What Is Thalassemia?
Thalassemias are genetic disorders caused by over 300 known mutations in the hemoglobin genes. Hemoglobin is a protein found in red blood cells that carry oxygen in the blood. Hemoglobin is composed of an iron-containing group (heme group) and protein subunits (globin) [1, 2].
Before birth, fetal hemoglobin is the main oxygen-carrying component in the blood. After birth, it gradually converts to adult hemoglobin. The types of hemoglobin found in the blood are :
- Adult hemoglobin: 2 alpha and 2 beta subunits (97% of hemoglobin)
- Hemoglobin alpha 2: 2 alpha and 2 delta subunits (2.5% of hemoglobin)
- Fetal hemoglobin: contains 2 alpha and 2 gamma subunits (0.5% of hemoglobin)
Thalassemia mutations produce defective or missing alpha, beta, or delta chains of the hemoglobin. As a result, hemoglobin levels are lower and there are fewer healthy red blood cells. Because they have fewer healthy blood cells, people with thalassemias often have mild to severe anemia .
Causes & Types of Thalassemia
Thalassemias are caused by changes or deletions in the hemoglobin genes. Everyone inherits 2 copies of each gene, one from each parent. Severe forms of thalassemia occur when a person inherits multiple defective copies. Men and women are at equal risk of inheriting it, meaning the genes that affect thalassemia are on non-sex chromosomes (autosomal disease) [5, 6].
- Alpha – HBA1 and HBA2, found on chromosome 16
- Beta – HBB, found on chromosome 11
- Delta – HBD, found on chromosome 11
- Gamma – HBG1 and HBG2, found on chromosome 11
Defective or reduced production of the alpha subunits results in alpha-thalassemia. All hemoglobin contains 2 alpha subunits. The genes associated with the alpha subunits are HBA1 and HBA2 :
Hemoglobin Bart Syndrome
- Characterized by a loss of all 4 alpha subunit gene copies
- Caused by deletions on both copies of HBA1 and both copies of HBA2
- Usually results in death before birth
- Pregnant women carrying a fetus with this syndrome can experience exacerbated anemia, preeclampsia, congestive heart failure, and miscarriage.
Hemoglobin H Disease
- Characterized by a loss of 3 alpha subunit gene copies
- Caused by deletion of both copies of the HBA1 or HBA2 gene and also either deletion or inactivation of 1 copy of the other gene
- Can also be caused by the Constant Spring variant (HBA2 gene) which produces inactive alpha subunits that are abnormally long and unstable
- Characterized by a loss of 2 alpha subunit gene copies
- Can be caused by deletion or inactivation of 2 alpha subunit genes or by inactive variants of both copies of the HBA2 gene
- People with alpha-thalassemia trait may have moderate symptoms
Alpha-Thalassemia Silent Carrier
- Characterized by a loss of 1 alpha subunit gene copy, due to deletion or inactivation
- People with this condition usually have no symptoms
Reduced production of the beta subunit and thus reduced adult hemoglobin levels in the blood can cause beta-thalassemia. Depending on the type of mutation, beta-thalassemia can be classified as [5, 1]:
- Also known as Cooley’s Anemia and Mediterranean Anemia
- Characterized by hemoglobin levels below 7 g/dL
- People with beta-thalassemia major require regular blood transfusions.
- Characterized by hemoglobin levels between 7-10 g/dL
- People with beta-thalassemia intermedia may require blood transfusions at some point(s) in their life.
- Characterized by below-average hemoglobin and red blood cell size.
- Generally, people with beta-thalassemia minor do not have severe symptoms
Hemoglobin E is a common, abnormally structured variant of beta hemoglobin, which is produced at reduced levels and by itself, has similar symptoms to beta-thalassemia minor. However, it can also occur simultaneously with alpha- or beta-thalassemias. The types of hemoglobin E thalassemias are [8, 9]:
- This condition accounts for approximately 50% of severe beta-thalassemias.
- It occurs when the structural variant (hemoglobin E) from one parent is inherited with a beta-thalassemia gene from the other parent.
- Many different factors affect the severity of this condition, such as the type of beta-thalassemia.
Hemoglobin AE/Bart’s Disease
- Characterized by the inheritance of hemoglobin H disease (3 defective copies of alpha subunit genes) with 1 copy of the hemoglobin E variant
- Considered an intermediate thalassemia disorder
Hemoglobin EF/Bart’s Disease
- Characterized by the inheritance of hemoglobin H disease (3 defective copies of alpha subunit genes) with either hemoglobin E/beta-thalassemia or both copies of the hemoglobin E variant
- Considered an intermediate thalassemia disorder
- Its symptoms are similar to hemoglobin H disease
Delta-thalassemia is a very rare mutation in the delta subunit gene (HBD gene). Since the hemoglobin-containing delta subunits only make up 2.5% of total hemoglobin, mutations in this gene are not severe. However, delta-thalassemia can occur with beta-thalassemia [10, 11, 12]:
- Results from the deletion of both the delta and beta subunit genes on chromosome 11
- Production of gamma subunits increases, which means increased levels of fetal hemoglobin, which can decrease symptom severity
- Deletion of one copy of delta and one copy of beta subunits is symptomatically similar to beta-thalassemia minor.
- Deletion of both copies of delta and both copies of beta subunits results in symptoms similar to beta-thalassemia intermedia.
How Common Are Thalassemia Conditions?
Multiple studies, including one meta-analysis, concluded that some thalassemia mutations offer protection from malaria, which could explain its prevalence in areas where malaria is common. Thalassemia is common in the Mediterranean, Middle-East, Transcaucasus, Central Asia, Indian subcontinent, and Far East regions and in people of African descent [13, 14, 15, 16, 17].
The most common thalassemia is alpha-thalassemia silent carrier (inactivation of 1 alpha subunit gene copy). It is not clinically significant due to a lack of symptoms .
Symptoms & Diagnosis
People with thalassemias conditions generally have similar symptoms, with the severity of the symptoms depends on the number of defective or absent genes. Milder forms of thalassemia may be misdiagnosed or identified quite late in life and have the following symptoms [5, 6, 1]:
- Delayed or stunted growth
- Feeding problems in infants
- Mild jaundice (yellowing of the skin and the whites of eyes)
- Pale skin/pallor
- Recurrent fever
- Enlarged stomach due to an enlarged liver or spleen
- Bone deformities and fractures
- Hemoglobin H patients develop gallstones and experience hemolysis (destruction of red blood cells) as a side effect of drugs and infections.
- Iron overload can occur due to repeated blood transfusions or increased iron absorption .
Laboratory tests usually include blood tests that reveal the size and appearance of the red blood cells and levels of specific hemoglobin. Small and pale red blood cells indicate low levels of hemoglobin, as hemoglobin is what makes the blood cells red and low levels of hemoglobin result in smaller cells. In mammals, red blood cells usually don’t contain a nucleus (the brain of the cell), except in babies. Thus, the presence of red blood cells with a nucleus in adults could indicate thalassemia (fetal hemoglobin) [6, 20].
Small, pale red blood cells would indicate thalassemia, in general. Hemoglobin H disease should also have a higher rate of red blood cell death (hemolytic anemia). Red blood cells with nuclei and decreased adult hemoglobin levels with increased fetal hemoglobin level would indicate beta-thalassemias. In hemoglobin Bart syndrome, an ultrasound would reveal a thickened placenta and build-up of fluid around major organs in the fetus [6, 5].
Genetic tests would reveal which genes have a mutation or deletion and therefore, detect the thalassemia type (or types). These tests are helpful because the blood tests are not as exact. Siblings of people with severe thalassemias can also get molecular genetic testing for known harmful SNPs in the family or blood testing if the harmful SNPs in the family are not known [6, 5, 6, 5].
Genetic counseling can reveal the likelihood of relatives having thalassemia. This can be very helpful because a lot of thalassemias are not caught until later in life, which can negatively affect the quality of life.
Genetic counseling can determine that a sibling of a person with beta-thalassemia has :
- A 25% chance of being affected
- A 50% chance of being a carrier with no symptoms
- A 25% chance of being unaffected and not a carrier
Treatment For Thalassemias
- Chelation therapy (binding and removal of excess iron) for iron overload
- Vitamin and mineral supplementation
- Red blood cell transfusions (occasional or chronic)
- Removal of the spleen (splenectomy)
- Surgery for gallstones and leg ulcers
- Radiotherapy or hydroxyurea (a drug) to prevent the formation of red blood cells outside the marrow
If hemoglobin Bart syndrome is diagnosed early, blood transfusions within the uterus and stem cell transplants can improve the outlook and reduce mortality .
Blood transfusion is the standard therapy for severe forms thalassemia (beta-thalassemia major, severe hemoglobin E/beta-thalassemia, hemoglobin H constant spring, and hemoglobin Bart syndrome) to maintain hemoglobin levels and reduce the production of defective red blood cells. Regular transfusion can prevent or eliminate the side effects of defective red blood cell production. However, it can lead to severe, long-term iron overload (too much iron in the blood) [1, 23].
New Therapies For Thalassemias
Bone marrow transplantation is an alternative treatment for beta-thalassemia. If successful, it can eliminate the need for iron chelation .
Umbilical cord blood transplantation can be a successful cure for beta-thalassemia, with lower risks as compared to bone marrow transplantation .
Women pregnant with a child with hemoglobin Bart syndrome are at risk for complications such as high blood pressure and premature delivery or miscarriage .
Pregnant women with hemoglobin H disease may experience exacerbated anemia, high blood pressure, and miscarriage and other complications .
Dealing With Thalassemia Symptoms
Thalassemia patients should closely monitor their diet to increase their quality of life. Thalassemia conditions can cause stunted growth during childhood. Thalassemia patients commonly have nutritional deficiencies. Therapies for thalassemia often results in iron overload, which can cause many issues. Regular nutrition check-ups can prevent complications [29, 30].
Nutritional requirements described below are by no means complete. Only an expert nutritionist can give a personalized insight into dietary requirements based on deficiencies. Nutritional counseling is especially essential for :
- Pregnant patients
- Diabetics (can be caused by iron overload)
- Vegetarians or vegans
- Lactose intolerant patients
- Patients with food allergies
Common Vitamin and Mineral Deficiencies
- Vitamin D (10x greater risk of low bone mass due to vitamin D deficiency)
- Vitamin A
- Vitamin E
- Vitamin K
- Vitamin B9
- Zinc (it can be accidentally removed along with iron in chelation therapy)
Complications of iron overload from blood transfusions include stunted growth and failure or delay of sexual maturation in children as well as heart conditions, HIV, hepatitis, enlarged spleen, osteoporosis, and imbalanced hormones in adults .
Natural Substances That Reduce Iron Intake
Some natural substances such as tea and curcumin (turmeric) can reduce iron absorption.
Tea (275 mg tannins/240 mL water) reduced iron absorption by 41-95% in 5 thalassemia patients. Since patients with thalassemia absorb a large percentage of iron, inhibitors of iron absorption are useful in the management of iron overload .
A daily dose of 500mg of curcumin (an active component of turmeric) reduced blood iron levels and oxidative stress in 21 hemoglobin E/beta-thalassemia patients. A similar study showed curcumin (1,000 mg/day for 12 weeks) decreased blood iron levels by 18% in the curcumin group (DB-RCT of 68 transfusion-dependent beta-thalassemia patients) [35, 36].
Thalassemia Patients Should Avoid…
People with alpha-thalassemias should abstain from inappropriate iron therapy and oxidant drugs, such as sulphonamides and some antimalarial medication because of the risk of red blood cell destruction .
Beta-thalassemia patients should avoid alcohol consumption and iron-containing preparations .
Thalassemia Genetics and SNPs
SNP, (pronounced “snips”) or single nucleotide polymorphism, is a single change (polymorphism) to one of the DNA building blocks (nucleotide) in a person’s DNA. SNPs are normal and occur every 300 nucleotides or so, meaning there are approximately 10 million SNPs in everyone’s genomes. Sequencing your genes would locate your SNPs, which can reveal a lot of helpful information about your health, such as your risk of developing specific diseases and how environmental factors and drugs might affect you .
If you’ve gotten your genes sequenced, SelfDecode can help you determine if your health issues may be a result of your genes, and then pinpoint what you can do about it.
SNPs That Benefit Thalassemia Patients
Thalassemias are a very complicated set of genetic diseases, as different thalassemias can occur simultaneously. Some combinations actually decrease the severity of symptoms. For instance, reduced production of both alpha and beta subunits can actually decrease the imbalance between these subunits [38, 5].
Similarly, beta-thalassemia patients with the rs7482144 SNP respond better to a drug that raises hemoglobin levels (hydroxyurea). This SNP also increases fetal hemoglobin levels and reduces the need for frequent blood transfusions [40, 41, 42].
Alpha-Subunit Genes (HBA1, HBA2)
Some SNPs related to alpha-thalassemia:
- rs41417548 (Hb Sallanches): risk of hemoglobin H disease [43, 44]
- rs41323248 (Hb Dartmouth): risk of hemoglobin H disease 
- rs34021271 (Hb Pak Num Po): transfusion-dependent hemoglobin H disease 
- rs41464951 (Hb Constant Spring): hemoglobin H disease or carrier 
- rs41412046 (Hb Pakse): hemoglobin H disease or carrier 
- rs41341344 (Hb Agrinio) 
- rs35992350 (Hb Heraklion) 
- rs35672478 (Hb Aghia Sophia) 
Beta-Subunit Genes (HBB)
SNPs that may increase the risk for beta-thalassemia:
- rs63751128: 2 copies of the G variant may lead to beta-thalassemia intermedia 
- rs34451549: the presence of the T variant may indicate beta-thalassemia carrier state [53, 54]
- rs33915217: [55, 56]
- rs33972047: 
- rs33944208: [58, 59]
- rs35699606: beta-thalassemia major 
- rs33960103: beta-thalassemia major [61, 62]
Delta-subunit Genes (HBD)
Following SNPs have the risk variants for delta-thalassemia:
If you’re sick and tired of guessing about your health, SelfDecode can help you find specific answers that conventional doctors/diagnostics may never uncover.
Limitations and Caveats
Because thalassemias conditions involve over 300 different known mutations, with a wide variety of complications, it is difficult to develop a complete picture of the disease .
Changes in hemoglobin genes can increase the risk of developing other genetic conditions like osteoporosis. Personalized genetic counseling can increase the quality of life of thalassemia patients .