Introduction to Thalassemia
Thalassemia is an inherited blood disorder that is transmitted genetically. It is potentially debilitating, primarily as a result of the severe anemia that is one of its most distinctive features. Beta thalassemias are due to mutations reducing (quantitative defects) or preventing (qualitative defects) beta-globin production. Symptoms depend on the nature of the mutation and range from moderate anemia to death, the most severe forms being transfusion dependent during the first year of life. Generally, the only treatment for persons with severe genetic defects is blood transfusion therapy, which causes iron overload requiring chelation therapy to remove excess iron. With regular transfusions and iron chelation therapy, people with this condition can live into their 50s. However, bone marrow transplantation is the only cure for the disorder. The word “thalassemia” is derived from the Greek words “thalassa”, meaning the sea, and “anemia”, meaning absence of hemoglobin.
The name “thalassemia” clearly describes the physical effects this condition has on the body. Red blood cells transport oxygen to the body’s tissues. Bone marrow generates and nourishes these cells. In individuals with thalassemia, altered bone marrow prevents the production of healthy hemoglobin. Hemoglobin is the protein in oxygen-carrying blood cells. Faulty or mutated hemoglobin damages the body’s cells. Thalassemia impairs cells’ ability to function properly and to survive. With thalassemia, red blood cells become small and lack proper hemoglobin, leading to anemia and reduced production of red blood cells by the marrow. Thalassemia depletes the body’s essential oxygen. Normally, red blood cells have a doughnut shape. Thalassemia changes this shape, causing an irregular shrinking that results in slimmer, darker cells. These altered cells struggle to exit the bone marrow, accumulating there until they are absorbed, which causes the marrow to stretch and the bones to enlarge.
Genetics of Thalassemia
Both alpha and beta thalassemia are common throughout the world and are particularly prevalent in certain Mediterranean, African, and Asian countries. While alpha thalassemia has about 300 mutations that could result in the condition, most of the mutations underlying beta thalassemia are single base-pair changes, but have different implications for the conditions established. It is evident that the choice of mutations causing thalassemia has an important impact on the consequences of the disease and the potential treatment required.
Hematopoietic stem cell transplantation can cure thalassemia, but limitations arise from the availability of tissue-matching donors and the significant risk of death. Although allogeneic hematopoietic stem cell transplantation can cure thalassemia, the same limitations apply, and it is not suitable for the majority of sufferers.
If researchers can identify the thalassemia-producing gene, genetic counseling and prenatal detection can be utilized. Although doctors usually perform prenatal diagnosis of thalassemia by discarding anomalies, researchers are developing a test that will cure the thalassemia gene. During fetal life, peripheral blood cells predominantly convert to fetal hemoglobin. If we can recognize the gene causing thalassemia and characterize an appropriate treatment, it is feasible to perform malignodaemic transplantation of either the mother’s or the baby’s hematopoietic stem cells to replace the affected siblings’ stem cells. In several cases of fetal hematopoietic stem cell transplantation in the pre-symptomatic phase, doctors have observed the presence of donor-derived cells within the hybrid marrow after delivery.
Inheritance Patterns
Thalassemias follow an autosomal recessive inheritance pattern. They are autosomal because the genes are located on the autosomes, and they are recessive because, in a heterozygote, only the feature of one allele is expressed, while the feature of the other allele remains hidden and only emerges when two such alleles combine in a zygote. Because the genes follow an autosomal inheritance pattern, neither sex of the progeny nor the parents shows a higher prevalence of thalassemia within the same category. Furthermore, consanguinity in their union or transmission does not significantly affect the disease prevalence.
Certain genes are involved in the synthesis of the hemoglobin molecule. Mutant varieties of these genes, known as thalassemic genes, produce defective hemoglobin molecules. These thalassemic genes are not occasional; rather, they are natural mutants of the wild-type genes responsible for hemoglobin synthesis. These genes undergo natural transformation at a relatively high rate. As a result, researchers know about many abnormal hemoglobin molecules. That are unrelated to each other and to thalassemia, and future technology will likely uncover more of them. Scientists will explore the reasons behind the high rates of transformation in the genes responsible for hemoglobin synthesis once they better understand the nature of hematopoiesis.
Mutations and Genetic Variants
To date, more than 350 HBB (Hemoglobin beta) mutations have been reported. Each type of mutation results in a shift in the ratio of α- and β-globin chains, with its own clinical implications. Thalassemia is commonly caused by the deletion of a 20 kilobase (kb) DNA fragment. The most common deletions are 619 bp (55.4%) and 627 bp (39.4%) in the β-globin gene. The second most common cause of β-thalassemia is nondeletion mutations. Currently, fifteen molecular defects have been identified, mainly point mutations, though splicing mutations are also frequent. Both deletional and nondeletion β-thalassemic patients with Cooley’s hemoglobinopathy may present with defective synthesis of the β-globin chain. This defect leads to an excess of the alpha chain.
In addition to HBB, a nondeletion hemoglobin variant causes β+-thalassemia. Among these variants, the most frequent and unstable mutations occur in β-codon 29. These mutations originate from the same base transversion as HBB E31K. The HBB gene is a polymorphic marker, frequently used in the study of human history due to its high number of genetic variants and special mutational susceptibility. The hemoglobin beta gene shows high levels of genetic variation. This includes thousands of known mutations and more than 100 common missense polymorphisms, many of which are population-specific.
Conclusion
Many aspects remain unresolved in respect of thalassemia, and further research is obligatory. The exact molecular mechanism concerning the regulation of the alpha/gamma. And beta/gamma globin promoter pops and the production of fetal hemoglobin needs further elucidation. The patient-doctor perspective regarding treatment adherence, psychosocial involvement, quality of life. And healthcare utilization should become an important research subject in the future stage. Overall, the strategy for regulating the relationship between the mutation and current pathophysiology requires greater cooperation and enduring research commitment.
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