Handbook of Genetic Counseling/Alpha Thalassemia

Alpha Thalassemia


 * Hemoglobin is the protein in blood that carries oxygen and gives blood its red color
 * A hemoglobin molecule contains four globin chains
 * There are different types of globin chains
 * One of the chains is designated alpha and the others can be grouped together and called non-alpha
 * The combination of two alpha chains and two non-alpha chains produces a complete hemoglobin molecule
 * The combination of two alpha chains and two gamma chains form "fetal" hemoglobin, termed "hemoglobin F"
 * Fetal hemoglobin is the primary hemoglobin in the developing fetus (With the exception of the first 10 to 12 weeks after conception.
 * The combination of two alpha chains and two beta chains form "adult" hemoglobin, also called "hemoglobin A". Although hemoglobin A is called "adult", it becomes the predominate hemoglobin within about 18 to 24 weeks of birth.
 * Must have the right amount of each type of globin being made if there is an imbalance this will result in thalassemia
 * There are different types of thalassemia
 * The severity and type of thalassemia depends on which genes are affected

Alpha Globin

 * The genes that tell the cell how to make alpha globin are found on chromosome 16
 * Each chromosome 16 has two alpha globin genes that are next to each other on the chromosome
 * Since each cell has two copies of chromosomes 16, a total of four alpha globin genes are usually present in each cell
 * There are several different possible outcomes depending on how many of these copies are not functioning (usually due to being deleted)

Silent Carrier

 * If one of the four copies of the alpha globin gene is not present in an individual they will not have any symptoms because they still make enough alpha globin.
 * This individual is often referred to as a silent carrier

Alpha Thalassemia Trait

 * If two of the genes are not present than the person is said to have the alpha thalassemia trait.
 * Does not cause health problems or symptoms
 * The red blood cells are often small and this is referred to as microcytosis
 * 2 ways of having alpha thalassemia trait which can become important when you want to determine risks to potential children
 * 2 genes on same chromosome not functioning (cis) figure 3
 * 1 gene on each chromosome (trans) figure 4

Hemoglobin H Disease

 * If there are three missing copies of the gene then there is even less alpha globin. This causes Hemoglobin H disease.
 * This causes more serious anemia which often requires transfusions
 * Other symptoms include: jaundice, enlarged spleen, and increased risk of infection
 * Called hemoglobin H disease because of an abnormal hemoglobin that forms from excess beta globin(excess beta globin is present and 4 of these come together instead of having 2 alpha globin chains)
 * Hemoglobin H does not carry oxygen and damages the membrane that surrounds the red cell, accelerating cell destruction.
 * The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia

HB Bart's Hydrops Fetalis

 * If there are no genes present than the effects are even more serious
 * Often the fetus is stillborn or dies shortly after birth
 * Rarely, problem is detected in utero, if the disorder occurred in an earlier child. In utero blood transfusions have saved some of these children. These patients require life-long transfusions and other medical support.

How does the screening test determine which category a baby fits?

 * Newborn screening test preformed in every US state measures the percentage of different types of hemoglobins. However, not every state newborn screening program tests and reports for alpha thalassemia.
 * Barts hemoglobin consists of 4 gamma globin chains (results from not enough alpha globin to pair up with to form the fetal hemoglobin consisting of 2 alpha and 2 gamma) (gamma globin is no longer made about 18-24 weeks after birth)
 * Depending on how much Barts hemoglobin an infant has will help categorize them
 * Less than 5% -- most likely missing one gene and may be silent carrier
 * 5-10% usually indicates loss of 2 genes and may have alpha thalassemia trait
 * >10% (usually 15-20%) may have Hemoglobin H disease

Testing

 * Testing can be performed to determine the parents' risks for future pregnancies. A primary care physician can order the following blood tests.
 * complete blood count (CBC) - a measurement of size, number, and maturity of different blood cells in a specific volume of blood.
 * hemoglobin electrophoresis with A2 and F quantitation - differentiation of the types of hemoglobin present
 * FEP (free-erythrocyte protoporphyrin) and ferritin - to exclude iron deficiency anemia.
 * The above testing is fairly inexpensive and covered by most types of insurance
 * Gene testing also available, but more expensive and usually not needed. Testing of the alpha globin genes is the only way to determine silent alpha thalassemia trait.
 * FISH can be performed to determine if there is a large deletion on chromosome 16 in the presence of severe developmental delay

Types of mutations

 * Most are deletions of the gene(s)
 * About 5% of alpha thalassemia is due to point mutations
 * Often cause more severe thalassemia than single gene deletions
 * Hemoglobin Constant Spring -- most common point mutation
 * Stop codon mutated results in large alpha globin protein (RNA unstable and little protein is made)
 * Mutations have also been found in regions of DNA that regulate expression of alpha globin gene

Hydrops Fetalis

 * Can be due to a number of different reasons (immune response to blood that is incompatible such as Rh incompatibility or nonimmune hydrops)
 * Nonimmune hydrops includes a number of explanations like cardiovascular, chromosome abnormality, pulmonary infection and homozygous alpha thalassemia (4 copies of alpha globin gene missing has even been seen in some with 3 missing copies)
 * Sometimes the reason can not be determined
 * Treatment for hydrops caused by some is starting to become available
 * Prognosis still is poor

How common is Alpha thalassemia

 * Occurs in people of all ethnic backgrounds
 * More common in Mediterranean, African, and South-east Asian populations
 * Individuals of African descent are more likely to be silent carriers or have alpha thalassemia trait
 * Individuals in Southeast Asia are more likely to have all four possibilities (estimates of carrier frequency are 1/30)
 * Carrier frequency in other populations is not certain

Rare cases of learning difficulties have been associated with alpha thalassemia.


 * Some due to large deletions of chromosome 16 (other genes presumably deleted too that cause learning difficulties)
 * Can also be due to mutation of the ATRX gene(DNA helicase/repair enzyme). This gene is found on chromosome X and is inherited in an X-linked recessive fashion. Individuals with a mutation in ATRX have a condition called Alpha-Thalassemia X-linked Intellectual Disability Syndrome. Symptoms can include: Developmental delay, distinctive facial features, genital anomalies, and anemia secondary to Hemoglobin H disease.

Types of mutations

 * Most are deletions
 * About 5% of alpha thalassemia is due to point mutations
 * Often cause more severe thalassemia than single gene deletions
 * Hemoglobin Constant Spring -- most common point mutation
 * Stop codon mutated results in large alpha globin protein (RNA unstable and little protein is made)
 * Mutations have also been found in regions of DNA that regulate expression of alpha globin gene

Are you planning more children?
A simple blood test can be performed that will detect most types of thalassemia trait
 * May want to consider testing for you and husband in the future so that it can be determined if there are risks for future pregnancies
 * We will have this information in letter so when and if you want to have the testing your physician can order it
 * May be potential risks to _____ offspring
 * Keep this in mind because she may decide with her partner to have him tested

Psychosocial concerns

 * may be nervous and think there is something serious
 * may be a lot of information to understand at once so talk about letter
 * guilt about passing on something
 * concern that other pregnancy with hydrops is related to this
 * help understand that other reasons for hydrops are more likely due to their ethnic background

Websites

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 * -- basic information about hemoglobin
 * -- great patient literature