Alpha thalassaemia, also known as alpha thalassemia, is an inherited blood disorder that affects the body’s ability to produce enough haemoglobin, the protein in red blood cells that carries oxygen throughout the body. This condition can range from having no symptoms at all to causing severe health problems that begin before birth.

What is Alpha Thalassaemia

Alpha thalassaemia is a condition that runs in families, passed down from parents to their children through genes. It affects how the body makes haemoglobin, which is the oxygen-carrying protein found inside red blood cells. When haemoglobin levels are too low, the body’s tissues do not get enough oxygen, leading to a condition called anaemia, where there are not enough healthy red blood cells to do the job properly.^[1]

The condition gets its name from the alpha-globin protein chains that are part of haemoglobin. Normally, haemoglobin is made up of four protein chains: two alpha chains and two non-alpha chains. In alpha thalassaemia, the body produces less alpha-globin than it should, or sometimes none at all. This imbalance causes red blood cells to break down more easily and affects how new red blood cells are formed in the bone marrow.^[2]

Epidemiology

Alpha thalassaemia is a fairly common blood disorder around the world, though it affects certain populations more than others. Thousands of babies are born each year with various forms of alpha thalassaemia, particularly in Southeast Asia. The condition also occurs frequently among people whose ancestors came from Mediterranean countries, Africa, the Middle East, India, and Central Asia.^[1]

The geographical pattern of alpha thalassaemia is closely linked to areas where malaria has been or still is common. The gene changes that cause thalassaemia originally appeared in human populations as a form of partial protection against malaria. This means that having one or two altered genes actually provided a survival advantage in regions where malaria was widespread. As a result, thalassaemia is more common in populations with ancestral links to parts of the world where malaria is or was prevalent, including Africa, Southern Europe, and West, South, and East Asia.^[2]

Approximately five percent of the world’s population carries a globin variant, though only about 1.7 percent has alpha or beta thalassaemia trait. The condition affects men and women equally, occurring in approximately 4.4 of every 10,000 live births. Among certain ethnic groups, the thalassaemia trait can affect anywhere from five to 30 percent of the population.^[12]

Causes

Alpha thalassaemia is almost always an inherited condition, meaning it is passed from biological parents to their children. It is considered a recessive trait, which means that having just one defective gene is usually not enough to cause serious illness. The condition involves changes or deletions in the genes that control the production of alpha-globin protein.^[3]

Every person normally has four alpha-globin genes, two inherited from their mother and two from their father. These genes, called HBA1 and HBA2, provide the instructions for making alpha-globin protein. Alpha thalassaemia typically results from deletions involving these genes. Less commonly, changes to the DNA sequence in or near these genes cause the condition. These changes are often referred to as nondeletion variants, and they tend to be more severe than simple deletions.^[1]

There are approximately 130 known mutations that can cause alpha thalassaemia. When one or more of these genes are defective or missing, the body cannot produce enough alpha-globin. This shortage means that cells make little or no normal haemoglobin. Instead, cells may produce abnormal forms of haemoglobin called haemoglobin Bart or haemoglobin H, which cannot effectively carry oxygen to the body’s tissues.^[1]

The severity of alpha thalassaemia depends on how many of the four alpha-globin genes are affected. If only one gene is defective or missing, the person is called a silent carrier and usually has no symptoms. When two genes are affected, the person has alpha thalassaemia trait or minor. Three defective genes result in haemoglobin H disease, which causes moderate to severe symptoms. When all four genes are defective or missing, it results in the most severe form, called alpha thalassaemia major or haemoglobin Bart hydrops fetalis syndrome.^[2]

Risk Factors

The primary risk factor for developing alpha thalassaemia is family history and ethnic background. Because this is an inherited condition, having parents who carry the altered genes significantly increases the risk. People whose ancestry traces to Asia, the Pacific Islands, the Mediterranean region, the Middle East, or Africa are at higher risk for thalassaemia.^[13]

Alpha thalassaemia major occurs only when both parents carry two non-functioning alpha-globin genes. In such cases, each pregnancy has a one in four, or 25 percent, chance that the baby will inherit both sets of non-functioning genes and develop this severe form of the condition. Preliminary screening of parents can be performed with a simple blood test called a complete blood count. If this test shows reduced mean corpuscular volume and the person is not anaemic due to iron deficiency, then specific testing for hereditary anaemias including alpha thalassaemia should be performed.^[13]

Individuals with one or two non-functioning genes are usually asymptomatic but can pass these genes to their children. This carrier status is common in populations from areas where malaria is or was endemic. Having alpha thalassaemia trait does not make a person sick, but it is important to know about it when planning to have children, especially if a partner might also carry the trait.^[6]

Symptoms

The symptoms of alpha thalassaemia vary greatly depending on how many alpha-globin genes are affected. People who are silent carriers, with only one defective gene, do not experience any symptoms at all. Similarly, those with alpha thalassaemia trait, where two genes are affected, may have very mild anaemia but often no noticeable symptoms. These individuals typically do not require any medical treatment.^[4]

When three alpha-globin genes are defective or missing, a condition called haemoglobin H disease develops. People with haemoglobin H disease experience moderate to severe anaemia. Symptoms can include extreme tiredness, pale skin, shortness of breath, a fast heartbeat, yellowing of the skin and eyes (jaundice), moodiness or irritability, and slow growth in children. Some people with this condition may also develop an enlarged spleen, which can cause discomfort or a feeling of fullness in the abdomen. Most children with haemoglobin H disease do not show symptoms when they are born, but signs appear during early childhood.^[4]

The most severe form, alpha thalassaemia major or haemoglobin Bart hydrops fetalis syndrome, causes serious problems even before birth. This condition is characterized by hydrops fetalis, where excess fluid builds up in the baby’s body before birth. Additional signs include severe anaemia, an enlarged liver and spleen, heart defects, and abnormalities of the urinary system or genitalia. Without treatment, most babies with this condition are stillborn or die soon after birth. This severe form can also cause dangerous complications for the mother during pregnancy, including dangerously high blood pressure with swelling (pre-eclampsia), premature delivery, and abnormal bleeding.^[1]

People with haemoglobin H disease or alpha thalassaemia major may also experience complications from iron buildup in the body, either from the disease itself or from frequent blood transfusions. This extra iron can damage important organs like the heart, liver, and endocrine system (the glands that produce hormones). Other serious health problems can include bone deformities from changes in the bone marrow, gallstones, and increased risk of infections, especially if the spleen has been removed.^[4]

Prevention

Because alpha thalassaemia is an inherited genetic condition, it cannot be prevented in the traditional sense. However, there are important steps that individuals and families can take to understand their risk and make informed decisions. Genetic counselling before conception is crucial for people who are at risk of having a child with thalassaemia. This counselling can help prospective parents understand whether they carry the genes for thalassaemia and what that means for their future children.^[3]

Preliminary screening involves a simple blood test called a complete blood count. If this test shows smaller and fewer red blood cells, and the person is not anaemic because of iron deficiency, then specific testing for thalassaemia should be performed. This can include haemoglobin typing and alpha-globin gene mutation analysis. For couples where both partners are found to carry two non-functioning genes, prenatal testing options such as chorionic villus sampling or amniocentesis can diagnose whether a developing baby has alpha thalassaemia major.^[13]

Genetic counselling can also discuss options such as using donor sperm or eggs, or undergoing in vitro fertilization with genetic testing of embryos before implantation. These approaches allow families to make informed choices about reproduction based on their values and circumstances.^[3]

For people already diagnosed with alpha thalassaemia, prevention focuses on avoiding complications. Keeping up-to-date with vaccinations is especially important, as people with thalassaemia are at higher risk for certain infections. This is particularly true for those who have had their spleen removed. Maintaining a healthy lifestyle with proper nutrition and regular exercise can also help prevent some complications. People with thalassaemia should discuss with their doctor whether they need to limit iron-rich foods in their diet, as too much iron can build up in the blood.^[14]

Pathophysiology

Understanding how alpha thalassaemia affects the body requires looking at how normal haemoglobin works. Haemoglobin consists of four protein chains: two alpha-globin chains and two non-alpha chains (either beta, gamma, or delta). These chains work together with an iron-containing molecule to carry oxygen from the lungs to tissues throughout the body. The type of haemoglobin depends on which chains are present. Babies primarily have fetal haemoglobin with gamma chains, but by around six months of age, they transition to adult haemoglobin with beta chains.^[12]

In alpha thalassaemia, the body produces reduced or absent amounts of alpha-globin chains due to defects in the HBA1 and HBA2 genes. Each person normally has four copies of these genes (two HBA1 and two HBA2), with two copies inherited from each parent. When one or more of these genes is deleted or altered, alpha-globin production decreases. The severity of the condition depends on how many genes are affected and whether the changes are deletions or nondeletion variants, with nondeletion variants generally being more severe.^[1]

When alpha-globin is deficient, the body cannot make enough normal haemoglobin. This shortage has two main effects. First, without enough haemoglobin, red blood cells cannot carry adequate oxygen to the body’s tissues, causing anaemia. Second, the excess beta-globin chains that are produced but cannot pair with alpha-globin become unstable. These unpaired chains form abnormal haemoglobin molecules such as haemoglobin Bart (found in newborns) or haemoglobin H (found in older children and adults). These abnormal haemoglobins are not only poor at carrying oxygen but also damage red blood cells, causing them to break down prematurely in a process called haemolysis.^[3]

The destruction of red blood cells has several consequences. The bone marrow tries to compensate by producing more red blood cells, working overtime to keep up with the loss. This increased activity in the bone marrow can lead to changes in bone structure, particularly in the face and skull. The breakdown of red blood cells also releases iron, which can accumulate in organs like the heart, liver, and endocrine glands, potentially causing damage over time. Additionally, the spleen, which filters damaged blood cells, often becomes enlarged as it works harder to remove the abnormal cells.^[12]

In the most severe form, alpha thalassaemia major, all four alpha-globin genes are absent or non-functional. This means no normal alpha-globin is produced at all. Without any functional alpha-globin, the developing fetus cannot make enough haemoglobin to support growth and development. Severe anaemia develops, and the fetus’s heart must work extremely hard to pump what little oxygenated blood is available. This strain can lead to heart failure, causing fluid to accumulate throughout the body in a condition called hydrops fetalis. The lack of oxygen also prevents normal organ development, leading to multiple serious complications.^[1]