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.