Current Genetic Understanding On Thalassemia Biology Essay


Genetic diseases are caused by an abnormality in genes or chromosomes which can be newly formed through the result of mutations or be passed over to next generations in a manifest (i.e. dominant) or hidden (i.e. recessive) way, as described by Nussbaum et al. (2004). These diseases can be classified according to their mechanism such as single gene defects (also known as monogenic diseases) which contain today the largest proportion of over 6000 known disorders, or multiple gene defects (also known as polygenic diseases) involving more than one gene along with environmental factors such as Diabetes mellitus, high blood pressure or Alzheimer's. Mutations in genes can alter the function, pattern, structure or number of genes present on certain chromosomes. A genetic disease is classified as X-linked if the sex chromosome is the affected or carrier chromosome, and autosomal if an autosome is the affected or carrier chromosome. A person with a dominant genetic disease will be affected if it has at least one gene presenting the disorder, whereas a person with a recessive trait can be a carrier for the genetic disorder if only one chromosome has it, or be affected if the pair of chromosomes both have a mutation for the gene.

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Thalassemia is an autosomal recessive inherited blood disorder which results in decreased or absent synthesis of globin chain (Weatherall, 2010, Chui et al, 2002).

Red blood cells carry oxygen with the help of a protein called haemoglobin which comprises of 2 α and 2 β globin chains controlled by a specific gene (Weatherall, 2010) and a defect in any of these chains will lead to an abnormal red cell production called ineffective erythropoiesis. Abnormal size (microcytosis) and shape of red blood cells can lead to the destruction of red blood cells (hemolysis) causing a shortage of blood (anaemia).

Due to the different oxygen requirements during early life development, haemoglobin forms changes from embryonic, to fetal and adult life.

Figure 1: Evolution of globins from fetal to adult life (Steinberg, 2001)

The haemoglobins are named Gower 1, 2 and Portland, and are dominant in the early embryo (Figure 1). Then synthesis of α, β and γ happens in the yolk sac from 6th week and in fetal liver and spleen from 10 to 12 week (Bain, 2006). Fetal haemoglobin is Hb F (composed of α2γ2), while the major haemoglobin in adult is Hb A (α2β2) and the minor one is A2 (α2δ2). These are variants of haemoglobins in unaffected people and thalassemia is characterised by a defect in one or more of the globin chains (Thein, 2005).

Alpha and β genes are found in clusters, i.e. they are a set of genes derived by duplication and variation from some ancestral gene (Hardies et al, 1984), which implies that they are prone to further evolution. The α genes are clustered on chromosome 16 and the beta globin genes are clustered on chromosome 11 and each gene cluster is regulated by a single regulatory region HS-40 in case of alpha globin and 4 regions in case of beta globin in combination called β-globin locus control region (Steinberg, 2001).

A normal person has 4 α-globin genes and 2 β-globin genes (Chui et al, 2006). Although it appears at first sight that a mutation on a beta gene has statistically (50%) more consequence, in reality it has little effect of the fetus due to being compensated by the γ globin being the major component of fetal haemoglobin (Steinberg, 2001).

In contrast, the α-globin gene is critical in prenatal and postnatal stages and therefore a single mutation in any of the 4 α-globin genes during the fetal stage can lead to fetal loss and to severe disease in later life (Chui et al, 2006).

In the case of α-thalassemia, the mutation in an α gene results firstly in excessive production of tetramer γ4 in case of homozygote designate as α° thalassemia called Hb Bart's hydrops which causes stillbirth (Figure 2, Figure 3) and edematous (hydropic) baby due to severe anaemia. Secondly, it can result in excess formation of β-chain resulting in tetramer β4 (HbH) abnormal haemoglobin variant designated α+, and called Hb H disease (Weatherall et al, 1997).

Figure 2: Red blood cells of baby who died from α-thalassemia (Steinberg, 2001)

Figure 3: Pathophysiology of α-thalassemia (Weatherall, 1997)

At 6 months of age, fetal Hb is less than 5% of normal Hb and at 2 years of age, it is less than 1% when a mutation of β globin shows clinical expression (Thein, 2005).

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Alpha-thalassemia will manifest at 6 months and if untreated, the child will die within 2 years.

Alpha-globin gene mutations are mostly caused by the deletion of one or both genes while a small proportion are caused by non-deletional mutations (Chui et al, 2006). The clinical severity of the disease is proportionally related to the size of the mutation i.e. the larger the mutation, the more severe the disease (Vichinsky et al, 2010).

Beta-thalassemia is mostly caused by a point mutation within a gene or immediate flanking sequence and mutations affecting RNA processingΒ0 where no β globin is formed and β+ where some β-globin is produced or β++ where its deficiency is minute (Thein, 2005).

Understanding the variable clinical expression of different mutations and in different ethnic groups is a big challenge. For example, Indian deletion β-thalassemia (Thein et al, 1984) is autosomal dominant unlike the common form of β-thalassemia.

There are three types of β-thalassemia according to (Thein, 2005):

Thalassemia trait as a result of a single β thalassemia allele, mostly asymptomatic or mild anaemia, raised Hb A2 and up to 2% variable Hb F, as described above diverse heterozygotic carrier state can range from mild to severe expression of β thalassemia disease for example in dominantly inherited β-thalassemia.

Thalassemia intermedia due to a single or two β-thalassemia alleles which can be mild in case of milder β-thalassemia allele (β++) or silent mutation or severe in case of Β0.

Where absent beta thalassemia is compensated by fetal Hb again it is diverse in phenotype for example co-inheritance of deletional α-thalassemia would be mild but coinheritance of extra α-globin would be severe.

Thalassemia major with absent β chain as a consequence of homozygotes or compound heterozygotes inheritance, onset at 6 months of age associated with severe anaemia regular blood transfusions if untreated die within 2 years.

Presentation of thalassemia

Ineffective red blood cell production will lead to anaemia and put pressure on other organ like spleen, liver to form blood which will result in the enlargement of these organs (Figure 4) and growth failure (Vichinsky et al, 2009).

Late complications would be weak bone, repeated infections due to blood transmitted infections and heart failure likely due to deposit of iron resulting from regular bloods transfusions (Fucharoen et al, 2007).

Recurrent blood transfusions will lead to iron accumulation in the body and can result in multi-organ failure.

There were 80 million carriers of β-thalassemia in 2005 (Thein, 2005).

Alpha-thalassemia is more common in Southeast Asia and southern China (Leung et al, 2008) and is becoming prevalent in North Europe and North America due to immigrants (Harteveld and Higgs, 2010).

Figure 4: Children affected by β-thalassemia (Weatherall and Clegg, 2000)

Risk assessment

Thalassemia has not yet been recognised as a global problem despite an estimated 270 million people (7% of world population) being carriers of an inherited haemoglobin disorder due to the lack of available data, especially from Asian countries and previously undiagnosed now having better treatment will increase their survival rate that will impose extra burden on healthcare systems (Weatherall, 2010).

The main risk factors are family history and ethnicity. One of the main reasons why ethnicity plays such a part is due to the fact that consanguineous marriages which are practiced by 25% of the world population (Weatherall, 2010) are more prevalent in some ethnic groups such as those from South Asian countries.

Alpha-thalassemia and the common form of β-thalassemia are autosomal recessive which means that to be affected the child has to be homozygous and has to inherit the carrier genes from both parents. The disease can equally affect either gender. The below table summarises the risk for a child to be affected or be a carrier depending on the parents:

Autosomal recessive risk

Parent B is affected

Parent B is carrier

Parent B is unaffected

Parent A is affected

Child has 100% risk of being affected

Child will be either affected (50% risk), or carrier (remaining 50% risk)

Child has 100% risk of being carrier

Parent A is carrier

Child will be either affected (50% risk), or carrier (remaining 50% risk)

Child has 25% risk of being affected and 50% risk of being a carrier

Child has 50% risk of being carrier

Parent A is unaffected

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Child has 100% risk of being carrier

Child has 50% risk of being carrier

Child has 0% risk of being carrier or affected

Beta-thalassemia also has autosomal dominant forms with severe effect, for which inheriting from a single parent is sufficient to trigger the disease.

Autosomal dominant risk

Parent B is affected

Parent B is unaffected

Parent A is affected

Child has 100% risk of being affected

Child has 50% risk of being affected

Parent A is unaffected

Child has 50% risk of being affected

Child has 0% risk of being affected

However, the existence of more than 200 β-globin gene mutations and its phenotypic variability (Thein, 2005) and similarly for α-globin (Oron-Karni et al, 2000) make it extremely challenging for an accurate risk assessment about the likelihood for a newborn to be affected or be a carrier and the potential impact on treatment dependency and life expectancy.

The current and future geographic distribution of the disease and diversity of population within a small region create another challenge in implementing screening and accurate risk assessment, with the added complexity of possible human migrations and the variability in clinical phenotype of the disease even with the same mutation (Weatherall, 2007).

It is suggested that haemoglobin disorders may increase in the future due to improvements in hygiene, prevention of malaria, early diagnosis and detection of complications and improving living standards in some countries. As of 2010, more than half a million children are born with Thalassemia or sickle cell disease annually (Weatherall, 2010).

Diagnosis & screening

According to Clarke and Higgins (2000), initial assessment is done by carrying a complete blood count to test for hypochromia by checking mean cell haemoglobin (MCH) and for microcytosis by checking mean cell volume (MCV). To quantity of HbA2 and Hb F, electrophoresis will be required. A MCH level of less than 27pg and an MCV level of less than 80fL may be a useful cutoff to detect thalassemia carriers (Ma et al, 2001).

High-performance liquid chromatography (HPLC), a technique in biochemistry to analyse and quantify a composition, can be used for screening of simple thalassemia disorders as it is a fast (results are available in minutes) and accurate method (Fucharoen et al, 1998). However, it is not able to detect β-thalassemia variants for newly born babies due to β globins not being fully functional at this stage.

To identify risks for the purpose of genetic counselling prior to conception, the DNA samples can be white blood cells taken from the couple. To find about possible mutations during pregnancy, the DNA test requires samples from the baby, the placenta or fluid around the baby, which pose a risk of miscarriage. Therefore, non-invasive methods are being investigated for high accuracy. One example is provided by Li et al. (2005) which states that it is possible to detect paternally inherited β-thalassemia point mutation using free cell DNA in maternal blood with a success rate of 86%.


Medical treatments include frequent blood transfusion accompanied by iron excreting agents like desferrioxamine to remove excess iron from the body. This method has significantly improved the survival rate in patients of thalassemia major as compared to untreated patients (Fucharoen et al, 2007).

Hemopoietic stem cell transplant in major β-thalassemia is another possible treatment. According to a study by Ramzi et al. (2010) which used retrospective data over the last 15 years, the treatment can improve the survival rate by 81% and increase the disease-free period by 62%. However, the sample size of 155 patients used in this study was small and the study did not use appropriate statistical approach for verification.

In comparison, a prior study carried out by Lucarelli et al. (2006) used a similar approach on HLA identical marrow transplant, had a larger sample of 350 patients, and applied rigorous statistical methods, therefore making it more reliable. This study came to similar results.

Finally, later treatment will include supportive treatment for infections, weak bones or even removal of spleen in some patient (Fucharoen et al, 2007).

Screening and treatment: the cost and ethical question

There is a significant risk of finding new mutations and being unable to provide an appropriate level of counselling due to insufficient data on such de novo mutations and the legal and ethical implications associated with false positive cases.

A study by Modell (2008) shows that in the UK, life expectancy of patients suffering from β-thalassemia major has improved significantly, as it namely increased from 17 years in 1970 to 40 years since 2000. In the UK, from 2007, the National Health Service offers a screening service for all pregnant women before 10 week of pregnancy.

Extra funding will be required to support the cost of screening, diagnosis, treatment and further research, especially in countries heavily affected by the disease.

The cost of blood transfusion and storage is going to be a big challenge. For example, in Iran, 25% of available blood supplies are solely used on thalassemia patients according to Abolghasemi et al (2007).

Unlike developed countries which have advanced healthcare systems, in Asian countries where the prevalence of this disease is significantly high, a strategy needs to be implemented to reduce the number of people affected. One strategy discussed by Sengupta (2008) emphasizes the targeted screening in Indian tribal regions where thalassemia is more common starting from extended tribal screening or targeted screening of all pregnant women of that specific population, which can help achieve up to 50% cost reduction, as treatment would prove more expensive. Premarital and prenatal screening would also be more appropriate. Lack of awareness and community participation and stigma attached with the disease are major hindrances in controlling the disease. It is also worth mentioning that some of those poor countries heavily affected by thalassemia, there is a gender bias against women, especially in rural areas, who are often prevented by their families from receiving any form of screening or treatment, which makes the situation more complex.

Prevention through Screening, Counselling and Education

To prevent Thalassemia disorders, prospective couples with family history could be screened before marriage or conception so that they could be advised about the risk for their offspring. This pre-marital screening and counselling option has been explored in Iran where a study carried out by Samavat and Modell (2004) showed that the number affected by Thalassemia was reduced by 30%. The results seem viable but need further validation from large randomised controlled trials.

Canada, as a country of high immigration, also faces the challenge of preventing and controlling thalassemia and has established clinical guidelines targeting couples with ethnicity deemed at risk as described by Figure 5 (Langlois et al., 2008). It seems to be a good approach, except for restricting the risk group to ethnicity, as patients with family history but outside ethnicities deemed highly affected may be missed.

Figure 5: Strategy for screening, a simplified version (Langlois et al, 2008)

When a pre-conception screening is not used, then prenatal screening and diagnosis should be used and the couple be advised on the risk accordingly. Hoppe (2009) proposes a primary newborn screening programme (Figure 6).

Advantages of her screening approach are that it can be integrated in a regional or national health programme and every child can be identified and followed-up. However, this has significant costs associated, but could be suitable for countries with high resources and high immigration such as the United States or Canada.

Figure 6: Approach for prenatal screening and diagnosis, a simplified version (Hoppe, 2009)

Couples at high risk due to being both carriers could be offered to have pre-implantation genetic diagnosis (PGD) (Kokkali et al, 2007). They showed that trophectoderm cells can be accurately and cost-effectively analysed, the error margin being minimized due to blastocyte transfer. As a result, such couples could be referred to a PGD specialised centre.

Targeted screening (i.e. micro-mapping) and comparison between the phenotypic expression of the disorder in developing countries heavily affected by the disorder and immigrants to developed countries may provide better understanding of the clinical heterogeneity of the disease (Weatherall, 2010).


As demonstrated so far, thalassemia is one of the most prevalent, diverse and complex hereditary genetic disorders which affects the human race, and with severe consequences. Continuous improvement in the understanding of genetic disorders such as thalassemia is necessary to unfold the course of the disease and further improve the diagnosis, treatment and management of patients and their families affected by such conditions. Genetic counselling for such a complex disease is extremely challenging, with so many variants such as Hb E β-thalassemia, which according to Weatherall and Clegg (2001) will be a global health problem in the next twenty years with prevalence of 60% in South East Asia.

An improved understanding can also help national health systems better direct their resources and research efforts, and reduce their cost by screening heavily at pre-conception and early pregnancy stages for people deemed to be at significant risk due to ethnicity or family history.