Thalassemia is a genetic disorder, most commonly encountered in countries with malaria prevalence or in people of corresponding descent. In affected individuals, hemoglobin synthesis is disturbed, which leads to hypochromic microcytic anemia of different severity.
Clinical presentation of thalassemia varies widely. And while some mutations are known to be particularly severe, the large number of different mutations and combinations thereof doesn't allow for the deduction of which genes are affected from physical examination or evaluation of blood counts. Thus, clinically, minor, intermediate and major forms of the disease are distinguished with regards to the severity:
In symptomatic thalassemia, symptoms provoked by anemia and hemolysis dominate the clinical picture. Patients may claim frequent headaches, dizziness, exertional dyspnea and palpitations. The reduced capacity for oxygen transport causes pallor and fatigue, and hemolysis results in jaundice and splenomegaly. Skeletal deformations may be observed and are due to bone marrow overstimulation and consequent expansion of erythroid cells.
Initially, laboratory analyses of blood tests are realized. In fact, pathological findings from the patient's hemogram often prompt a tentative diagnosis of thalassemia. Usually, the disease is associated with microcytosis, hypochromia and anemia. The mean corpuscular volume (MCV) is reduced, i.e., values are below 70 fl and 80 fl in children and adults, respectively . Erythrocytes are loaded with few hemoglobin, and mean corpuscular hemoglobin concentrations (MCHC) are lower than physiological values (reference range is 30-35 g/dl). Total hemoglobin concentrations are typically below 10 g/dl in thalassemia intermedia, and below 7 g/dl in thalassemia major (physiological range is 12-17 g/dl). Red blood cell distribution width may be enhanced, and blood films may reveal anisocytosis and poikilocytosis. While thrombocytic counts are generally unaltered, leukocytosis may be detected. Thrombocytopenia and leucopenia may be observed in patients presenting with splenomegaly.
Hemoglobin electrophoresis is needed to assess the composition of hemoglobin with regards to its polypeptide chains. Findings are usually diagnostic for or β-thalassemia. However, in α-thalassemia, molecular biological techniques have to be applied to identify the mutated gene(s) in an individual patient. Polymerase chain reactions may also be carried out to detect specific genetic mutations.
No specific therapy is required thalassemia minor. In contrast, thalassemia major and possible thalassemia intermedia patients may be dependent on regular, treatment throughout life.
For patients presenting with asymptomatic thalassemia, the prognosis is excellent. However, with increasing severity of the disease, morbidity and mortality augment. The life expectancy of an individual patient also depends on their access to health care services. People suffering from thalassemia intermedia or major may require transfusions of blood products, and anemic and aplastic crises are life-threatening if medical attention is not provided in a timely manner. Furthermore, secondary iron overload, anemia and subsequent heart failure may be fatal. Thalassemia patients are at higher risks of developing cholelithiasis, urolithiasis and gout. It is not uncommon to observe growth retardation in affected individuals. Certain types of thalassemia are incompatible with life. α-thalassemia major, for instance, causes hydrops fetalis and death in utero.
Thalassemia results from an insufficient synthesis of functional hemoglobin and this condition is provoked by a wide variety of mutations to be found on chromosomes 11 and 16. Genes encoding for all types of globin chains, i.e., for Hbα, Hbβ, Hbγ and Hbδ, are located on these chromosomes, and this also applies to their respective regulatory sequences. In this context, a total of six genes needs to be considered when discussing thalassemia, and distinct forms of this disease are defined accordingly:
All known mutations provoking thalassemia are inherited as an autosomal recessive trait.
Thalassemia is a rather common disease, and occurs in about 1 in 2,500 live births . Incidence rates are even higher among people of African, Asian or Middle Eastern decent, and in determined ethnicities, more than a third of the population carries thalassemia-related mutations  . Geographical differences regarding thalassemia incidence very clearly show how natural selection works: Thalassemia provides partial protection against malaria and thus confers an evolutionary advantage to carriers in subtropical and tropical regions, but the opposite is the case in areas without prevalence of this parasitic disease. In general, β-thalassemias predominate, but the ratio between prevalences of α- and β-thalassemia is higher in Africa and Southeast Asia than in other parts of Asia and the Middle East.
Despite thalassemia being a genetic disorder, symptom onset rarely occurs during the first year of life. This is due to an ongoing synthesis of fetal hemoglobin during infancy. In rare cases, production of fetal hemoglobin does not cease until the age of a few years, and this may mask even severe forms of thalassemia.
Females and males are affected equally.
Every hemoglobin molecule consists of four globin chains. In patients aged one year and older, about 97% of total hemoglobin correspond to hemoglobin A1, which is constituted of each two Hbα and Hbβ. The remaining 3% almost exclusively correspond to hemoglobin A2, and this form of hemoglobin is composed by each two Hbα and Hbδ. Other hemoglobin variants play important roles only during fetal and early postnatal development.
Moreover, each globin chain is associated with a heme group that, in turn, contains a ferrous ion. In pulmonary capillaries, iron-containing heme groups bind oxygen and carry it to all kinds of tissues. If this process is disturbed by either qualitative or quantitative alterations of hemoglobin synthesis, oxygen supply to dependent cells would be impaired. Patients suffering from thalassemia dispose of insufficient functional hemoglobin and thus present with hypochromic microcytic anemia.
In an attempt to compensate for a decreased synthesis of Hbα and Hbβ in α- and β-thalassemia, respectively, production of the other globin chain is stimulated in excess . Additionally, Hbγ and Hbδ synthesis may be altered. Such imbalances in globin chain composition provoke the formation of inclusion bodies in circulating erythrocytes, augment oxidative stress and predispose for hemolysis. Premature lysis of erythrocytes further contributes to anemia and shortage of oxygen supply.
If an individual disposes of functional copies of genes HBA1, HBA2 or HBB, the aforedescribed pathophysiological events occur to minor degrees and patients may either be completely asymptomatic or merely show hematological alterations without experiencing any symptoms. Such forms of thalassemia are typically classified as minor thalassemia. Other patients are diagnosed with thalassemia intermedia or major, but there is a smooth transition between all those types of hemoglobinopathy.
Thalassemia is a genetic disorder inherited with an autosomal recessive trait. Thus, patients with a family history of thalassemia may benefit from genetic counseling. Prenatal diagnosis of thalassemia and other hemoglobinopathies can be realized. Nowadays, non-invasive, early applicable methods are available to this end .
Thalassemia is a general term referring to different genetic disorders that are all associated with a disturbed hemoglobin synthesis.
A functional hemoglobin molecule consists of four polypeptide chains - generally, each two identical α and β chains (Hbα and Hbβ, respectively) - and four iron-containing heme groups. Only a minor share of human hemoglobin molecules contains γ or δ globin chains (Hbγ and Hbδ, respectively). Genes located on chromosomes 11 and 16 encode for all these globin chains, and mutations of those genes trigger hemoglobinopathies. Both coding sequences and regulatory elements can be affected by mutations and accordingly, two types of hemoglobinopathies are distinguished: Structural hemoglobinopathies, which are associated with dysfunctional hemoglobin due to coding sequence alterations; and thalassemia syndromes, characterized by an insufficient production of functional hemoglobin owing to defective regulation of globin synthesis .
As has been implied in the previous paragraph, there is no one gene defect that provokes thalassemia. In fact, several hundred mutations have been related with this disease so far, and while their respective incidence varies largely, it may be surprising to read about high prevalence rates of thalassemia in subtropical and tropical regions of almost all continents. This is due to the fact that carriers of thalassemia-associated mutations are partially protected from the most severe form of malaria, induced by infection with Plasmodium falciparum. More recent studies suggest that protection is not only conferred for malaria tropica, but also for uncomplicated forms of this disease .
Thalassemia is a type of hemoglobinopathy, i.e., a condition that affects the ability of hemoglobin and red blood cells to supply all tissues with oxygen. It is a genetic disorder inherited with an autosomal recessive trait. In simple terms, this means that a child will only develop thalassemia if they inherit a mutated gene from both parents.
Under physiological conditions, oxygen is bound to hemoglobin molecules in pulmonary capillaries. In thalassemia patients, however, the capacity for oxygen transport is significantly diminished, since reduced quantities of functional hemoglobin are synthesized. In detail, a hemoglobin molecule consists of distinct protein chains, mainly α and β chains, and thus, thalassemia may result from a disturbed synthesis of either type of chain. As soon as the precise pathomechanism is identified, a patient may be diagnosed with α- or β-thalassemia or less common forms of the disease.
The majority of people carrying gene variants associated with thalassemia do not experience any symptoms. In such cases, thalassemia might be suspected upon laboratory analyses of blood samples realized for any other reasons. More severe forms of thalassemia are characterized by anemia and premature death of red blood cells. These conditions provoke pallor or jaundice, fatigue, headaches and dizziness. Patients may have breathing difficulties under exercise. Anemic crises may be triggered by infection, folate deficiency or pregnancy, and are associated with an acute exacerbation of the aforementioned symptoms.
Mild forms of thalassemia don't require any treatment. Patients diagnosed with thalassemia of intermediate severity may suffer anemic crises and may need occasional transfusions of blood products. Severe thalassemia is a life-threatening disease and affected individuals need to adhere to a strict schedule of regular transfusions. Additionally, drugs may be prescribed to compensate for folate deficiency and possible secondary iron overload.