Thalassaemia is a genetic blood disorder. The disorder causes people affected to not be able to make enough haemoglobin, the molecule that carries oxygen on red blood cells. Haemoglobin is important because it delivers the oxygen the cells require to carry out cellular respiration. This is a crucial process because it is how people get their energy. Thalassaemia limits the amount of oxygen that can be transported around the body. This impacts organs of the body because they become starved of oxygen and cannot function correctly.
There are two types of Thalassaemia: Alpha Thalassaemia and Beta Thalassaemia. The type of Thalassaemia is dependant on the type of haemoglobin affected. A normal human has roughly 95% haemoglobin A. Haemoglobin A is composed of two alpha and two beta globins. The genes for the different globins are carried on different chromosomes.
In a thalassaemia patient, a deletion or mutation of the genes that control the production of globins occur. The proportions of the globins are resultantly incorrect. The globin that is controlled by the affected gene is produced in little amounts and the globin that is produced as normal is created in excess. As the excess globin builds up in the red blood cells, the cell membrane of the cells are damaged and can lead to premature cell death.
Beta thalassaemia is caused by the excess of alpha globins. The haemoglobin molecule in a person with beta thalassaemia consists of 4 alpha globins rather than the two to two ratio of normal haemoglobin molecules.These abnormal haemoglobin molecules accumulate in immature red blood cells and interfere with cell maturation and cell membrane function. Alpha thalassaemia is caused by the excess of beta globins. This forms haemoglobin H, made of 4 beta globins. This type of haemoglobin can shorten the life of red blood cells.
Different types of thalassaemia can be known as Mediterranean anaemia, Cooley’s anaemia, haemoglobin H disease and hydrops fetalis.
Facts and Symptoms
The symptoms that a person with thalassaemia will experience varies depending on the type of thalassaemia that they have. The symptoms are caused by a lack of oxygen in the bloodstream.
Alpha Thalassaemia silent carriers, people with one missing or damaged gene and three normal genes, usually have no symptoms. Blood test results are usually normal. The body’s haemoglobin works normally in silent carriers. They can, however, pass it on to their children.
People with alpha or beta thalassaemia trait may experience mild anaemia. Alpha thalassaemia trait is caused by a change in two copies of the alpha globin gene and beta thalassaemia trait is caused by a change in one copy of the beta globin gene. People with these thalassaemia traits can experience no symptoms at all. Those who do experience anaemia may feel tired. The anaemia caused by the alpha trait can be misidentified as iron-deficiency anaemia.
Beta thalassaemia intermedia is more severe than beta thalassaemia trait and milder than thalassaemia major. It can be caused by one or two damaged or missing beta genes. The signs and symptoms of thalassaemia intermedia appear in early childhood or later in life. Affected individuals have mild to moderate anaemia and may also have slowed growth and bone abnormalities. Thalassaemia can cause the bone marrow to expand and can lead to the bones growing wider than normal. They can become brittle and can break easily. Puberty can also be delayed because anaemia can slow down a child’s growth and development. People with beta thalassaemia intermedia can develop an enlarged spleen. The spleen is an organ that helps fight infection and the thalassaemia causes it to work harder. This can lead to spleen becoming larger, making the anaemia worse. If the spleen becomes too large, it must be removed.
Cooley’s anaemia (also known as beta thalassaemia major) occurs when both beta genes are missing. This causes moderate to severe anaemia. Symptoms begin to appear within the first 2 years of life. Other symptoms of this type of thalassaemia include a pale and listless appearance, poor appetite and jaundice, a yellow colour of the skinner whites of the eyes. People with this can experience dark urine, a sign that their red blood cells are breaking down, or the symptoms of beta thalassaemia intermedia, an enlarged spleen, liver or heart, slowed growth, delayed puberty and bone problems.
Alpha thalassaemia major occurs when all four alpha globin genes are missing. This causes severe anaemia, however, in most cases, a baby with this condition will die before or shortly after birth.
Other complication of thalassaemia include heart and liver diseases, increased risk of infection and osteoporosis. The heart can be affected by regular blood transfusions, overloading the body with iron. Heart disease caused by thalassaemia is the main cause of death in people with thalassaemia. People who have their spleen removed because of thalassaemia are at greater risk of infection.
Who is likely to contract thalassaemia?
Thalassaemia is a genetic disease and a person’s parents must have the genetic mutation for them
Worldwide, 15 million patients have clinically apparent thalassaemic disorders. Reportedly, thalassaemia carriers in India alone number approximately 30 million.
– https://www.myvmc.com/diseases/thalassaemia-mediterranean-anemia-cooleys-anemia/ to have it themselves. Alpha thalassaemia occurs most often in people of African and Southeast Asian descent. Beta thalassaemia is most common in of Mediterranean, African and Southeast Asian descent. On average 3 in 100 people in the world’s population have a thalassaemia gene. However, the chance of having a specific gene caries depending on the person’s family origin. For example, beta thalassaemia genes are carried by: 1 in 7 Greek Cypriots, 1 in 12 Turks, 1 in 20 Asians and 1 in 1,000 English of North European origin. Thalassaemia affects approximately the same number of females and males. About 300,000 to 400,000 severely affected infants are born worldwide every year. More than 95% of these births occur in Asia, India and the Middle East. It is estimated that 15% of African Americans in the USA are silent carriers of thalassaemia. The highest concentration of people with thalassaemia are in areas where the rate of malaria is still high. It is thought that, in malarial regions of the world, natural selection has been responsible for elevating and maintaining the gene frequencies of thalassaemia.
What is the prognosis for someone with thalassaemia?
The prognosis varies depending on the type of thalassaemia and the severity of the disease that a person has. The prognosis of alpha thalassaemia major is death. Babies with this type usually die before they are born or shortly afterwards. People with beta thalassaemia major must receive regular blood transfusions and extensive mescal care in order to survive past childhood. Even if they were to survive, this treatment would have to be continued throughout their life.
Carriers of thalassaemia have a normal life expectancy and usually enjoy good health. People with haemoglobin H disease, people who have 3 out of 4 alpha genes damaged, usually survive into adulthood, however can have a lower quality of life due to the disease. People with mild forms of thalassaemia have a relatively normal life expectancy with generally good health, although they should be informed of possible consequences of having the disease and may like to see a genetic counsellor.
The prognosis for people with Cooley’s anaemia depends on their reaction to treatment and how frequent they receive treatment. The treatment can be so troublesome and painful that people can give up. If no treatment is received, it can lead to death from heart failure or infection.
What is the mode of inheritance?
Thalassaemia is a genetic disease that is passed on from parents to children. It is caused by a genetic mutation on chromosome 11 or chromosome 16, depending on the type of thalassaemia. This means the disease is autosomal, meaning being carries on an autosome, a chromosome that is not involved with sex determination. Thalassaemia is also said to be a recessive condition. This is because having only one or two defective genes does not result in the condition being shown.
The abnormal gene responsible for beta thalassaemia is found on chromosome 11. Alpha thalassaemia is caused by two abnormal genes on chromosome 16. Both serious forms of the disease are recessive. Children who inherit such genes from just one parent may have a mild form of thalassaemia.
As it is recessive, a child could be born with 2 defective beta genes from two parents that do not show any traits. This can be shown in the punnet square below.
Each child receives one alleles from each parent. Because both parents in this case have the recessive allele, there is a 25% that their child with receive both recessive alleles. These two parents have a 25% of producing a completely normal child and a 50% chase of producing a child with the beta thalassaemia trait, being heterozygous.
The inheritance of the alpha genes are slightly more complicated because there are 2 genes that control the trait and they are located on the same chromosome. This means that 2 of the parents alleles are inherited together. The following dihybrid cross represents the inheritance of the alpha genes.
Two parents, who both have alpha thalassaemia trait and can experience no symptoms, can produce children with all possible genotypes. The expected phenotypic ratio produced in a cross of two individuals heterozygous at each loci will always be 9:3:3:1. This is shown above. These two parents can produce a child who is completely normal (AADD), an alpha thalassaemia silent carrier (AADd or AaDD), have alpha thalassaemia trait (AaDd), haemoglobin h disease (aaDd or Aadd) or the fatal alpha thalassaemia major (aadd).
Is there a cure or treatment?
The standard treatment for thalassaemia is regular transfusions of ‘packed’ red blood cells. Most thalassaemia major patients require transfusions every 2-4 weeks, depending on the individual’s consumption of the infused cells. While regular transfusions greatly contribute to the quality and length of life of thalassaemia major patients, they also leave patients with an excess of iron in their bodies. This dangerous side effect is known as iron overload.
Regular use of a drug called desferrioxiamine can be used to treat severe cases of thalassaemia. It reduces the levels of iron in the tissues that has accumulated from repeated blood transfusions. Excess iron can damage the liver, endocrine glands and heart. The drug is given by subcutaneous infusion over 8-12 hours several times a week. Ascorbic acid may also be prescribed at the same time to increase iron output in the urine.
Bone marrow transplants can be done to treat people affected by thalassaemia. This treatment is most effective when carried out earlier in life. Hematopoietic cell transplantation relies on high-dose chemotherapy to eliminate thalassemia-producing cells in the marrow and replaces them with healthy donor cells from bone marrow or umbilical cord blood. This treatment is only an option when the patient has a suitable donor.
The spleen can also be removed, a procedure known as a splenectomy. This is done when the patients spleen is enlarged. This can have adverse effects because the spleen fights infection and the body is vulnerable without it. Anti-pneumococcal and anti-Haemophilus vaccines and penicillin V are given to the patient to protect them from disease.
Are there any advance in current research using gene therapies or treatment?
The development of gene transfer for the treatment of thalassaemia has been a goal for more than three decades. The anticipated targets for gene transfer are hematopoietic stem cells. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Various types of vectors have been considered for gene transfer into stem cells, with integrating retroviruses being the leading candidate. Recently, one participant in an ongoing gene transfer trial for severe beta-thalassaemia has achieved clinical benefit with elimination of their transfusion requirement. Rather than transferring a globin gene, another approach would involve the activation of the endogenous gamma-globin genes to compensate for the lack of beta-globin synthesis. Recently, alternative targets for gene transfer including induced pluripotent stem cells derived from patients’ somatic cells have been proposed, although the development of this strategy is far more distant than stem cell–targeted gene transfer.
Genetic Testing
Genetic screening and testing is a contentious issue because although it will have an impact on the individual, it may also have an impact on their family and society as a whole.
What genetic testing is available for thalassaemia and how accurate are the results?
Genetic testing for thalassaemia often starts with a simple blood test. A complete blood count (CBC) is an evaluation of the cells in the blood. Among other things, the CBC determines the number of red blood cells present and how much haemoglobin is in them. It evaluates the size and shape of the red blood cells present. The results can be quite accurate in measuring the cells in the blood but the results cannot definitively prove the person has thalassaemia.
A haemoglobin electrophoresis is a blood test used to measure and identify the different types of haemoglobin in the bloodstream. It is another test that is used to determine whether someone has thalassaemia. A haemoglobin electrophoresis test doesn’t tell you about the amount of haemoglobin in your blood — that’s done in a complete blood count. The levels that a haemoglobin electrophoresis test refer to are the percentages of the different types of haemoglobin that may be found in your blood. This is important because it if an abnormal amount of a specific type of haemoglobin is detected, a blood disorder is likely. It cannot definitively determine whether thalassaemia is the disorder that is causing the abnormality.
Iron deficiency can confuse the interpretation of test results, so iron studies are also often required. DNA analysis may be needed to detect the carrier state, particularly in carriers. In some of these cases, they experience none of the symptoms and their blood is not affected. DNA analysis is the only way to detect a mutation in these cases.
What is the procedure for this testing?
A simple blood test can be undertaken and all of the above tests can be done from the one sample.
In the past, counting the cells in a patient's blood was performed manually, by viewing a slide prepared with a sample of the patient's blood. More sophisticated modern analysers can provide extended differential counts and more accurate results. Blood counting machines draw out a very small amount of the specimen through narrow tubing followed by an aperture and a laser flow cell. The instrument measures the type of blood cell by analysing data about the size and aspects of light as they pass through the cells. In addition to counting, measuring and analysing red blood cells, white blood cells and platelets, automated haematology analysers also measure the amount of haemoglobin in the blood and within each red blood cell. This is done by adding a diluent that lyses the cells which is then pumped into a spectro-photometric measuring cuvette. The change in colour of the lysate indicates to the haemoglobin content of the blood.
Haemoglobin electrophoresis is done to identify the levels of different types of haemoglobin. In the laboratory, a process called electrophoresis passes an electrical current through the haemoglobin in your blood sample. This causes the different types of haemoglobin to separate into different bands. Your blood sample is then compared to a healthy sample to determine which types of haemoglobin are present. High amounts of either beta or alpha haemoglobin can help diagnose thalassaemia.
DNA testing can be done to identify the genotype of a person suspected of having thalassaemia. DNA is extracted from the blood sample and undergoes a process called Polymerase Chain Reaction (PCR). During the first step of PCR, called denaturation, the tube containing the sample DNA is heated to more than 90 degrees Celsius, which separates the double-stranded DNA into two separate strands. The high temperature breaks the relatively weak bonds between the nucleotides that form the double helix of DNA. PCR does not copy all of the DNA in the sample. It copies only a very specific sequence of genetic code, targeted by the PCR primers. The primers bind to the beginning of the sequence that will be copied. The DNA is then heated again and nucleotides are added to solution forming 2 identical strands of the required DNA. This process is repeated again and again until their is enough DNA to analyse. Gel electrophoresis, a process very similar to haemoglobin electrophoresis can then be undertaken to analyse the results.
Who should be tested?
Thalassaemia testing should be performed if a person has family history of thalassaemia and, although not part of first trimester screening in most pregnancies, should be considered in at-risk groups, e.g. people of Mediterranean, African, Subcontinent and Asian descent.
If you're expecting a baby and you and your partner are thalassaemia carriers, you may want to consider prenatal testing. Prenatal testing involves taking a sample of amniotic fluid or tissue from the placenta. Tests done on the fluid or tissue can show whether your baby has thalassaemia and how severe it might be.
Genetic Counselling
Genetic counselling is the communication process of providing information and support to individuals and families with a diagnosis and/or risk of occurrence of an inherited disorder. Culturally sensitive genetic counselling, with an emphasis on reproductive issues, is an integral and necessary component of comprehensive care for patients and parents affected by all forms of thalassaemia disease and trait.
Medical implications
After receiving the results of a genetic testing, finding out that a person has thalassaemia can have a major impact on members of their family. In particular, it has a number of medical implications. The results of one family members test can indicate the genotype of their parents and can suggest possible genotypes of any siblings. This could affect their decision to get a genetic test or to start a family.
Treatment could also be too painful. Some people believe that treatment is essential but for people with thalassaemia who cannot bear the pain, it can be thought to believe as better to live out the disease. This is a controversial topic.
Psychological implications
It is now universally recognised that thalassaemia, like other chronic diseases, has important psychological implications. The way in which the family and the patient come to terms with the disease and its treatment will have a critical effect on the patient’s survival and quality of life. Without an understanding and acceptance of the disease and its implications, the difficulties of lifelong transfusion and chelation therapy will not be faced, leading to an increased risk of disease complications and poorer survival. A key role for treating physicians and other health care professionals is to help patients and families to face up to the difficult demands of treatment, while maintaining a positive role.
Social implications
Many social issues can arise from having thalassaemia. One of these is privacy such as who has the right to know that a person has thalassaemia? Another issue than can arise is discrimination. Employers might chose to hire a healthy person over someone with thalassaemia if they find out. Health care insurers may make insurance more expensive for people who know they have thalassaemia. Would it be better to not disclose this information to anyone?
What information and support networks could be provided to the family?
A genetic counsellor would be the main source of information for people with thalassaemia and their families. Many foundations and smaller support groups exist that allow families to come together and discuss strategies to cope with thalassaemia. Examples of these are the Thalassaemia and Sickle cell Anaemia Society of Australia and the Thalassaemia Society of NSW.
Decision Making
Who are the stakeholders in the decision making process and what values and priorities do these affected groups have?
The first stakeholder is the person making the decision. This will most likely be the person who is thought to have or does have thalassaemia. The parents of this person would also be involved in the decision making process. For example, if their child was to have a test done to identify whether they had the disorder, it would indicate whether the parents had the gene. They might have not wanted to get the test done and by having their child do it, they would known.
The affected person’s siblings could have a part in the decision. Test results would indicate the likelihood they could have the disorder. The decision would impact them as well and therefore they might have some say in the choice.
The person’s children could affected. Results of a test would indicate the likelihood that they would have the abnormal gene. The child could not want to know the likelihood they could have thalassaemia or would encourage the test because they wanted to know.
The person’s spouse would play a large role in the decision making process. Whether a person was to have children based on the likelihood of passing on the disorder, would also impact the spouse. Prenatal testing would also have to involving the spouse and whether an unborn child would be aborted if it was discovered that it had inherited a sever form of thalassaemia.
The genetic counsellor would be involved. They are there to give the information, facts and statistics to the person. This can highly impact the overall decision. The genetic counsellor is there to support the person through decision they make and ultimately want them to make the right decision for themselves.
What decisions might need to be made?
Genetic disorders often require many decisions to be made. They can play a large role in deciding whether to start a family or not. Some other dilemmas might be:
Should two carriers undergo prenatal testing so that their child does not inherit thalassaemia?
If an unborn child if found to have thalassaemia, should the child be aborted?
Who should know this information?
Do family members need to know the results of the test?
A positive result showing that one or both of the parents is a carrier. Should the whole extended family undergo testing?
Ultimately, it is up the person and depends on their values and opinions.
Social and Ethical Implications
Ethical issues concern what is moral or right, legal issues concern the protection that laws and regulations provide and social issues concern how society and individuals will be affected.
Legal implications
The legal concept of autonomy (the capacity to make an informed, un-coerced decision) serves as the basis for numerous decisions protecting a person's bodily integrity. In particular, cases have held that competent adults have the right to choose whether or not to undergo medical interventions. Before people make such a choice, they have a right to be informed of facts that might be material to their decision, such as the nature of their condition and its prognosis, the potential risks and benefits of a proposed test or treatment, and the alternatives to the proposed intervention. Previously, health care providers have been held liable for not providing the information that a genetic test is available.
Communicating Test Results
A genetic counsellor should always do what is best for the patient. It is critical that genetic test results are discussed with patients in an understandable manner. As many genetic tests will not provide simple positive/negative results, but potentially inconclusive results or risk estimates, it is important that patients understand the extent of the information actually provided from a genetic test. Results should be released only to those individuals for whom the test recipient has given consent. The method of communication should be chosen in advance (for example by phone, or in person) to minimise the likelihood that results will be shared with unauthorised persons or organisations. Under no circumstances should results with identifiers be provided to any outside parties, including employers, insurers, or government agencies, without the test recipient’s written consent.
Duty to Disclose
The results of a genetic test may have implications for a patient’s family members. However, health care providers have an obligation to the person being tested not to inform other family members without the permission of the person tested, except in extreme circumstances. If a health professional believes family members may be at risk, the patient may be encouraged to discuss test results with other family members. In general, families are opposed to doctors informing at-risk members without their consent, even in cases where the disease is easily preventable. The duty to inform varies by state, and courts have ruled on differing sides in different cases.
The suggested by the American Society of Human Genetics that disclosure to at-risk individuals is permissible when the following criteria are met:
• Attempts to encourage disclosure on the part of the patient have failed
• Harm is highly likely, serious, imminent, and foreseeable
• At-risk relatives are identifiable
• Disease is preventable, or medically accepted standards for treatment or screening are available
• The harm from failing to disclose outweighs the harm from disclosure
Informed Consent
To help ensure that patients understand the risks and benefits of health care choices, informed consent is an important part of the medical decision-making process. For patients considering genetic testing, the following items should be carefully discussed and understood before consent is obtained:
• Testing is voluntary
• Risks, limitations, and benefits of testing or not testing
• Alternatives to genetic testing
• Details of the testing process (for example, what type of sample is required, accuracy of test, turn-around time, etc.)
• Privacy/confidentiality of test results
• Potential consequences related to results including
◦ Impact on health
◦ Possible emotional and psychological reactions
◦ Treatment/prevention options
◦ Ramifications for family
Social Implications
Genetic Discrimination
When considering genetic testing, a major concern often raised is the potential of discrimination based on genetic information. Since genetic test results are typically included in a patient’s medical record, patients should be aware that the results may be accessible to others. As a result, genetic test results could affect a person’s insurance coverage or employment.
In addition, members of minority communities often fear that genetic information will be used to stigmatise them. Health providers should be sensitive to the fact that some groups may mistrust the use of genetics as a health tool.
Privacy
Genetic information has enormous implications to an individual and his or her family. The privacy of that information is a major concern to patients: in particular, who should have or needs access to that information. In order to protect personal genetic information and to avoid its inclusion in a patient’s medical record, some patients may wish to pay for genetic testing out-of-pocket if possible.
Psychosocial Impact
Every individual will respond differently to news of his or her genetic test results whether negative or positive. As there is no right or wrong response, health professionals should refrain from judgment and help the patient understand what the test results mean with respect to their own health, available interventions or follow-up, and risks to their family. An individual may respond to genetic information on several levels, the individual level, family level, or on a community and society level. Referrals to genetic counsellors, psychologists, or social workers should be made as needed.
Ethical implications
Reproductive Issues
Genetic information is routinely used to inform reproductive decisions and medical care. Risk factors for genetic conditions for which preconception or prenatal genetic testing may be considered include advanced maternal age, family history, multiple miscarriages, or drug and alcohol exposure. As these procedures carry risks and benefits, parents should carefully consider and discuss these options with a physician or genetic counsellor. Providers should take a non-directive stance, especially when the only management option is termination of pregnancy.
Societal Values
Genetic information can raise questions about personal responsibility, personal choice versus genetic determinism/fate, and concepts of health and disease. Personal factors, family values, and community and cultural beliefs will influence responses to these issues. While genetic information may influence one individual to change his or her lifestyle or behaviour in order to reduce risk or disease severity, others may choose to respond differently. Health professionals should be respectful and sensitive to cultural and societal values and work with the patient to define the appropriate course of action for them with respect to genetic testing and follow-up care.
Test Utility
The useful application of genetic tests will depend on the correct interpretation of test results and their utility in guiding medical care and treatment. However, for some genetic conditions, the utility of genetic test results may be limited if no treatment is available or if the results are inconclusive. These issues should be discussed with patients or parents of patients when a genetic test is being considered. Even if a test is not considered to be medically useful, a patient or the family may still gain benefit from testing. Clinical guidelines should be consulted for recommended follow-up care and treatment.
Test Validity
Several issues regarding test validity should be considered prior to ordering a genetic test. The analytical and clinical validity of a test are generally measured as test specificity, sensitivity, and predictive value. This information should be shared with the patient as they consider whether or not testing is appropriate for them.