Alpha thalassemia is a blood disorder that reduces the production of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen to cells throughout the body.

In people with the characteristic features of alpha thalassemia, a reduction in the amount of hemoglobin prevents enough oxygen from reaching the body's tissues. Affected individuals also have a shortage of red blood cells (anemia), which can cause pale skin, weakness, fatigue, and more serious complications.

Two types of alpha thalassemia can cause health problems. The more severe type is known as hemoglobin Bart hydrops fetalis syndrome, which is also called Hb Bart syndrome or alpha thalassemia major. The milder form is called HbH disease.

Hb Bart syndrome is characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Additional signs and symptoms can include severe anemia, an enlarged liver and spleen (hepatosplenomegaly), heart defects, and abnormalities of the urinary system or genitalia. Without treatment, most babies with this condition are stillborn or die soon after birth because of these serious health problems. Hb Bart syndrome can also cause serious complications for women during pregnancy, including dangerously high blood pressure with swelling (preeclampsia), premature delivery, and abnormal bleeding.

HbH disease causes mild to moderate anemia, hepatosplenomegaly, and yellowing of the eyes and skin (jaundice). The features of HbH disease usually appear in early childhood, and affected individuals typically live into adulthood.

Thalassemia is an inherited (i.e., passed from parents to children through genes) blood disorder caused when the body doesn’t make enough of a protein called hemoglobin, an important part of red blood cells. When there isn’t enough hemoglobin, the body’s red blood cells don’t function properly and they last shorter periods of time, so there are fewer healthy red blood cells traveling in the bloodstream.

Red blood cells carry oxygen to all the cells of the body. Oxygen is a sort of food that cells use to function. When there are not enough healthy red blood cells, there is also not enough oxygen delivered to all the other cells of the body, which may cause a person to feel tired, weak or short of breath. This is a condition called anemia. People with thalassemia may have mild or severe anemia. Severe anemia can damage organs and lead to death.

What are the different types of thalassemia?

When we talk about different “types” of thalassemia, we might be talking about one of two things: the specific part of hemoglobin that is affected (usually either “alpha” or “beta”), or the severity of thalassemia, which is noted by words like trait, carrier, intermedia, or major.

Hemoglobin, which carries oxygen to all cells in the body, is made of two different parts, called alpha and beta. When thalassemia is called “alpha” or “beta,” this refers to the part of hemoglobin that isn’t being made. If either the alpha or beta part is not made, there aren’t enough building blocks to make normal amounts of hemoglobin. Low alpha is called alpha thalassemia. Low beta is called beta thalassemia.

When the words “trait,” “minor,” “intermedia,” or “major” are used, these words describe how severe the thalassemia is. A person who has thalassemia trait may not have any symptoms at all or may have only mild anemia, while a person with thalassemia major may have severe symptoms and may need regular blood transfusions.

In the same way that traits for hair color and body structure are passed down from parents to children, thalassemia traits are passed from parents to children. The type of thalassemia that a person has depends on how many and what type of traits for thalassemia a person has inherited, or received from their parents. For instance, if a person receives a beta thalassemia trait from his father and another from his mother, he will have beta thalassemia major. If a person received an alpha thalassemia trait from her mother and the normal alpha parts from her father, she would have alpha thalassemia trait (also called alpha thalassemia minor). Having a thalassemia trait means that you may not have any symptoms, but you might pass that trait on to your children and increase their risk for having thalassemia.

Sometimes, thalassemias have other names, like Constant Spring, Cooley’s Anemia, or hemoglobin Bart hydrops fetalis. These names are specific to certain thalassemias – for instance, Cooley’s Anemia is the same thing as beta thalassemia major.

How do I know if I have thalassemia?

People with moderate and severe forms of thalassemia usually find out about their condition in childhood, since they have symptoms of severe anemia early in life. People with less severe forms of thalassemia may only find out because they are having symptoms of anemia, or maybe because a doctor finds anemia on a routine blood test or a test done for another reason.

Because thalassemias are inherited, the condition sometimes runs in families. Some people find out about their thalassemia because they have relatives with a similar condition.

People who have family members from certain parts of the world have a higher risk for having thalassemia. Traits for thalassemia are more common in people from Mediterranean countries, like Greece and Turkey, and in people from Asia, Africa, and the Middle East. If you have anemia and you also have family members from these areas, your doctor might test your blood further to find out if you have thalassemia.

Can I prevent thalassemia?

Because thalassemia is passed from parents to children, it is very hard to prevent. However, if you or your partner knows of family members with thalassemia, or if you both have family members from places in the world where thalassemia is common, you can speak to a genetic counselor (go to: https://www.nsgc.org/page/find-a-genetic-counselor) to determine what your risk would be of passing thalassemia to your children.

Alpha thalassemia typically results from deletions involving the HBA1 and HBA2 genes. Less commonly, changes to the DNA sequence in or near these genes cause alpha thalassemia. Such changes are often referred to as nondeletion variants. Both the HBA1 and HBA2 genes provide instructions for making a protein called alpha-globin, which is a component (subunit) of hemoglobin.

People have two copies of the HBA1 gene and two copies of the HBA2 gene in each cell. Each copy is called an allele. For each gene, one allele is inherited from a person's father, and the other is inherited from a person's mother. As a result, there are four alleles that produce alpha-globin. The different types of alpha thalassemia result from the loss or alteration of some or all of these alleles.

Deletions and nondeletion variants in one or more alleles reduce the amount of alpha-globin cells produce. Nondeletion variants tend to reduce alpha-globin more than deletions.

Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. Such changes prevent the production of any normal alpha-globin.

HbH disease is usually caused by loss or alteration of three of the four alpha-globin alleles, which sharply reduces the amount of normal alpha-globin produced. Because nondeletion variants are usually more severe than deletions, nondeletion variants in two of the four alpha-globin alleles can result in HbH disease.

With a shortage of alpha-globin, cells make little or no normal hemoglobin. Instead, cells produce abnormal forms of hemoglobin called hemoglobin Bart (Hb Bart) or hemoglobin H (HbH). These abnormal hemoglobin molecules cannot effectively carry oxygen to the body's tissues. The substitution of Hb Bart or HbH for normal hemoglobin causes anemia and the other serious health problems associated with alpha thalassemia.

Two additional forms of alpha thalassemia are related to a reduced amount of alpha-globin. Because cells still produce some normal hemoglobin, these forms tend to cause few or no health problems. A loss of two of the four alpha-globin alleles results in alpha thalassemia trait. People with alpha thalassemia trait may have unusually small, pale red blood cells and mild anemia. A loss of one alpha-globin allele is found in alpha thalassemia silent carriers. These individuals typically have no thalassemia-related signs or symptoms.

Nondeletion variants in one or two alleles cause a range of conditions, from alpha thalassemia silent carrier to HbH disease, depending on the allele involved.

Normal Function

The HBA1 gene provides instructions for making a protein called alpha-globin. This protein is also produced from a nearly identical gene called HBA2. These two alpha-globin genes are located close together in a region of chromosome 16 known as the alpha-globin locus.

Alpha-globin is a component (subunit) of a larger protein called hemoglobin, which is the protein in red blood cells that carries oxygen to cells and tissues throughout the body. Hemoglobin is made up of four subunits: two subunits of alpha-globin and two subunits of another type of globin. Alpha-globin is a component of both fetal hemoglobin, which is active only before birth and in the newborn period, and adult hemoglobin, which is active throughout the rest of life.

Each of the four protein subunits of hemoglobin carries an iron-containing molecule called heme. Heme molecules are necessary for red blood cells to pick up oxygen in the lungs and deliver it to the body's tissues. A complete hemoglobin protein is capable of carrying four oxygen molecules at a time (one attached to each heme molecule). Oxygen attached to hemoglobin gives blood its bright red color.

Health Conditions Related to Genetic Changes

Alpha thalassemia

Deletions of the HBA1 and/or HBA2 genes are the most common cause of alpha thalassemia. Less commonly, variants (also known as mutations) in or near these genes cause the condition. The signs and symptoms of alpha thalassemia tend to be more severe when the disease results from variants in the alpha-globin genes than when it is caused by deletions of these genes.

People have two copies of the HBA1 gene and two copies of the HBA2 gene in each cell. Each copy is called an allele. For each gene, one allele is inherited from a person's father, and the other is inherited from a person's mother. As a result, there are four alleles that produce alpha-globin. The different types of alpha thalassemia result from the loss or alteration of some or all of these alleles.

Deletions and variants affecting one or more alleles reduce the amount of alpha-globin cells produce. Variants tend to reduce alpha-globin more than deletions.

Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. This condition is characterized by a buildup of excess fluid in the body before birth (hydrops fetalis), a shortage of red blood cells (anemia), and an enlarged liver and spleen (hepatosplenomegaly).

HbH disease, which is milder, is usually caused by loss of three of the four alpha-globin alleles. Because genetic variants affecting HBA1 or HBA2 can be more severe than deletions, variants in two of the four alpha-globin alleles can result in HbH disease. HbH disease is characterized by mild to moderate anemia, hepatosplenomegaly, and yellowing of the eyes and skin (jaundice).

In Hb Bart syndrome and HbH disease, a shortage of alpha-globin hinders the production of normal hemoglobin. Instead, cells produce abnormal forms of hemoglobin called hemoglobin Bart (Hb Bart) or hemoglobin H (HbH). These abnormal hemoglobin molecules cannot effectively carry oxygen to the body's tissues. The substitution of Hb Bart or HbH for normal hemoglobin causes anemia and the other serious health problems associated with alpha thalassemia.

Two additional forms of alpha thalassemia are related to a reduced amount of alpha-globin. Because cells still produce some normal hemoglobin, these forms tend to cause few or no health problems. A loss of two of the four alpha-globin alleles results in alpha thalassemia trait. People with alpha thalassemia trait may have unusually small, pale red blood cells and mild anemia. A loss of one alpha-globin allele is found in alpha thalassemia silent carriers. These individuals typically have no thalassemia-related signs or symptoms.

Variants in one or two alpha-globin alleles cause a range of conditions, from alpha thalassemia silent carrier to HbH disease, depending on the alleles involved.

Other disorders

A condition called alpha-thalassemia-intellectual disability syndrome, chromosome 16-related (ATR-16) results from a large deletion of genetic material from the short (p) arm of chromosome 16. The signs and symptoms of this condition result from the loss of many genes, including HBA1 and HBA2.

A deletion of the HBA1 and HBA2 genes leads to alpha thalassemia trait in most people with ATR-16. The loss of other genes causes additional features of the disorder, including intellectual disability, severely delayed language skills, an unusually small head size (microcephaly), and distinctive facial features. Affected males may also have undescended testes (cryptorchidism) and the urethra opening on the underside of the penis (hypospadias).

The signs and symptoms of ATR-16 vary depending on the size of the deletion. A particularly large deletion may include the PKD1 gene, which is responsible for polycystic kidney disease. A loss of this gene leads to the growth of multiple cysts in the kidneys. If the deletion also includes the TSC2 gene, an affected individual will develop tuberous sclerosis complex. This condition is characterized by the growth of noncancerous tumors in many parts of the body.

Other Names for This Gene

• alpha 1 globin
• alpha one globin
• alpha-1 globin
• alpha-1-globin
• CD31
• HBA-T3
• HBA_HUMAN
• hemoglobin alpha 1 globin chain
• hemoglobin alpha-1 chain
• hemoglobin, alpha 1
• MGC126895
• MGC126897

Genomic Location

Normal Function

The HBA2 gene provides instructions for making a protein called alpha-globin. This protein is also produced from a nearly identical gene called HBA1. These two alpha-globin genes are located close together in a region of chromosome 16 known as the alpha-globin locus.

Alpha-globin is a component (subunit) of a larger protein called hemoglobin, which is the protein in red blood cells that carries oxygen to cells and tissues throughout the body. Hemoglobin is made up of four subunits: two subunits of alpha-globin and two subunits of another type of globin. Alpha-globin is a component of both fetal hemoglobin, which is active only before birth and in the newborn period, and adult hemoglobin, which is active throughout the rest of life.

Each of the four protein subunits of hemoglobin carries an iron-containing molecule called heme. Heme molecules are necessary for red blood cells to pick up oxygen in the lungs and deliver it to the body's tissues. A complete hemoglobin protein is capable of carrying four oxygen molecules at a time (one attached to each heme molecule). Oxygen attached to hemoglobin gives blood its bright red color.

Health Conditions Related to Genetic Changes

Alpha thalassemia

Deletions of the HBA1 and/or HBA2 genes are the most common cause of alpha thalassemia. Less commonly, variants (also called mutations) in or near these genes cause the condition. The signs and symptoms of alpha thalassemia tend to be more severe when the disease results from variants in the alpha-globin genes than when it is caused by deletions of these genes.

People have two copies of the HBA1 gene and two copies of the HBA2 gene in each cell. Each copy is called an allele. For each gene, one allele is inherited from a person's father, and the other is inherited from a person's mother. As a result, there are four alleles that produce alpha-globin. The different types of alpha thalassemia result from the loss of some or all of these alleles.

Deletions and variants affecting one or more alleles reduce the amount of alpha-globin cells produce. Variants tend to reduce alpha-globin more than deletions.

Hb Bart syndrome, the most severe form of alpha thalassemia, results from the loss or alteration of all four alpha-globin alleles. This condition is characterized by a buildup of excess fluid in the body before birth (hydrops fetalis), a shortage of red blood cells (anemia), and an enlarged liver and spleen (hepatosplenomegaly).

HbH disease, which is milder, is usually caused by a loss of three of the four alpha-globin alleles. Because variants affecting HBA1 or HBA2 can be more severe than deletions, variants in two of the four alpha-globin alleles can result in HbH disease. HbH disease is characterized by mild to moderate anemia, hepatosplenomegaly, and yellowing of the eyes and skin (jaundice).

In Hb Bart syndrome and HbH disease, a shortage of alpha-globin hinders the production of normal hemoglobin. Instead, cells produce abnormal forms of hemoglobin called hemoglobin Bart (Hb Bart) or hemoglobin H (HbH). These abnormal hemoglobin molecules cannot effectively carry oxygen to the body's tissues. The substitution of Hb Bart or HbH for normal hemoglobin causes anemia and the other serious health problems associated with alpha thalassemia.

Two additional forms of alpha thalassemia are related to a reduced amount of alpha-globin. Because cells still produce some normal hemoglobin, these forms tend to cause few or no health problems. A loss of two of the four alpha-globin alleles results in alpha thalassemia trait. People with alpha thalassemia trait may have unusually small, pale red blood cells and mild anemia. A loss of one alpha-globin allele is found in alpha thalassemia silent carriers. These individuals typically have no thalassemia-related signs or symptoms.

Variants in one or two alpha-globin alleles cause a range of conditions, from alpha thalassemia silent carrier to HbH disease, depending on the alleles involved.

Other disorders

A condition called alpha-thalassemia-intellectual disability syndrome, chromosome 16-related (ATR-16) results from a large deletion of genetic material from the short (p) arm of chromosome 16. The signs and symptoms of this condition result from the loss of many genes, including HBA1 and HBA2.

A deletion of the HBA1 and HBA2 genes leads to alpha thalassemia trait in most people with ATR-16. The loss of other genes causes additional features of the disorder, including intellectual disability, severely delayed language skills, an unusually small head size (microcephaly), and distinctive facial features. Affected males may also have undescended testes (cryptorchidism) and the urethra opening on the underside of the penis (hypospadias).

The signs and symptoms of ATR-16 vary depending on the size of the deletion. A particularly large deletion may include the PKD1 gene, which is responsible for polycystic kidney disease. A loss of this gene leads to the growth of multiple cysts in the kidneys. If the deletion also includes the TSC2 gene, an affected individual will develop tuberous sclerosis complex. This condition is characterized by the growth of noncancerous tumors in many parts of the body.

Other Names for This Gene

• alpha 2 globin
• alpha globin
• alpha-2 globin
• alpha-globin locus, second
• HBA-T2
• HBA_HUMAN
• hemoglobin, alpha 2
• hemoglobin-alpha locus 2
• major alpha-globin locus

Genomic Location

Alpha thalassemia is a genetic condition. Babies inherit it from their biological (birth) parents.

• Alpha thalassemia is inherited in a complex way, but usually in an autosomal recessive manner.
• For each of the two alpha-globin genes (HBA1 and HBA2) one allele is inherited from the mother, and the other allele is inherited from the father.
• Babies inherit the silent carrier type of Alpha thalassemia when only one parent passes down one missing HBA1 or HBA2 allele.
• Babies inherit Alpha thalassemia minor when parents pass down two missing HBA1 or HBA2 alleles.
• Babies inherit HbH disease when parents pass down three missing HBA1 or HBA2 alleles.
  • If one parent has Alpha thalassemia minor and the other parent is a silent carrier, there is a 1 in 4 chance with each pregnancy that the baby will have HbH disease.
• Babies inherit Alpha thalassemia major when parents pass down four missing HBA1 or HBA2 alleles.
  • If both parents have Alpha thalassemia minor, there is a 1 in 4 chance with each pregnancy that the baby will have Alpha thalassemia major.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs and symptoms of Alpha thalassemia depend on the type of Alpha thalassemia a baby has. In some cases, signs of the condition appear right at birth. In these cases, it is important to see a doctor and start treatment quickly. Other children may only have minor signs and symptoms.

Signs of the condition may include the following:

Silent Carrier

• Usually has no signs or symptoms

Alpha thalassemia Minor

• Typically, no signs or symptoms at birth
• May develop mild anemia (low levels of red blood cells)

HbH Disease

• Typically, no signs or symptoms at birth
• Usually develop moderate to severe anemia (low levels of red blood cells) in childhood, which leads to:
  • Pale or yellow skin or eyes (jaundice)
  • Feeling tired or weak
  • Large liver and spleen (hepatosplenomegaly)
  • Slow growth or delayed puberty
  • Bone problems
  • Darker urine

Alpha Thalassemia Major

• These babies usually do not live very long after birth, unless the disorder is identified in utero and in utero transfusions are provided.

Newborn screening for Alpha thalassemia requires collecting a small amount of blood from your baby’s heel. Screening measures certain types of hemoglobins in your baby’s blood. Babies with a hemoglobin known as “Bart’s hemoglobin” may have one of the types of Alpha thalassemia. Typically, the more Bart’s hemoglobin present, the more severe the type of Alpha thalassemia. Bart’s hemoglobin gets its name because it was originally discovered at St. Bartholomew’s Hospital in London.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for Alpha thalassemia needs follow-up, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result usually means that your baby has one of the Alpha thalassemia types and your baby may need more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with severe types of Alpha thalassemia can have serious health problems if they are not diagnosed and treated.

False-positive newborn screening results for this condition are rare. However, screening samples that are collected after a baby receives red blood cells from someone else (a red cell transfusion) will be inaccurate.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your healthcare provider about which treatment(s) are best for your baby. The goal of treatment is to prevent and minimize the health problems caused by this condition.

Treatments may include the following:

• Surgery to remove the spleen, in some cases
• Blood transfusion in cases of severe anemia
• These babies will require lifelong transfusions and medical care.
• Medicines to reduce extra iron from your body
• Avoidance of certain oxidant drugs (like antimalarial drugs and aspirin)
• Sometimes a family knows during pregnancy that the baby has Alpha thalassemia major due to prenatal testing or ultrasound findings. In this case, blood transfusions for the baby before birth (intrauterine transfusions) may increase the chance for survival.

Children who receive early health care and treatment for Alpha thalassemia can have healthier lives than those who do not receive treatment.

What can a person living with thalassemia do to stay healthy?

A healthy lifestyle is important for everyone. For people living with thalassemia, it is especially important to know that a healthy lifestyle means “managing the disorder”, as well as making healthy choices.

Managing Thalassemia

Thalassemia is a treatable disorder that can be well-managed with blood transfusions and chelation therapy. A person with thalassemia will need to receive medical care on a regular basis from a hematologist (a medical specialist who treats diseases or disorders of the blood) or a doctor who specializes in treating patients with thalassemia. If a doctor has prescribed either blood transfusions or chelation therapy, the most important thing a person with thalassemia can do is stick to their transfusion and chelation schedules to prevent severe anemia and possible organ damage from iron overload, respectively.

Healthy Choices for People Living with Thalassemia

Other healthy choices a person with thalassemia should consider include keeping vaccinations up-to-date, eating nutritious meals, exercising, and developing positive relationships.

Vaccines

Vaccines are a great way to prevent many serious infections. Children and adults with thalassemia should get all recommended vaccinations, including a flu vaccination. People with thalassemia are considered “high risk” for certain infections, especially if they have had their spleen removed, and should follow a special vaccination schedule for the following vaccines:

Haemophilus influenzae type b (Hib)
Pneumococcal vaccines
Meningococcal vaccines

See the most up-to-date vaccination schedules. Pay special attention to the footnotes that provide special instructions for people with thalassemia.

Nutrition

Eating nutritious foods is important for everyone to maintain a healthy lifestyle – a diet, high in fruits and vegetables and low in fats is ideal for gaining the essential nutrients our bodies need. For people living with thalassemia, because too much iron may build up in the blood, foods high in iron may need to be limited. Iron can be found in meat, fish, and some vegetables (e.g., spinach). Other products, like cereal and orange juice, may contain extra iron. Persons with thalassemia should discuss with their doctor whether or not they should limit the amount of iron in their diet.

Exercise

Exercise is part of an overall healthy lifestyle and helps lead to better health outcomes. Although some people with thalassemia may have trouble participating in vigorous forms of exercise, many people with thalassemia can participate in moderate physical activities including biking, running, and walking. If a person with thalassemia has problems with their joints, there are many kinds of low-impact activities to choose from including yoga, swimming, or water aerobics. If you have thalassemia, you should discuss with your doctor the level of exercise that would be best for you.

Relationships

Having warm, supportive relationships is an important part of life. Friends, including co-workers, classmates, and family members can offer support in managing thalassemia (e.g., offering a ride to the transfusion center, gentle reminders about your chelation schedule, etc.) and coping with stress of daily life.

Romantic relationships can also offer a source of support. If a romantic relationship becomes sexual, it is important for everyone to make healthy decisions, such as getting tested for sexually transmitted diseases and negotiating condom use. In addition, if you have thalassemia, thalassemia trait, or know someone in your family with thalassemia, genetic counseling is recommended prior to any pregnancy so that you and your partner can be informed of your risk of having a child with thalassemia.c

Alpha thalassemia is a fairly common blood disorder worldwide. Thousands of infants with Hb Bart syndrome and HbH disease are born each year, particularly in Southeast Asia. Alpha thalassemia also occurs frequently in people from Mediterranean countries, Africa, the Middle East, India, and Central Asia.