled cells, hemolysis, anemia and end-organ injury. While pain is the hallmark symptom of SCD, chronic organ injury as a result of anemia, inflammation and progressive vasculopathy play a major role in morbidity and mortality. Due to the complex pathophysiology of SCD, the need for an individualized, multi-modal pharmacologic approach is apparent. Until 2018, hydroxyurea was the only disease-modifying pharmacologic therapy approved for use in SCD. Since then, three new agents have been approved including voxelotor, the subject of this review.: Published pre-clinical and clinical data are reviewed. Voxelotor is a first-in-class small-molecule agent that binds to Hb and increases oxygen affinity, preventing polymerization. Recent clinical trials have shown that it increases Hb concentration and reduces hemolysis in patients with SCD. This increase in Hb concentration may significantly impact morbidity and mortality from chronic organ injury.: The mechanism of action, published studies and current opinions on the clinical use of voxelotor in SCD are presented.
Topics: Anemia, Sickle Cell; Benzaldehydes; Humans; Pyrazines; Pyrazoles
PubMed: 33602029
DOI: 10.1080/17474086.2021.1893688 -
Blood Mar 2021In this issue of , guided by clinical observations and needs, Gong et al have identified a germline missense mutation in DNA methyltransferase 1 (), a ubiquitously...
In this issue of , guided by clinical observations and needs, Gong et al have identified a germline missense mutation in DNA methyltransferase 1 (), a ubiquitously expressed key epigenetic regulator, as a cause of hereditary persistence of fetal hemoglobin (HPFH). HPFH protects against β-thalassemia and sickle cell disease (the β-hemoglobinopathies). Discussed here is how these findings by Gong et al continue the pioneering role of the β-hemoglobinopathies as a model of discovery for all biomedicine. Sickle cell disease, after all, is the “first molecular disease”: altered migration of sickle vs normal hemoglobin in gel electrophoresis demonstrated, for the first time, that the structure–chemical basis for disease is discoverable and knowable.
Topics: Hemoglobinopathies; Humans; beta-Globins
PubMed: 33764430
DOI: 10.1182/blood.2020009961 -
Frontiers in Endocrinology 2022Hemoglobinopathies are autosomal recessive disorders that occur when genetic mutations negatively impact the function of hemoglobin. Common hemoglobinopathies that are... (Review)
Review
Hemoglobinopathies are autosomal recessive disorders that occur when genetic mutations negatively impact the function of hemoglobin. Common hemoglobinopathies that are clinically significant include sickle cell disease, alpha thalassemia, and beta thalassemia. Advancements in disease-modifying and curative treatments for the common hemoglobinopathies over the past thirty years have led to improvements in patient quality of life and longevity for those who are affected. However, the diseases, their treatments and cures pose infertility risks, making fertility preservation counseling and treatment an important part of the contemporary comprehensive patient care. Sickle cell disease negatively impacts both male and female infertility, primarily by testicular failure and decreased ovarian reserve, respectively. Fertility in both males and females with beta thalassemia major are negatively impacted by iron deposition due to chronic blood transfusions. Hematopoietic stem cell transplant (HSCT) is currently the only curative treatment for SCD and transfusion dependent beta thalassemia. Many of the conditioning regimens for HSCT contain chemotherapeutic agents with known gonadotoxicity and whole-body radiation. Although most clinical studies on toxicity and impact of HSCT on long-term health do not evaluate fertility, gonadal failure is common. Male fertility preservation modalities that exist prior to gonadotoxic treatment include sperm banking for pubertal males and testicular cryopreservation for pre-pubertal boys. For female patients, fertility preservation options include oocyte cryopreservation and ovarian tissue cryopreservation. Oocyte cryopreservation requires controlled ovarian hyperstimulation (COH) with ten to fourteen days of intensive monitoring and medication administration. This is feasible once the patient has undergone menarche. Follicular growth is monitored transvaginal or transabdominal ultrasound, and hormone levels are monitored through frequent blood work. Oocytes are then harvested a minimally invasive approach under anesthesia. Complications of COH are more common in patients with hemoglobinopathies. Ovarian hyperstimulation syndrome creates a greater risk to patients with underlying vascular, pulmonary, and renal injury, as they may be less able to tolerate fluids shifts. Thus, it is critical to monitor patients undergoing COH closely with close collaboration between the hematology team and the reproductive endocrinology team. Counseling patients and families about future fertility must take into consideration the patient's disease, treatment history, and planned treatment, acknowledging current knowledge gaps.
Topics: Humans; Male; Female; Fertility Preservation; beta-Thalassemia; Quality of Life; Semen; Counseling; Anemia, Sickle Cell; Ovarian Hyperstimulation Syndrome
PubMed: 36353243
DOI: 10.3389/fendo.2022.985525 -
JCI Insight Oct 2022Individuals with β-thalassemia or sickle cell disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% fetal hemoglobin (HbF) appear to be symptom...
Individuals with β-thalassemia or sickle cell disease and hereditary persistence of fetal hemoglobin (HPFH) possessing 30% fetal hemoglobin (HbF) appear to be symptom free. Here, we used a nonintegrating HDAd5/35++ vector expressing a highly efficient and accurate version of an adenine base editor (ABE8e) to install, in vivo, a -113 A>G HPFH mutation in the γ-globin promoters in healthy CD46/β-YAC mice carrying the human β-globin locus. Our in vivo hematopoietic stem cell (HSC) editing/selection strategy involves only s.c. and i.v. injections and does not require myeloablation and HSC transplantation. In vivo HSC base editing in CD46/β-YAC mice resulted in > 60% -113 A>G conversion, with 30% γ-globin of β-globin expressed in 70% of erythrocytes. Importantly, no off-target editing at sites predicted by CIRCLE-Seq or in silico was detected. Furthermore, no critical alterations in the transcriptome of in vivo edited mice were found by RNA-Seq. In vitro, in HSCs from β-thalassemia and patients with sickle cell disease, transduction with the base editor vector mediated efficient -113 A>G conversion and reactivation of γ-globin expression with subsequent phenotypic correction of erythroid cells. Because our in vivo base editing strategy is safe and technically simple, it has the potential for clinical application in developing countries where hemoglobinopathies are prevalent.
Topics: Adenine; Anemia, Sickle Cell; Animals; CRISPR-Cas Systems; Fetal Hemoglobin; Gene Editing; Hemoglobinopathies; Humans; Mice; beta-Globins; beta-Thalassemia; gamma-Globins
PubMed: 36006707
DOI: 10.1172/jci.insight.162939 -
Seminars in Hematology Jan 2021Human hemoglobin switching describes the highly regulated, sequential expression of the 5 β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene... (Review)
Review
Human hemoglobin switching describes the highly regulated, sequential expression of the 5 β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene complex. The sequential activation of these β or β-like globin genes during human development from early embryonic through late fetal ('adult') stages, and during erythroid maturation, occurs in an order corresponding to their 5' to 3' location on chromosome 11. The β-hemoglobinopathies are the most common inherited diseases in humanity, and are diseases of mutated HBB or its altered regulation. Since the other β-like globin genes can potentially substitute for defective HBB, much translational research is directed toward understanding and manipulating sequential activation at the human β-globin gene complex to treat β-hemoglobinopathies. Non-human primates provide a vital contribution to such efforts because of their recapitulation of the developmental/maturational switch in hemoglobin production as observed in humans (mice do not model this switch). Valuable insights into druggable epigenetic forces that mediate the switch have been thereby gained. We review important lessons learned in non-human primates, complemented by other studies, and suggest rational next steps.
Topics: Animals; Epigenesis, Genetic; Hemoglobinopathies; Humans; Mice; Primates; beta-Globins
PubMed: 33509438
DOI: 10.1053/j.seminhematol.2020.12.001 -
Hemoglobin Nov 2020Hemoglobinopathies are the most common single-gene diseases and are estimated to affect millions of people worldwide. Thalassemia and sickle cell disease are the most... (Review)
Review
Hemoglobinopathies are the most common single-gene diseases and are estimated to affect millions of people worldwide. Thalassemia and sickle cell disease are the most prevalent diseases of this group. Today, despite the decreasing number of newborns diagnosed with a hemoglobinopathy, it remains an important health problem for many countries. Although regular red blood cell (RBC) transfusions, advanced iron chelation, and supportive therapy alternatives have improved life expectancy, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with hemoglobinopathies to prevent irreversible organ damage. Modern transplantation approaches and careful posttransplantation follow-up of patients have improved survival outcomes, and HSCT has now been performed in several patients with hemoglobinopathies worldwide. Considering current experiences, hematopoietic stem cell transplantation is recommended in cases of β-thalassemia (β-thal) in the presence of a matched family or unrelated donor, without secondary organ damage due to transfusion. In patients with sickle cell anemia, transplantation indications include transfusion dependence and cases of secondary organ damage. Recently, gene therapy as a possible treatment option has yielded promising results, though it is not in routine clinical use at its current stage.
Topics: Aftercare; Anemia, Sickle Cell; Combined Modality Therapy; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hemoglobinopathies; Humans; Prognosis; Quality of Life; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; beta-Thalassemia
PubMed: 33050763
DOI: 10.1080/03630269.2020.1832516 -
Expert Review of Hematology Oct 2021Drug efficacy and toxicity are closely related to the unique genetic profile of individuals, or pharmacogenomics. Despite the fact that cardiology, psychiatry and...
Drug efficacy and toxicity are closely related to the unique genetic profile of individuals, or pharmacogenomics. Despite the fact that cardiology, psychiatry and oncology are among the clinical specialties in which pharmacogenomics has become a clinical reality, the utility of pharmacogenomics has yet to be demonstrated for several other medical specialties. Over the last 15 years, genomic variants in a number of loci have been shown to be significantly associated with the fetal hemoglobin (HbF) response to hydroxyurea, the only approved drug for HbF induction for sickle cell disease. Here, we provide an update and discuss future challenges to the application of pharmacogenomics to improve therapies for β-hemoglobinopathies in relation to the current pharmacological treatment modalities for those disorders.
Topics: Anemia, Sickle Cell; Hemoglobinopathies; Humans; Hydroxyurea; Pharmacogenetics; beta-Thalassemia
PubMed: 34490838
DOI: 10.1080/17474086.2021.1977117 -
Annals of Hematology Aug 2022Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a... (Review)
Review
Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD + + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD. Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy.
Topics: Anemia, Sickle Cell; Glutamine; Hemoglobinopathies; Humans; NAD; Oxidation-Reduction; Volatile Organic Compounds
PubMed: 35568758
DOI: 10.1007/s00277-022-04867-y