# 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?

* 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

* 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

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

## References

* 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

The information in this outline was last updated in 2002.