Beta-thalassemia major, also known as Cooley's anemia, happens when the body is unable to make an important blood protein called beta globin. Everyone receives two copies of the beta globin gene from their parents, one from their mother and one from their father.  The beta globin gene is on chromosome 11. In most people, both of these beta globin genes contain instructions for making the protein.  The cellular machinery in every newly developing red blood cell reads the genes' instructions to build beta globin proteins. But in a person with beta-thalassemia, the two copies of the gene contain mutations that garble the instructions.  Though the mutations can be small – as small as a single letter change in a gene that has 1,600 letters of code – they completely turn off the production of beta globin. Beta globin is needed to make hemoglobin – the molecule used to deliver oxygen to every cell in your body.  The beta globin carries the heme  group that binds the oxygen molecule. Two beta globin proteins combine with two similar-looking alpha globin proteins and their heme groups to make one hemoglobin molecule. When the beta globins are not made, the alpha globins accumulate inside new red blood cells.  There is nothing for the alpha globins to bind with and thus no hemoglobin is made. Without hemoglobin, oxygen cannot be delivered properly.  The body senses this and tries to compensate by increasing the production of two other types of proteins that can also bind with the alpha globins.  Gamma chains combine with alphas to make hemoglobin F, the type of hemoglobin that’s predominant during fetal life. Delta chains combine with alphas to make hemoglobin A2, the secondary adult hemoglobin. The more alpha chains that stick to the membrane, the worse it is for the cell.  Though the exact process is unknown, the clumps of alpha chains tell the cell to kill itself. This kills 95% of the newly formed red blood cells. Oxygen delivery rests solely on these alternate hemoglobins, but not enough can be made.  Excess alpha globins are left unbound in the cell, and they clump together on the inside of the cell’s membrane. The red blood cells that do manage to mature are not quite normal.  They are smaller than average and they look pale from the lack of hemoglobin. Inside the surviving beta-thalassemia blood cells, clumps of alpha chains continue to damage the cells.  These mutant cells do not last as long as normal red blood cells.  Left untreated, the lack of red blood cells and resulting anemia in the patient directs the bone marrow to increase cell production up to 10 times the normal rate.  But the strategy to increase the number of cells doesn’t work.  The vast majority of these cells die as well. The pumped-up production of red blood cells and the massive numbers of cell deaths have several effects on the body of a person with beta-thalassemia.  To accommodate the increased cell production, the size of the bone marrow grows and pushes bones outward.  This could distort the person’s appearance, particularly in the face and head. The sheer number of damaged red blood cells can overwhelm the spleen, which is in charge of removing the injured and dying cells from the bloodstream.  The harder the spleen works to remove the damaged red blood cells, the harder the body works to create more cells.  This feedback loop stresses the bodies' systems; sometimes removal of the spleen can relieve some of this stress. Without frequent transfusions of blood, a child with severe thalassemia will fail to grow and develop properly and will eventually die prematurely. 

When a child is brought to the doctor with symptoms that suggest beta-thalassemia, several tests on the blood will determine if the child has microcytic anemia, the type of anemia present in beta-thalassemia.  One test is to look at the blood under a microscope. Blood cells from a patient with beta-thalassemia will tend to be smaller than normal cells, but with a wide range of cell sizes.  They will be pale in color and may be oddly-shaped, spiky, or elongated. The differences in the cells can be quantified in several ways.  One test measures the "mean corpuscular volume," or MCV, of a blood sample.  Beta-thalassemia blood cells will be smaller than normal, because there is not enough hemoglobin to fill up the entire cell volume. Another test measures the average weight of hemoglobin within each cell, which will be lower than normal in a person with beta-thalassemia.  This is called the "mean corpuscular hemoglobin," or MCH, of a blood sample.  A cell with a low MCH will be much paler than a cell with a high MCH. A third test measures the total concentration of hemoglobin in the blood, which will also be lower for a person with beta-thalassemia.  This test is simply known as "hemoglobin" or Hb. Beta-thalassemia can also be diagnosed by looking at the types of hemoglobin proteins circulating in the blood.  A person with beta-thalassemia will not have any hemoglobin A, because they cannot make any beta globin.  Their predominant hemoglobin is hemoglobin F, the fetal hemoglobin, made out of two alpha globins and two gamma globins. This shows up in a test, called electrophoresis, which identifies the amounts of different types of hemoglobin in the blood.  The test from a person with beta-thalassemia (who produces no beta globin) shows an absence of hemoglobin A, and very high levels of hemoglobin F.  People without beta-thalassemia have no hemoglobin F. A person with thalassemia intermedia will produce more hemoglobin A than a person with beta-thalassemia, but lower than an unaffected person.  They also have higher than normal hemoglobin F. Finally, a carrier will show nearly normal levels of hemoglobin A and low levels of hemoglobin F. When neither parent has beta-thalassemia, their child can still inherit the disease IF both carry a mutated beta globin gene.  To see why, we'll construct a Punnett square. First, we place the parents' genes on the outside of the square.  (The + symbol represents the "normal" gene; the b symbol represents the mutated gene) Each box inside the Punnett square represents a possible child of this couple.  To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes beta-thalassemia (b/b).  Out of four boxes, only one has this combination, so each child of this couple has a 1-in-4 (25%) chance of getting beta-thalassemia. When neither parent has beta-thalassemia, their child can still inherit the disease IF both carry a mutated beta globin gene.  To see why, we'll construct a Punnett square.  First, we place the parents' genes on the outside of the square.  (The + symbol represents the "normal" gene; the b symbol represents the mutated gene). Each box inside the Punnett square represents a possible child of this couple.  To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes beta-thalassemia (b/b).  Out of four boxes, only one has this combination, so each child of this couple has a 1-in-4 (25%) chance of getting beta-thalassemia. 

The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 25% chance of inheriting beta-thalassemia. In this family, one in four children has the genes for beta-thalassemia.  Other couples with the mutation may have two, three, four, or even no children with the disorder. If one parent has beta-thalassemia, the chance of having a child with the same disorder depends on the genes of the other parent.  If the other parent has one mutated gene, the chance is 50%, or 1-in-2.  To see why, we'll construct a Punnett square. To set up the square, we first arrange each parent's genes on the outer edges, as shown.  (The + symbols represent "normal" beta globin genes; the ß's represent mutated genes). Each box inside the Punnett square represents a possible child of this couple.  To complete the boxes, we move one gene from each parent into every box, as shown below. Now we inspect the boxes for the pair of genes that causes beta-thalassemia (bb). Two out of four boxes contain this pair, so each child of this couple has a 1-in-2 (50%) chance of inheriting both genes and getting beta-thalassemia. The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 50% chance of inheriting beta-thalassemia. In this family, one in four children inherited beta-thalassemia.  Other couples with the mutation may have two, three, four, or even no children with the disorder. A person with beta-thalassemia – including those with major and intermediate forms – has two mutated beta globin genes.  (A person with one mutated beta globin gene has very minor symptoms of the disease). These genes were passed down from this person's parents, each of whom carried at least one mutated beta globin gene (tagged with the red asterisks). When a sperm carrying the mutated type fertilizes an egg carrying the mutated type, the resulting child inherits both genes and develops beta-thalassemia. When the father and mother produced sperm and eggs, only one of their two beta globin genes entered each cell.  About half the cells got the mutated type (b), and half got the normal type (+).Two different types of mutations are possible.  The beta globin gene can be mutated to produce no beta globin proteins at all.  If the parents pass on this type of gene, the child has thalassemia major.  

Beta globin genes that fail to produce any protein are labeled    . The beta globin gene can have a mutation that produces lower-than-normal amounts of beta globin protein.  If the parents pass on this type of gene, the child has thalassemia intermedia.  A gene that produces less than the normal amount of beta globin is labeled    . Beta-thalassemia is one of a group of inherited blood disorders known as thalassemias.  Beta-thal is recessive; a person must inherit two copies of a mutated beta globin gene (one from each parent) to develop symptoms.  The beta globin mutation may have developed to act in conjunction with sickle cell as protective measures against malaria.  Early signs of beta-thalassemia include irritability, difficulty feeding, and progressive paleness.  These symptoms can appear as early as 6 months of age.  Without treatment, children will grow slowly, have an enlarged spleen, and display a "rat-like" face due to deformities in the skull. Thalassemias are the most common genetic disorders in the world.  Beta-thalassemia is the most common of this group, particularly in people from the Mediterranean, Africa, and southeast Asia.  The incidence of beta-thalassemia can be as high as 1 in 10 in some Mediterranean areas.  The incidence is much lower in the U.S., however, it is estimated that 2 million Americans may be carriers or have some form of thalassemia. Beta-thalassemia and other hemoglobin disorders are frequently detected during newborn screening tests.  If not, the disorder is usually diagnosed before the child is two years old.  The diagnosis depends on identifying the types of hemoglobin present in the blood.  People with thalassemia major do not have any of the normal adult type of hemoglobin (A). Beta-thalassemia is an inherited disorder in which a critical blood protein – beta globin – is missing from the oxygen-carrying red blood cells.  The lack of beta globin leads to the death of most of the red blood cells, which in turn causes severe anemia.  Left untreated, complications from the anemia can result in death, usually before age 30. Regular blood transfusions are necessary for a person with beta-thalassemia major to grow properly and survive.  Along with transfusion therapy, a person with beta-thalassemia major will also have to adhere to a difficult therapy for removal of excess iron introduced into the body by the transfusions.  Excess iron will damage the liver and heart, as it does in another genetic disorder, hemochromatosis. Mean Corpuscular Volume Dr. Dominick Sabintino explains mean corpuscular volume (MCV) and how it is used as a possible indication of beta-thalassemia. Anemia Anemia is a symptom of beta-thalassemia. 

Dr. Sabatino, Nassau University Medical Center, talks about anemia and some of its many causes. Iron Overload Dr. Sabatino discusses the problem of iron overload from blood transfusions. Getting Iron Out Dr. Sabatino explains why iron cannot be taken out before a blood transfusion. He also talks about how to deal with the extra iron. Desferal Dr. Sabatino talks about Desferal – a medication used for iron removal. Splenectomy Dr. Sabatino discusses how splenectomy – spleen removal – may play a role in thalassemia care. Transfusion frequency Dr. Sabatino describes three situations in which the frequency of transfusions may need to be increased. Other Problems Dr. Sabatino talks about the psychodynamics of thalassemia, and the social problems that can arise once a child reaches puberty. Diagnosis Tara Cervo talks about when and how her son, Anthony, was diagnosed with beta-thalassemia. Treatment Anthony describes his weekly trips to the hospital where he gets intravenous blood transfusions. Veins Anthony talks about how he keeps his veins pumped up for blood transfusions and an alternate method for getting blood into his body. When to Transfuse Anthony explains how he knows when it is time for a blood transfusion. Post-Transfusion Anthony describes how he feels after he gets a blood transfusion. School Anthony talks about the effect that beta-thalassemia has on his school routine and the limitations he has to be wary of. Family Vacations Tara and Anthony talk about how the family plans ahead for long vacations. Safety of Blood Transfusions Tara recalls the scare they had several years ago when the blood Anthony was transfused with wasn’t tested properly. They now participate in a directed donor program. Mom’s Point of View. Tara talks about how she treats Anthony.