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Alpha-thalassemia ( α-thalassemia, α-thalassaemia) is an inherited blood disorder and a form of thalassemia. Thalassemias are a group of Genetic disorder Blood diseases which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Symptoms depend on the extent to which hemoglobin is deficient, and include anemia, pallor, Fatigue, Splenomegaly, iron overload, abnormal bone structure, jaundice, and Gallstone. In severe cases death ensues, often in infancy, or death of the unborn fetus.
The disease is characterised by reduced production of the alpha-globin component of hemoglobin, caused by Genetic disorder mutations affecting the genes HBA1 and HBA2. This causes reduced levels of hemoglobin leading to anemia, while the accumulation of surplus beta-globin, the other structural component of hemoglobin, damages red blood cells and shortens their life. Diagnosis is by checking the medical history of near relatives, microscopic examination of blood smear, ferritin test, hemoglobin electrophoresis, and DNA sequencing.
As an inherited condition, alpha thalassemia cannot be prevented although genetic counselling of parents prior to Fertilisation can propose the use of Sperm donation or Egg donation. The principle form of management is blood transfusion every 3 to 4 weeks, which relieves the anemia but leads to iron overload and possible Immune response. Medication includes folate supplementation, iron chelation, Bisphosphonate, and Splenectomy. Alpha thalassemia can also be treated by bone marrow transplant from a well matched donor.
Thalassemias were first identified in severely sick children in 1925, with identification of alpha and beta subtypes in 1965. Alpha thalassemia has its greatest prevalence in populations originating from Southeast Asia, Mediterranean countries, Africa, the Middle East, India, and Central Asia. Having a mild form of alpha thalassemia has been demonstrated to protect against malaria and thus can be an advantage in malaria endemic areas.
Normal individuals carry 4 alpha-globin genes, comprising Autosome pairs of the HBA1 and HBA2 genes. There are approximately 130 known mutations which can cause alpha thalassemia, mainly comprising deletion of part or all of a gene which then fails to produce alpha globin. If either one gene or two out of the four is faulty, the remaining genes produce sufficient alpha globin for normal life. If three genes are faulty, the sole functioning gene produces relatively small quantities of alpha globin, causing anemia and HbH disease. Four faulty genes (and therefore zero alpha globin) is incompatible with life.
In rare cases alpha thalassemia can be acquired as a consequence of myelodysplastic cancer.
Full alpha thalassemia with all four genes failing to synthesise alpha-globin, is generally fatal to the unborn child. The absence of alpha globin means that zero functional hemoglobin is produced during gestation. Unmatched gamma globin chains cluster to form Hemoglobin Barts, which is ineffective at transporting oxygen. In this situation, a fetus will develop hydrops fetalis, a form of edema, which can be detected on prenatal ultrasound. The child will normally die before or shortly after birth, unless intrauterine blood transfusion is performed. Less severe alpha thalassemia may affect growth and development.
If thalassemia is untreated or undetected in the infant, this can lead to developmental issues such as slowed growth, delayed puberty, bone abnormalities, and intellectual impairment.
More generally, impaired production of hemoglobin causes anemia, resulting in tiredness and a general lack of energy, shortness of breath, rapid or irregular heartbeat, dizziness, pale skin, yellowing of the skin and eyes (jaundice).
In thalassemia, ineffective erythropoiesis causes the bone marrow to expand. This expansion is a compensatory response to the damage caused to red blood cells by the imbalanced production of globin chains. Bone marrow expansion can lead to abnormal bone structure, particularly in the skull and face. Expansion of the bone marrow in the developing child leads to a distinctive facial shape often referred to as "Chipmunk facies". Other skeletal changes include osteoporosis, growth retardation, and Kyphosis.
People with thalassemia can get Iron overload in their bodies, either from the disease itself as RBCs are destroyed, or as a consequence of frequent blood transfusions. Excess iron is not excreted, but forms toxic non-transferrin-bound iron. This can lead to organ damage, potentially affecting the heart, liver, endocrine system, bones and spleen. Symptoms include an irregular heartbeat, cardiomyopathy, cirrhosis of the liver, hypothyroidism, delayed puberty and fertility problems, brittle and deformed bones, and an enlarged spleen.
The spleen is the organ which removes damaged red blood cells from circulation; in thalassemia patients it is abnormally active, causing it to Splenomegaly and possibly become hyperactive, a condition called Splenomegaly.
The immune system can become compromised in a number of ways; anemia, iron overload, and hypersplenism may affect the immune response and increase the risk of severe infection.
The prognosis when all four genes are affected, leading to Hb Bart's hydrops fetalis, is very poor, with most affected fetuses dying or shortly after birth due to severe fetal hypoxia. It can be treated with intrauterine transfusions, however survival remains low and the infant requires lifelong blood transfusions. As of 2017, 69 patients were known who have survived past infancy.
For those with severe forms of thalassemia (thalassemia major, or transfusion-dependent thalassemia), the three principal treatments are red blood cell transfusions to relieve anemia, iron chelation to mitigate the side effects of transfusion, and folic acid supplementation to encourage the growth of new blood cells. Other forms of treatment available depending on individual circumstances.
The first HSC transplant for thalassemia was carried out in 1981 on a patient with beta thalassemia major. Since then, a number of patients have received bone marrow transplants from healthy matched donors, although this procedure has a high level of risk.
In 2018 an unborn child with hydrops fetalis, a potentially fatal complication of alpha thalassemia, was successfully transfused with her mother's stem cells.
HSCT is a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. Risks associated with HSCT can include graft-versus host disease, failure of the graft, and other toxicity related to the transplant. In one study of 31 people, the procedure was successful for 22 whose hemoglobin levels improved to the normal range, in seven the graft failed and they continued to live with thalassemia, and two died of transplantation-related causes.
Alpha thalassemia genes have a high prevalence in populations originating in sub-Saharan Africa, Mediterranean, Middle East, and Southeast Asia and east Asia; all areas which historically have been malaria endemic. The prevalence of these genes has increased in previously non-endemic areas as a consequence of migration flows, slave-trade, and colonization.
A number of mechanisms have been proposed to explain the increased chance of survival for the carrier of an abnormal hemoglobin trait.
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