Thalassemia, Pregnancy and Gene Therapy

Thalassemia: A genetic condition

First the background. Thalassemia (also spelt ‘Thalassaemia’) is a genetic condition affecting the oxygen carrying component in the blood, namely haemoglobin. Thalassemia belongs to a group of conditions collectively known as haemoglobinopathies. The most well known haemoglobinopathy is Sickle Cell Disease. All these conditions are characterised by defective haemoglobin and consequently a low blood count or anaemia. However, Thalassemia and Sickle Cell Disease are two completely distinct conditions.

Alpha and Beta Thalassemia

To add to a bit of confusion, there are two types of Thalassemia which are distinct from each other.

Alpha Thalassemia, found throughout the world but with highest concentrations in Southeast Asia is caused by missing ‘alpha’ genes in the oxygen carrying component (haemoglobin). We will not be discussing alpha thalassemia in this hub.

Beta-thalassemia results from defective beta genes in haemoglobin. In other words, even though in both conditions, haemoglobin is the area that is affected, the problem is different and affects different genes.

Worldwide destribution

Beta thalassemia is a condition most prevalent in the North Mediterranean and among people who trace their ancestry from that part of the world. In fact, the name ‘Thalassemia’ is derived from the Greek word ‘thalassa’ which means ‘the sea’. So, whilst in Britain the carrier rate for beta-thalassemia is 1 in 1500; in countries like Cyprus it is many times that at almost 1 in 7. In the United States, the carrier rate is highest among Greek and Italian immigrants and their descendants. Beta thalassemia is also common in India and South East Asia.

Beta thalassemia also goes by the name ‘Cooley’s anaemia’ after the Paediatrician (Dr Thomas Cooley) who first described the condition among children at the beginning of the 20th century.

People from around the Mediterranean are the ones most affected by Beta-thalassemia. Also affected are people from parts of India and South East Asia
People from around the Mediterranean are the ones most affected by Beta-thalassemia. Also affected are people from parts of India and South East Asia

Mode of inheritance

There are two beta genes in haemoglobin. A person inherits one of these genes from each parent. To have the full-blown beta-thalassemia (thalassemia major), an individual has to inherit two defective genes. If a person inherits one defective beta gene and one normal gene, he/she will be a carrier and lead an almost entirely normal life. Many, probably most, people who are carriers (also called beta-thalassemia trait) aren’t even aware of their status.

With two defective genes, a child will be born with the full-blown condition; that is Thalassemia major.

Managing Thalassemia Major

The mainstay of management in Thalassemia major is blood transfusion. This will start early in childhood and continue throughout life. Blood transfusion may be required at a frequency of once a month throughout the person’s life. People with thalassemia major have a shortened life expectancy.

Thalassemia and planning for a family

If an individual with Thalassemia trait (a carrier) has a baby with a partner who has normal haemoglobin, their offspring could inherit the defective gene and end up as a carrier. There is no possibility of having a child with the full blown condition (Thalassemia major). As mentioned earlier, for that to happen, a child has to have two defective genes inherited from both parents.

Two carriers

If two individuals with Thalassemia trait get together as a couple, the permutations are like this:

  • A child could inherit a normal gene from each parent. The child will therefore be completely healthy. There is a 25% chance of this happening.
  • A child could inherit one normal gene from one parent and one defective gene from the other parent. This child will be a carrier like the parents. There is a 50% chance of this happening.
  • A child could inherit two defective genes, one from each parent. This child will have the full-blown Thalassemia major. There is a 25% chance of this happening.

The illustration below shows how this happens (click to see a larger image).

How the genes are passed on

Whether parents pass on the defective gene is a matter of chance, as shown in this illustration.
Whether parents pass on the defective gene is a matter of chance, as shown in this illustration. | Source

Life Partner Choice inThalassemia

For an individual who is a carrier of Thalassemia (Thalassemia trait), there are things that can be done to minimise or eliminate the risk of having a child with Thalassemia major.

The easiest way of achieving this is arguably the most controversial. It is possible to have a simple blood screening test done. If a prospective partner is also a thalassemia carrier, a hard-headed decision will need to be made whether that union should go ahead or not. If the answer is yes, then the couple will need to be aware that there is a 1 in 4 chance that their child will have thalassemia major, with moderate to severe disease and curtailed life expectancy.

There is another way that such a couple can avoid having a child with the condition. This too is not without controversy and involves assisted conception technology as discussed below

Assisted Conception and Pre-implantation Genetic Diagnosis (PGD)

For a couple described above, if they have access to the medical technology and have the financial resources, they can still have a healthy child, completely free from thalassemia. Here is what is done.

Eggs are harvested from the mother and fertilised using the male partner’s sperm as in any other in vitro fertilisation (IVF) procedure. The resulting embryos are then genetically tested to identify those not affected by thalassemia. Those are the ones that are put back into the mother’s womb. With successful implantation and pregnancy, the couple will be guaranteed that the child or children to be born will be free of thalassemia. That is the Pre-implantation Genetic Diagnosis technology in play. Unfortunately this kind of technology is not yet available everywhere and, even where available, it may be too expensive for many couples. There is also the hugely controversial issue of selecting embryos which may be difficult or impossible for some people to embrace, on religious or purely moral grounds.

Cutting-edge medical technology is bringing the reality of gene therapy ever closer. Insertion of normal gene in a Thalassemia major patient's DNA has been successfully done
Cutting-edge medical technology is bringing the reality of gene therapy ever closer. Insertion of normal gene in a Thalassemia major patient's DNA has been successfully done

Thalassemia and gene therapy

Stem Cell research is an area that offers a great deal of promise for curing hitherto incurable genetic conditions like thalassemia. In September, 2010; the scientific journal Nature published details of a breakthrough in gene therapy in a patient with Thalassemia major. The teenager, who had had monthly blood transfusion since the age of three had the treatment in 2007 at the age of 15. Bone marrow cells had been extracted and these cells had normal gene introduced into them. The modified cells were then transplanted back into the patient. A year after the transplant (in June 2008) he stopped receiving transfusions. For the two years until the point of publication of the report, he had not required a transfusion. This was a huge breakthrough.

The iron overload curse

It is important to be aware that, for thalassemia patients, blood transfusion is their life-line and without the transfusions, their lives will be severely curtailed. Five or so decades ago, thalassemia major patients rarely survived beyond the age of 10. Even today, few get into their 30s. However, repeat blood transfusion is also what ultimately kills them. The biggest problem associated with such frequent blood transfusion is the resulting accumulation of iron in the body. The problem of iron accumulation in the tissues is combated using what are known as ‘iron-chelating agents’. The most common iron-chelating agent is a medication called deferoxamine. Even though this has been available for over 3 decades, it remains expensive and largely out of reach for children in developing countries without the safety net of a health service provided by the state. Iron overload eventually leads to vital organ failure, (mainly the heart and liver) and death.

Gene therapy does therefore offer tremendous promise for possibly current and certainly for future generations of thalassemia sufferers. Formidable hurdles remain to perfect the therapy and, critically, to bring it within reach universally. Between 60,000 and 100,000 children are born with thalassemia major every year. For these children, only gene therapy holds any realistic hope of liberating them from the ravages of this genetic condition and a promise of a normal life.

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