- To date, more than 1000 disorders of hemoglobin synthesis and/or structure have been identified and characterized.
- If our red blood cells cannot transport enough oxygen, the whole body suffers as a result. Organs become undersupplied or may even fail
- There are several different types of globin chains, named alpha, beta, delta, and gamma.
- Beta thalassemia is caused by mutations in one or both of the beta globin genes. There have been more than 250 mutations identified, but only about 20 are the most common.
- Sickle cell anemia is the most common and severe hemoglobinopathy, characterized frequently by recurrent painful symptoms. Sickle cell anemia affects about 90,000 to 100,000 people in the United States
- Alpha thalassemia is sometimes confused with iron deficiency anemia because both disorders have smaller than usual (microcytic) red blood cells.
Hemoglobin disorders (also called hemoglobinopathies) are rare blood conditions that are caused by impairment of the red blood pigment hemoglobin. Hemoglobin is a protein in the blood that carries oxygen. It is made up of heme, which is the iron-containing portion, and globin chains, which are proteins. The globin protein consists of chains of amino acids, the “building blocks” of proteins. There are several different types of globin chains, named alpha, beta, delta, and gamma.
Our blood transports oxygen and nutrients to each individual cell. Roughly half of the blood volume is made up of cells, primarily red blood cells (erythrocytes). These cells use the red blood pigment hemoglobin, an iron-containing protein, to transport oxygen: like a molecular vessel, it collects this essential gas in the lungs and delivers it to the cells and organs throughout the body
Normal hemoglobin types include:
Hemoglobin A (Hb A): makes up about 95%-98% of hemoglobin found in adults; it contains two alpha (α) chains and two betas (β) protein chains.
Hemoglobin A2 (Hb A2 ): makes up about 2%-3% of hemoglobin found in adults; it has two alpha (α) and two deltas (δ) protein chains.
Hemoglobin F (Hb F, fetal hemoglobin): makes up to 1%-2% of hemoglobin found in adults; it has two alpha (α) and two gammas (γ) protein chains. It is the primary hemoglobin produced by the fetus during pregnancy; its production usually falls shortly after birth and reaches an adult level within 1-2 years.
Genetic changes (mutations) in the globin genes cause alterations in the globin protein, resulting in structurally altered hemoglobin, such as hemoglobin S, which causes sickle cell, or a decrease in globin chain production (thalassemia). In thalassemia, the reduced production of one of the globin chains upsets the balance of alpha to beta chains and causes abnormal hemoglobin to form (alpha thalassemia) or causes an increase of minor hemoglobin components, such as Hb A2 or Hb F (beta thalassemia).
Four genes code for the alpha globin chains, and two genes (each) code for the beta, delta, and gamma globin chains. Mutations may occur in either the alpha or beta globin genes. The most common alpha-chain-related condition is alpha thalassemia. The severity of this condition depends on the number of genes affected.
Mutations in the beta gene are mostly inherited in an autosomal recessive fashion. This means that the person must have two altered gene copies, one from each parent, to have a hemoglobin variant-related disease. If one normal beta gene and one abnormal beta gene are inherited, the person is heterozygous for the abnormal hemoglobin, known as a carrier. The abnormal gene can be passed on to any children, but it generally does not cause symptoms or significant health concerns in the carrier.
If two abnormal beta genes of the same type are inherited, the person is homozygous. The person would produce the associated hemoglobin variant and may have some associated symptoms and potential for complications. The severity of the condition depends on the genetic mutation and varies from person to person. A copy of the abnormal beta gene would be passed on to any children.
If two abnormal beta genes of different types are inherited, the person is “doubly heterozygous” or “compound heterozygous.” The affected person would typically have symptoms related to one or both of the hemoglobin variants that he or she produces. One of the abnormal beta genes would be passed on to children.
There are different kinds of hemoglobin in the blood, and there are many kinds of hemoglobin disorders. Some are caused when hemoglobin doesn’t form correctly or when your body doesn’t make enough hemoglobin.
These conditions are inherited. This means they’re passed from parent to child through genes. Genes are parts of your body’s cells that store instructions for the way your body grows and works. In the United States, all babies have newborn screening tests to see if they may have certain inherited conditions when they’re born.
To date, more than 1000 disorders of hemoglobin synthesis and/or structure have been identified and characterized.
Before presenting a brief overview of these disorders, we provide a summary of the structure and function of hemoglobin, along with the mechanism of assembly of its subunits, as background for the understanding and basis of the different categories of disorders in the classification.
Each globin subunit must form a stable linkage with heme (ferroprotoporphyrin IX) situated on the external surface of the protein so that oxygen in the RBC cytosol can bind reversibly to the hemes’ iron atoms. Moreover, the hydrophobic cleft into which the heme is inserted must be able to protect the Fe2+ heme iron from oxidation to Fe3+, which is incapable of binding oxygen.3 Delicate noncovalent interactions between unlike globin subunits are required for the hemoglobin tetramer α2β2 to bind and unload oxygen in a cooperative manner, thereby assuring maximal transport to actively metabolizing cells.
To endow the blood with high oxygen carrying capacity hemoglobin must be stuffed into flexible circulating RBCs. A remarkably high degree of solubility is required for hemoglobin to achieve an intracellular concentration of ∼34 g/dl or 5 mm (tetramer).
If our red blood cells cannot transport enough oxygen, the whole body suffers as a result. Organs become undersupplied or may even fail
Impairment of hemoglobin solubility can be caused either by the formation of intracellular polymers (sickle cell disease) or by the development of amorphous precipitates (congenital Heinz body hemolytic anemia). Abnormalities of oxygen binding can lead either to erythrocytosis (high O2 affinity mutants) or to cyanosis (low O2 affinity mutants). Some globin mutants have structural alterations within the heme pocket that result in oxidation of the heme iron and pseudocyanosis because of methemoglobinemia.
CLASSIFICATION OF HEMOGLOBIN DISORDERS
- Those in which there is a quantitative defect in the production of one of the globin subunits, either total absence or marked reduction. These are called the thalassemia syndromes.
- Those in which there is a structural defect in one of the globin subunits such as sickle cell and hemoglobin C. These are referred as Structural disorders or qualitative disorders
THE THALASSEMIA SYNDROMES
The thalassemia syndromes are inherited disorders characterized by absence or markedly decreased synthesis of one of the globin subunits of hemoglobin. In the alpha (α)-thalassemias, there is absent or decreased production of α-globin subunits, whereas, in the beta (β)-thalassemias, there is the absent or reduced production of β-globin subunits. Rare thalassemias affecting the production of delta (δ)- or gamma (γ)-globin subunits have also been described but are not clinically significant disorders. Combined deficiency of δ + β-globin subunits, or of all of the β-like globin subunits also occurs.
The β-thalassemias can be subclassified into those in which there is a total absence of normal β-globin subunit synthesis or accumulation, the β0-thalassemias, and those in which some structurally normal β-globin subunits are synthesized, but in markedly decreased amounts, the β+-thalassemias.
Beta thalassemia is found most commonly in populations of Mediterranean, African, and Southeast Asian descent in the U.S.
Over 200 different mutations have been described
Beta thalassemia is caused by mutations in one or both of the beta globin genes. There have been more than 250 mutations identified, but only about 20 are the most common. The severity of the anemia caused by beta thalassemia depends on which mutations are present and whether there is decreased beta globin production (called beta+ thalassemia) or if production is completely absent (called beta0 thalassemia). The different types of beta thalassemia include:
Beta Thalassemia Trait or Beta Thalassemia Minor. Individuals with this condition have one normal gene and one with a mutation, causing a mild decrease in beta globin production. They usually have no health problems other than abnormally small red blood cells and a possible mild anemia that will not respond to iron supplements. It does not require treatment with regular blood transfusions
Thalassemia Intermedia. In this condition, an affected person has two abnormal genes, causing moderate to severe decrease in beta globin production. These individuals may develop symptoms later than those with thalassemia major (see below) and often with milder symptoms. They rarely require treatment with blood transfusion. The severity of the anemia and health problems experienced depends on the mutation types present. The dividing line between thalassemia intermedia and thalassemia major is the degree of anemia and the number and frequency of blood transfusions required. Those with thalassemia intermedia may need occasional transfusions but do not require them on a regular basis.
Thalassemia Major or Cooley’s Anemia. This is the most severe form of beta thalassemia. These individuals have two abnormal genes that cause either a severe decrease or complete lack of beta globin production, preventing the production of significant amounts of normal hemoglobin (Hb A). This condition usually appears within the first two years of life and causes life-threatening anemia, poor growth, and skeletal abnormalities during infancy. This anemia requires lifelong regular blood transfusions and considerable ongoing medical care. Over time, these frequent transfusions lead to excessive amounts of iron in the body. Left untreated, this excess iron can deposit in the liver, heart, and other organs and can lead to a premature death from organ failure. Therefore, individuals undergoing transfusion may need chelation therapy to reduce iron overload.
The Alpha thalassemia Syndromes
Alpha thalassemia is a blood disorder that reduces the production of hemoglobin.
Genes that regulate both the synthesis and the structure of different globins are organized into separate clusters. The alpha-globin genes are encoded on chromosome 16, and the gamma-, delta-, and beta-globin genes are encoded on chromosome 11. Healthy individuals have alpha-globin genes, 2 on each chromosome 16). Alpha thalassemia syndromes are caused by deficient expression of 1 or more of the 4 alpha-globin genes on chromosome 16 and are characterized by absent or reduced synthesis of alpha-globin chains.
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.
The frequency of alpha thalassemia is low among whites. It is estimated that about 15% of American blacks are silent carriers for alpha thalassemia and about 3% have alpha thalassemia trait; HbH disease is rare in this population. In North America, many multicultural communities are growing, and these populations have increased frequencies of thalassemia syndromes.
Alpha thalassemia is perhaps the most common single-gene disorder in the world. It is estimated that there are 270 million carriers of mutant globin genes that can potentially cause severe forms of thalassemia. In addition, 300,000-400,000 severely affected infants are born every year, more than 95% of whom are in Asia, India, or the Middle East.
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.
Abnormal production of alpha-globin chains results in a relative excess of gamma-globin chains in fetuses and newborns and of beta-globin chains in children and adults. Furthermore, the beta-globin chains are capable of forming soluble tetramers (β4, or hemoglobin H [HbH]); yet this form of hemoglobin is unstable and tends to precipitate within the cell, forming insoluble inclusions (Heinz bodies) that damage the red cell membrane.
From a genetic standpoint, alpha thalassemia syndromes are extremely heterogeneous; however, their phenotypic expression may be described in simplified clinical terms related to the number of inherited alpha-globin genes. Alpha thalassemia may be broadly classified according to whether the loss of alpha-globin genes is complete or partial—that is, alpha(0) thalassemia or alpha(+) thalassemia. Some subclasses are present within the latter category, based on the number of genes affected.
The most common mechanism of aberrant alpha-globin production involves deletion of either portion of the alpha-globin genes themselves or the genetic regulatory elements that control their expression.
In all, there are four general forms of alpha thalassemia.
More than 20 different genetic mutations resulting in the functional deletion of both pairs of alpha-globin genes (–/–) have been identified. The resulting disorder is referred to as hydrops fetalis, alpha thalassemia major, or hemoglobin Bart’s. Individuals with this disorder cannot produce any functional alpha globin and thus are unable to make any functional hemoglobin A, F, or A2. Hydrops fetalis is incompatible with extrauterine life. Fetuses with this condition die either in utero or shortly after birth because of severe anemia.
There are more than 15 different genetic mutations that result in decreased production of alpha globin, usually through functional deletion of 1 or more of the 4 alpha-globin genes. Alpha(+) thalassemia is subclassified into the following three general forms on the basis of the number of inherited alpha genes.
Silent carrier. Persons who inherit 3 normal alpha-globin genes (-α/αα) are referred to clinically as silent carriers. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha(+) thalassemia minor. The affected individuals exhibit no clinical abnormalities and may be hematologically normal or have slight reductions in RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).
Alpha thalassemia trait. Inheritance of 2 normal alpha-globin genes through either heterozygosity for alpha(0) thalassemia (αα/–) or homozygosity for alpha(+) thalassemia (-α/-α) results in the development of alpha thalassemia trait, also referred to as alpha thalassemia minor or alpha thalassemia-1 trait. If both alpha2- and alpha1-globin genes are deleted on the same chromosome (–/αα), the genotype is said to have the cis form; if the 2 alpha2 -globin genes of both alleles of chromosome 16 are deleted but the alpha1 -globin genes are intact (-α/-α), it is said to have the trans-form. The affected individuals are clinically normal but frequently have minimal aanemia.
HbH disease causes mild to moderate anemia, hepatosplenomegaly, and yellowing of the eyes and skin (jaundice). Some affected individuals also have bone changes such as overgrowth of the upper jaw and an unusually prominent forehead. The features of HbH disease usually appear in early childhood, and affected individuals typically live into adulthood.
Inheritance of only one out of the four normal alpha-globin genes (-α/–) leads to a condition known as HbH disease or alpha thalassemia intermedia. The loss of 3 alpha-globin genes results in the abundant formation of HbH, which is characterized by a high ratio of beta globin to alpha globin and a 2-fold to 5-fold excess in beta-globin production. The excess beta chains aggregate into tetramers, which account for 5-30% of the hemoglobin level in patients with HbH disease.
Hb Bart syndrome
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. As a result of these serious health problems, most babies with this condition are stillborn or die soon after birth. 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.
Abnormal hemoglobin protein structures or qualitative hemoglobin disorders
Hemoglobin S: this is the primary hemoglobin in people with sickle cell disease (also known as sickle cell anemia). Sickle cell anemia is the most common and severe hemoglobinopathy, characterized frequently by recurrent painful symptoms. Sickle cell anemia affects about 90,000 to 100,000 people in the United States, including one in every 500 African-American babies and one in every 36,000 Hispanic babies. and about 100,000 Americans live with the disorder, according to the Centers for Disease Control and Prevention. The disease can also affect people of Hispanic, Arabic, Indian or Mediterranean descent.
Signs and Symptoms Related to Sickle cell disease include Pain. This pain throughout the body is a common symptom of sickle cell anemia – sickle cell crisis. Affect the bones, lungs, abdomen, and joints. Occur when sickled red blood cells block blood flow to the limbs and organs. Acute or chronic, but acute pain is more common. Acute pain is sudden and can range from mild to very severe, lasts from hours to as long as a week or more. Chronic pain often lasts for weeks or months and can be hard to bear and mentally draining. (Chronic pain may limit your daily activities). Can damage the bones, kidneys, lungs, eyes, heart, and liver.
Those with Hb S disease have two abnormal beta chains and two normal alpha chains. The presence of hemoglobin S causes the red blood cell to deform and assume a sickle shape when exposed to decreased amounts of oxygen (such as might happen when someone exercises or has an infection in the lungs). Sickled red blood cells are rigid and can block small blood vessels, causing pain, impaired circulation, and decreased oxygen delivery, as well as shortened red cell survival. A single beta (βS) copy (known as sickle cell trait, which is present in approximately 8% of African Americans) typically does not cause significant symptoms unless it is combined with another hemoglobin mutation, such as that causing Hb C or beta thalassemia.
Sickle cell anemia can cause pain, infections, and damage to body organs. The pain symptoms of sickle cell anemia appear during a period called a crisis. A crisis can last from a few hours to a week in length. Other symptoms of sickle cell anemia include fever; pain in hands, feet, and joints; shortness of breath; pneumonia-like symptoms; dizziness; a headache; sores on the legs and an enlarged spleen or liver. All babies born in the USA are tested for hemoglobin disease and trait. Babies with hemoglobin disease are referred to medical specialty care soon after birth for treatment.
Hemoglobin C: about 2-3% of African Americans in the United States are heterozygotes for hemoglobin C (have one copy, known as hemoglobin C trait) and are often asymptomatic. Hemoglobin C disease (seen in homozygotes, those with two copies) is rare (0.02% of African Americans) and relatively mild. It usually causes a minor amount of hemolytic anemia and a mild to moderate enlargement of the spleen.
Hemoglobin E: Hemoglobin E is one of the most common beta chains of hemoglobin variants in the world. It is very prevalent in Southeast Asia, especially in Cambodia, Laos, and Thailand, and in individuals of Southeast Asian descent. People who are homozygous for Hb E (have two copies of βE) generally have a mild hemolytic anemia, microcytic red blood cells, and a mild enlargement of the spleen. A single copy of the hemoglobin E gene does not cause symptoms unless it is combined with another mutation, such as the one for beta thalassemia trait.
Tests and Diagnosis
Several laboratory tests may be used to help detect and diagnose thalassemia:
Complete blood count (CBC). The CBC is an evaluation of the cells in the blood. Among other things, the CBC determines the number of red blood cells present and how much hemoglobin is in them. It evaluates the size and shape of the red blood cells present, reported as the red cell indices. These include the mean corpuscular volume (MCV), a measurement of the size of the red blood cells. A low MCV is often the first indication of thalassemia. If the MCV is low and iron deficiency has been ruled out as a cause, thalassemia should be considered.
Blood smear (also called peripheral smear and manual differential). In this test, a trained laboratory professional examines a thin layer of blood that is treated with a special stain, on a slide, under a microscope. The number and type of white blood cells, red blood cells, and platelets are evaluated to see if they are normal and mature. With thalassemia, the red blood cells often appear smaller than normal (microcytic, low MCV). Red cells may also: Be paler than normal (hypochromic), Vary in size and shape (anisocytosis and poikilocytosis), Be nucleated (normal, mature RBCs do not have a nucleus), Have uneven hemoglobin distribution (producing “target cells” that look like a bull’s-eye under the microscope). The greater the percentage of abnormal-looking red blood cells, the greater the likelihood of an underlying disorder and decreased the ability of the RBCs to carry oxygen.
Iron studies. These may include: iron, ferritin, unsaturated iron binding capacity (UIBC), total iron binding capacity (TIBC), and percent saturation of transferrin. These tests measure different aspects of the body’s iron storage and usage. The tests are ordered to help determine whether an iron deficiency is the cause of a person’s anemia. One or more of them may also be ordered to help monitor the degree of iron overload in an individual with thalassemia.
Alpha thalassemia is sometimes confused with iron deficiency anemia because both disorders have smaller than usual (microcytic) red blood cells. If someone has thalassemia, his or her iron levels are not expected to be low. Iron therapy will not help people with alpha thalassemia and may lead to iron overload, which can cause organ damage over time.
Erythrocyte porphyrin tests may be used to distinguish an unclear beta thalassemia minor diagnosis from iron deficiency or lead poisoning. Individuals with beta thalassemia will have normal porphyrin levels, but those with the latter conditions will have elevated porphyrin.
Hemoglobinopathy (Hb) evaluation (hemoglobin electrophoresis). In electrophoresis, an electrical current is used to separate the different types of hemoglobin and thus detect abnormal hemoglobin. This test assesses the type and relative amounts of hemoglobin present in red blood cells. Hemoglobin A (Hb A), composed of both alpha and beta globin, is the type of hemoglobin that normally makes up 95% to 98% of hemoglobin in adults. Hemoglobin A2 (HbA2) is usually 2% to 3% of hemoglobin in adults, while hemoglobin F usually makes up less than 2%.
Beta thalassemia upsets the balance of beta and alpha hemoglobin chain formation and causes an increase in those minor hemoglobin components. So individuals with the beta thalassemia major usually have larger percentages of Hb F. Those with beta thalassemia minor usually have elevated fraction of Hb A2. Hb H is a less common form of hemoglobin that may be seen in some cases of alpha thalassemia. Hb S is the hemoglobin more common in people with sickle cell disease.
Hemoglobinopathy (Hb) evaluations are used for state-mandated newborn hemoglobin screening and prenatal screening when parents are at high risk for hemoglobin abnormalities.
DNA analysis. These tests are used to help confirm mutations in the alpha and beta globin-producing genes. DNA testing is not routinely done but can be used to help diagnose thalassemia and to determine carrier status, if indicated.
For beta-thalassemia, the hemoglobin beta gene, HBB, may be analyzed or sequenced to confirm the presence of thalassemia-causing mutations. Genetic tests may also be given for other HBB mutations such as Hb S mutation, which is associated with sickle cell disease. More than 250 mutations have been associated with beta thalassemia, though some cause no signs or symptoms. However, others decrease the amount of beta globin production and some prevent it completely. The presence of one of those mutations confirms a diagnosis of beta thalassemia.
The primary molecular test available for alpha thalassemia detects common mutations (e.g., deletions) in the two alpha genes HBA1 and HBA2. Each person has two copies of each of these genes, called alleles, in their cells, one from their mother and one from their father. These alleles govern alpha globin production and if mutations lead to functional loss of one or more of alpha genes, alpha thalassemia occurs.
Since having relatives who carry mutations for thalassemia increases a person’s risk of carrying the same mutant gene, family studies may be done to evaluate carrier status and the types of mutations present in other family members if deemed necessary by a healthcare practitioner.
Genetic testing of amniotic fluid is used in the rare instances a fetus is at increased risk for thalassemia. This is especially important if both parents likely carry a mutation because that increases the risk that their child may inherit a combination of abnormal genes, causing a more severe form of thalassemia.
Treatment varies depending on the symptoms and their severity. Some people do not need treatment.
Most individuals with mild thalassemia traits require no treatment. They may want to consider genetic counseling, however, because they may pass the mutant gene on to their children.
People with hemoglobin H disease or beta thalassemia intermedia will experience variable amounts of anemia throughout their life. They can live relatively normal lives but will require regular monitoring and may occasionally need a blood transfusion. Folic acid supplementation is often given, but iron supplementation is not recommended.
Those with beta thalassemia major will usually require regular blood transfusions, as frequently as every few weeks, and chelation therapy to remove iron throughout their life. These transfusions help maintain hemoglobin at a high enough level to provide oxygen to the body and prevent growth abnormalities and organ damage. Frequent transfusions, however, can raise body iron to toxic levels, resulting in deposits of iron in the liver, heart, and other organs. Regular iron chelation therapy is used to help decrease iron in the body.
Bone marrow transplant known as hematopoietic stem cell transplantation can also be used for the treatment of beta thalassemia major.
Fetuses with alpha thalassemia major are usually miscarried, stillborn, or die shortly after birth. Experimental treatments, such as fetal blood transfusions and even fetal marrow transplant, have been successful in a very few cases in bringing a baby to term.
The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.
- American Cancer Society
- The National Cancer Institute
- National Comprehensive Cancer Network
- American Academy of Gastroenterology
- National Institute of Health
- MD Anderson Cancer Center
- Memorial Sloan Kettering Cancer Center
- American Academy of Hematology