Introduction
Hemoglobin is a specialized protein present in red blood cells that transport large quantities of oxygen in the blood. Alpha thalassemia is an inherited (passed on from parents to their children by genes) disorder where there is defective production of hemoglobin (Hb). Red blood cells (RBCs) with abnormal hemoglobin do not function properly. Their oxygen-carrying capacity is reduced, and also these RBCs last for only a shorter lifespan. This leads to anemia with various degrees of severity in affected individuals. Alpha thalassemia is common in communities of Southeast Asian, African, Southern Chinese, Middle Eastern, and Mediterranean origin.
What Is Alpha Thalassemia?
Adult hemoglobin (HbA) is made up of two alpha and two beta chains. Abnormalities in the rate of production of alpha polypeptide chains are termed alpha thalassemia. Two copies of genes that code for hemoglobin alpha chain (HBA1 and HBA2) are located on chromosome 16, where each encodes for one alpha chain. These syndromes are caused due to gene deletions (removal of genetic information) that carry the code for alpha chain synthesis. Depending on the number of missing genes, their clinical manifestations vary from asymptomatic carriers to severe anemic conditions.
What Are the Risk Factors for Alpha Thalassemia?
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Genetic inheritance is a risk factor.
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Family history of occurrence of symptoms.
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Ethnic groups (Mediterranean belt).
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Consanguineous marriages within affected family members.
What Are the Types of Alpha Thalassemia?
There are four types of alpha thalassemia depending on the number of missing genes that code for alpha chain synthesis.
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Alpha Thalassemia Major - It is also known as hemoglobin Bart (Hb Bart) syndrome or hydrops fetalis, where all the four genes coding for the alpha chain are missing. It is the most severe form, and death occurs in utero or neonatal stage.
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Hemoglobin H Disease (HbH) - In this condition, only one gene is working, and the other three globin genes are missing. It has a broad spectrum of phenotype characteristics ranging from moderate to severe anemia.
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Alpha Thalassemia Trait - Here, two genes are missing; one alpha gene in each chromosome, known as trans variant, or two genes in the same chromosome, called cis variant. Though these individuals show mild anemia, they have a higher chance of getting children with Hb Bart syndrome.
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Alpha Thalassemia Minor (Silent Carrier) - Only one gene is missing. These individuals are asymptomatic and have a 25% chance of passing on the defective gene to their offspring.
What Are the Signs and Symptoms of Alpha Thalassemia?
Due to multiple combinations and expressions of genotypes, the clinical manifestations of the disorder vary among different people. The severity of the disease is dependent on the type of alpha thalassemia inherited. Common symptoms for each type may include:
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Alpha Thalassemia Minor (Silent Carrier) - These individuals are asymptomatic.
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Alpha Thalassemia Trait - Individuals do not show signs of health problems. Some of them have mild anemia. They show mild symptoms such as fatigue and exercise intolerance.
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Hemoglobin H Disease - This type shows moderate to severe symptoms. HbH individuals are asymptomatic in early childhood and are only diagnosed during normal hematological screening tests. Enlargement of the spleen (due to destruction of defective RBCs), yellowish discoloration of the skin, mild jaundice, leg ulcers, and bone changes are common clinical features in such individuals. They experience recurrent hemolytic episodes during infections and acquire gallstones. They have a high risk of having an alpha thalassemia major child with severe complications.
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Alpha Thalassemia Major (Hb Bart) - The survival rate of babies born with this disorder is very minimal, and they die before the time of birth. Symptoms in surviving neonates include the prenatal occurrence of generalized edema, pleural or pericardial effusions due to congestive heart failure, and severe anemia. The presence of extramedullary erythropoiesis, hepatosplenomegaly, and swollen placenta are common clinical manifestations.
How Is Alpha Thalassemia Detected?
The diagnosis of alpha thalassemia is established by initial screening hematologic and hemoglobin (Hb) tests followed by molecular genetic testing along with tracing of the index case (asserting the presence of genetic disorder from family members).
Hematological Screening Tests
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Red Blood Cell Count (RBC) - It detects the total number of red blood cells in a unit of blood volume. RBC count is decreased in moderate to severe anemic conditions.
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Hematocrit Findings - Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) are deceased due to defective hemoglobin and RBCs.
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Peripheral Blood Smear - It shows microcytic (smaller size) and hypochromic (reduced color) red blood cells.
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Hemoglobin Electrophoresis - It is done to separate globin chains and study the defects.
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FEP (Free-Erythrocyte Protoporphyrin) And Serum Ferritin Levels - It is done to differentiate alpha thalassemia from iron deficiency anemia. Iron levels remain normal in alpha thalassemia.
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In Pregnancy - Chorionic villus sampling or amniocentesis (amniotic fluid from the fetus) is tested to detect alpha thalassemia.
Molecular Genetic Testing
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A DNA test is done to diagnose the presence of alpha thalassemia.
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Proband - Assertion from the affected individual belonging to the family where genetic disorder is detected through genetic counseling.
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Molecular Genotyping - It is done to detect alpha thalassemia variants.
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DNA sequencing of the gene to detect the missing genetic information.
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Amplification (hybridization methods like qPCR (quantitative polymerized chain reaction) and comparative genomic hybridization (CGH) to identify the copy number of variants with one or more genes.
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Genome sequencing is done to study the expression of defective genes.
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These molecular techniques help to identify the carrier, heterozygous or homozygous state of the affected individuals and their status of passing on the defective gene to their children.
How to Manage Alpha Thalassemia?
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Symptomatic Treatment - Intrauterine blood transfusions for neonates with Hb Bart syndrome and hematopoietic stem cell transplant for the survival of the babies. In the case of HbH disease, red cell transfusions are needed during hemolytic episodes and associated cardiac dysfunction.
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Preventive Measures - Genetic counseling, prenatal testing, and early termination of pregnancies that are at greater risk should be taken into consideration. Recent technological advances in intrauterine and postnatal therapy have provided enormous treatment options to minimize ethical issues for both healthcare providers as well as families with affected pregnancies.
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Preventing Secondary Complications - Monitoring hemolytic episodes and creating awareness in individuals with HbH disease who are in need of chronic red blood cell transfusions. Iron supplementation is not needed in such cases and would lead to iron toxicity.
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Surveillance of Individuals With Severe Clinical Symptoms - Hematologic evaluation for every 6 to 12 months in HbH disease. Growth assessment and development monitoring in children with alpha thalassemia trait for every 6 to 12 months.
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Evaluation of Risk Among Family Members - Testing of the siblings of proband when suspicion arises.
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Management During Pregnancy - Anticipating and monitoring complications in pregnant alpha thalassemic women, such as worsening anemic condition, preeclampsia (increased blood pressure during delivery), congestive cardiac failure, and miscarriage, is highly valuable.
How Does Genetic Counseling Benefit Alpha Thalassemic Individuals?
Alpha thalassemia is inherited in an autosomal recessive gene pattern.
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Knowledge and awareness with professional counseling about alpha thalassemia running through the family would greatly reduce its complications.
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Family members with alpha thalassemia and individuals from ethnic groups where alpha thalassemia is common should consult a genetic counselor to analyze the risk of passing thalassemia to their children.
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Carrier testing should be done on family members, members belonging to susceptible ethnic groups, and gamete donors.
Conclusion
Alpha thalassemia is a blood disorder acquired through genetic inheritance. There are four types of alpha thalassemia depending on the genes missing. People who possess these genes have an increased risk of passing them on to their children. Though not completely curable, recent advances in molecular detection and therapeutics are immensely helpful in the efficient management of the symptoms. Awareness among family members and genetic counseling would effectively prevent the inheritance of alpha thalassemia.
