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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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?
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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
edit- 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?
edit- 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
A simple blood test can be performed that will detect most types of thalassemia trait
- 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
edit- 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
editReferences
edit- Giardina P, Hilgartner M. Update on thalassemia. Pediatr Rev 1992;13:55-62.
- Rund, D Rachmilewitz, E. Thalassemia major 1995: older patients, new therapies. Blood Rev 1995; 9:25-32
- Piomelli S, Loew T. Management of thalassemia major (Cooley's anemia). Hematol Oncol Clin North Am 1991;5:557-69.
- The Metabolic and Molecular Bases of Inherited Disease (8th edition). 2001. McGraw Hill. Chapter 181 Hemoglobinopathies . Weatherall, D.J., Clegg, J.B., Higgs, D.R., Wood, W.G.
- Guideline: The laboratory diagnosis of haemoglobinopathies. British Journal of Haematology. 1998. 101 (783-792)
Notes
editThe information in this outline was last updated in 2002.