✓ Thalassemia: all you need to know about the disease, about the risks for carrier couples, about prenatal diagnosis

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In Del Paese they are approx 3 million healthy people with beta thalassemia, a disease that leads to anemia and can be very serious. Healthy carriers - as the word itself says - do not show particular symptoms, but if both partners are in a couple healthy carriers sick children can be born. For this reason, many carrier couples decide to carry out prenatal diagnosis and terminate the pregnancy if the fetus is sick. Other couples, on the other hand, choose to undertake a path of assisted fertilization with preimplantation diagnosis of the embryo: a path that has recently also been feasible in our country.

What is beta thalassemia?

Beta-thalassemia, also called Mediterranean anemia or simply thalassemia, it is the most severe and most widespread form of thalassemia in Del Paese. Thalassemias are a group of hereditary diseases characterized by anemia of varying severity and caused by defects in the hemoglobin production, a protein found in the red blood cells, where it has the function of loading and carrying oxygen. Since hemoglobin is made up of different protein fragments (called alpha and beta types), there can be two main types of thalassemia, precisely called alpha and beta depending on which are the defective fragments. The defects of the fragments depend in turn on alterations - technically we speak of mutations - in the DNA sequence of the starting genes.

As there is no official register national population of patients with beta-thalassemia, we do not know exactly how many Del Paeseni are sick, but the estimates speak of about 7000 people, concentrated above all in the city, Sardinia, Calabria and in the Po Delta area. "Alpha-thalassemia is much rarer and, at least in Del Paese, gives milder symptoms" explains Dr. Claudia Cesaretti, medical geneticist of the Polyclinic of our city.

What are the symptoms of beta thalassemia?

There are two forms of the disease, depending on the type of mutations involved. There major form ("major") causes a very important anemia and, if not properly treated, leads from early childhood to symptoms such as growth retardation, jaundice, fever, enlarged liver and spleen, alterations of the skeleton. If left untreated, it usually leads to early death. In intermediate formon the other hand, the anemia is milder and the general effects are also more limited.

How do you live with thalassemia?

"Today this disease is no longer as scary as it used to be, because it can be kept under control", explains Dr. Giovanbattista Leoni, pediatrician at the Microcitemico Hospital of Cagliari, specialized in the cure and treatment of thalassemia. "A sick person succeeds in lead a normal life after all - he can go to school and university, go to work, go on vacation, even have children - and his life expectancy is open "says the doctor who, despite being a pediatrician, now also follows adults: his young patients once grown up now. "All this, however, provided that two fundamental therapies are always followed that is, periodic blood transfusions and iron chelation therapy, which allows for the capture of excess iron carried by transfusions, which in the long run is harmful to the body ".

In the case of thalassemia major, transfusions begin around the 8-10 months of life and they go repeated every two to three weeks to avoid anemia, i.e. that the hemoglobin levels in the blood drop below a certain threshold.

If thalassemia is intermediate, transfusions may be less frequent, with a frequency depending on the severity of the anemia. However, there is a downside. "In severe forms, transfusion after transfusion iron begins to accumulate in the body"explains Leoni. The affected organs - heart, liver, thyroid, ovaries - are affected, suffer, get sick, with negative consequences on the quality and duration of life." For this reason it is essential that transfusions are accompanied by iron chelation therapy, which captures iron in the circulation. "Three different drugs are available: one that must be injected slowly under the skin, through an insulin pump to be kept on for 10-12 hours a day, and two others that can be taken by mouth.

Today we live on thalassemia, and you live without particular suffering, even if some patients suffer from joint and lumbar pains which tend to become chronic. Life, however, is marked by therapies and checks.

Everything revolves around transfusions, which generally require an abundant half day: it therefore means that every two to three weeks you miss a day of school or work, and one must organize one's life accordingly. Even taking into account the fact that in the days immediately preceding the transfusion, when the hemoglobin levels are now low, it is easy to feel more tired and fatigued than usual. "Then there is the daily iron chelation therapy. Even if it involves taking a simple pill, it is not always easy to resign oneself to the idea of having to do it for a lifetime, and often there is the temptation to let it go for a while" says Dr. Cesaretti. Still, it can't be done because if the therapy is skipped, the disease returns to attack.

To all this, finally, are added checks: at least once a year you have to take into account ultrasounds, magnetic resonances, blood tests. So it is not a walk in the park: if it is true that, from many points of view, life with thalassemia is practically normal, it is equally true that there are many limitations, not always easy to accept especially by children and adolescents.

Read also: Hemophilia, all you need to know about the disease

Can it be healed?

Transfusions and iron chelation therapy allow people with beta-thalassemia to survive and lead an almost normal existence, but do not cure the disease. The only possibility of definitive cure is represented, at the moment, by the hematopoietic stem cell transplantation, progenitors of blood cells that can be taken from bone marrow or umbilical cord blood.

The stem cell donor for the transplant can be a family compatible, usually a brother or sister, or a volunteer, always compatible, that he donated his cells to a public bank. "The chances of recovery are excellent in the first case and very good in the second, although there is still a minimal risk of rejection", emphasizes Leoni. "If a sick child has a brother or sister, the probability that he is compatible is 25%, while the probability of finding a compatible donor in a bank can be as high as 50%".

Until now, parents could not act as donors, because they were only half compatible: in this case, therefore, the risks associated with transplantation were very high. Recently, however, the team of Dr. Franco Locatelli, Head of the department of oncohematology and transfusion medicine of the Bambino Gesù Pediatric Hospital in the city, has developed a stem cell manipulation technique that allows also resort to cells that are not perfectly compatible, like those of the parents.

Read also: Alessandro Maria will be transferred to the city for a parent marrow transplant

Gene therapy, a hope for the future

The great hope for patients with thalassemia lies in two words: gene therapy. In 2022 the European Commission authorized gene therapy with autotemcel betibeglogene (beti-cel), under the trade name Zynteglo.

As the Advanced Therapies Observatory explains well, "it is a treatment capable of add functional copies of a modified form of the β-globin gene in the patient's own hematopoietic stem cells. At this point the patient is potentially able to produce a type of gene therapy-derived hemoglobin in quantities that greatly reduce or completely eliminate the need for transfusions.

In addition, data from a long-term follow-up study with the bee-cell gene therapy in patients with transfusion-dependent beta thalassemia. The study results show that all beti-cel-treated participants achieve transfusion independence remain free from transfusions, with the longest observation period reaching as much as seven years.

Scientific research is revolutionizing the therapy of beta thalassemia and it is finally possible to reduce the number of necessary transfusions, thus making patients freer and their life "easier".

How is the disease transmitted?

Each of us has two copies of each gene: one inherited from mom and one from dad. The disease manifests itself when two defective copies of the responsible gene are inherited from the parents, which always happens when both parents are sick (but it is a very rare circumstance) and can happen in a certain percentage of cases if the parents are healthy carriers, or if one is sick and the other is a carrier.

What does it mean to be a healthy carrier of thalassemia?

If a person inherits a single defective copy of the gene involved in the disease from his parents, he will not be sick, but a carrier. In fact will have no particular symptoms, but blood tests will reveal small red blood cells (microcythemia) and hemoglobin values a little lower than normal, although not so low as to be a problem. In these cases we speak of thalassemia minor.

"The only specific indication for healthy carriers is to periodically take folic acid" specifies Dr. Cesaretti. For the rest, no special checks are needed. "Sometimes it can happen that there is one iron deficiency, but exactly as it happens in the general population. "In this case, the assumption of a supplement, but always under strict medical supervision. "At other times, however, there may be a tendency to have levels of ferritin (the supply of iron) towards the high limits of the norm, but high levels are not reached and there is absolutely no need for any therapy ".

The only real problem, for a wearer, arises if he decides to start a family with another carrier, or with a sick person. In these cases, in fact, it is possible that the children are ill.

For a carrier couple, the likelihood of a child being sick is del 25% with each pregnancy (one in four chance), while there is a one in four chance that the child is perfectly healthy and one in two that he is a carrier himself. If the future parents are instead one carrier and the other sick, the risk of a child suffering from thalassemia is higher, and is equal to 50%.

"Today, in general, anyone who is a carrier of thalassemia knows"Claudia Cesaretti says." Either because a parent was also a carrier and had him undergo tests as a child to see his status, or because during some routine blood tests, elements emerged, such as microcythemia, which they did suspect this condition. The test that can raise doubts is the blood count, while the confirmation of the diagnosis is obtained with a detailed analysis of the protein fragments of hemoglobin, through tests called electrophoresis or Hplc ".

However, it happens that, in a couple, maybe only one of the partners is sure of being a carrier. "In this case, before looking for a pregnancy it is good to understand if the other partner is healthy or a carrier", says Cesaretti. "If they are both you must also go to see what the mutations of each are, to predict what the severity of the disease could be if a child inherited both. To do this, just a simple one DNA examination of the two partners, starting from a blood sample ".

Read also: Choosing the prenatal diagnosis: screening test, fetal DNA test or amniocentesis / villocentesis

What should a carrier couple do in order to become pregnant?

First, be aware of the possibility that the baby is sick. Secondly, decide how to deal with this possibility. Some couples decide to welcome her peacefully. Others - in Del Paese they are the vast majority - believe that the burden of the disease would be too heavy for the child and the family, and prefer to carry out an antenatal diagnosis.

This allows, in case of fetal disease, to evaluate the hypothesis of termination of pregnancy (therapeutic abortion). "In the nineties we had the lowest number of births of thalassemic children in Del Paese," says Leoni. "Since then there has been a small recovery, because thanks to the availability of therapies some parents choose to continue the pregnancy anyway".

If you decide to make an antenatal diagnosis, the technique of choice is the villocentesis. "It can be done before the amniocentesis and allows to collect the most suitable material for genetic analysis", explains Cesaretti. Since it is an invasive technique, it carries a minimal risk of miscarriage, is only recommended for couples who intend to terminate the pregnancy in case of fetal disease. If you already know a priori that you want to continue the pregnancy anyway, it is useless to take risks.

Coelocentesis: a possible alternative to villocentesis?

It's called celocentesis, and it's one new prenatal diagnosis technique for genetic diseases such as thalassemia developed by the team of dr. Aurelio Maggio, head of the hematology department of the Villa Sofia - Cervello hospital in Palermo. Which is also, at least for now, the only center in the Paeseno where it is possible to do it.

The technique, developed with the fundamental support of the Piera Cutino Association, provides the withdrawal of a very small amount of the liquid present in a particular cavity, called coelom, which forms inside the gestational chamber in the first weeks of pregnancy, and then gives way to the amniotic cavity. The withdrawal is done transvaginally, always with ultrasound control. "In the coelomic fluid there are fetal cells that can be analyzed to find out if the fetus is affected or not by a particular genetic disease," explains Maggio.

The big advantage over CVS is that the withdrawal can be done earlier, between seven and nine weeks, because then the coelomic cavity disappears. "That means almost a month earlier than CVS, basically a couple of weeks after she found out she was pregnant." A significant time advantage if you are thinking of terminating pregnancy in the event of fetal disease.

Over the past 7-8 years, Dr. May performed several hundred coelocentesis. As detailed in a scientific article published in the journal Praenatal Diagnosis, the technique has proved to be very reliable in identifying hemoglobinopathies. It should be emphasized, however, that it is an invasive technique, so it can be there risk of fetal loss. According to a study published in 2002 by the Greek George Makrydimas, one of the fathers of coelocentesis, the risk of associated abortion would be two percent. "Our latest data - says Maggio - instead speak of a lower risk, around one percent".

This new technique has so far concentrated mainly on single genetic defects, such as those at the basis of thalassemia or other hemoglobinopathies. According to some recent results, however, it may also be able to offer indications on chromosomal abnormalities such as Down syndrome, offering an overview of the chromosomes of the fetus. An application perspective that Prof. Maggio's group is working on, in collaboration with other research centers.

The choice of what to do when faced with the possibility of a sick fetus is not simple, it is very individual, and depends on various factors that have to do with faiths, value systems, and more. Precisely because it is a complex choice, it would be good ask yourself the problem even before the pregnancy begins, so as not to be taken by surprise and not to have to make demanding decisions in a rush. In this path of awareness, the advice from a geneticist expert and it may be important to discuss with doctors who deal with thalassamias on a daily basis and with patient associations.

Read also: Karyotype examination: what it is, what it is for, when to do it

Preimplantation Diagnosis

For carrier couples who do not want to run the risk of having a sick child or of having to terminate a pregnancy, there is another possibility: preimplantation embryonic diagnosis. To follow this path, however, we must go through an assisted reproductive procedure: in this way it is possible to obtain, in test tubes, embryos to be analyzed, to transfer only the healthy ones or, at the most, carriers into the uterus.

"This avoids the risk of therapeutic abortion, but it should be noted that it is a long procedure - it can take several months before reaching the implant - which requires a series of tests and hormonal stimulation for the woman, and which does not give guarantees of successful, in the sense that the implant may not take place or the pregnancy may be terminated prematurely "explains Cesaretti. Furthermore, it should be emphasized that embryo diagnosis is not a perfect technique: it is estimated that there may be errors in 3% of cases. For this reason, couples who do it are still advised to also make an invasive prenatal diagnosis to make sure the fetus is healthy.

Other sources used for the article: information material from the Rare Diseases Observatory (OMaR); information material of the Istituto Superiore di Sanità (ISS); information material of the Advanced Therapy Observatory (OTA).

- Updated on 29.11.2022

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