Beta-thalassemias: molecular, epidemiological, diagnostical and clinical aspects

Abstract

Les bêta-thalassémies représentent une des maladies autosomiques récessives les plus fréquentes dans le monde. En France, on dénombre 5 à 10 nouveaux cas de formes majeures ou intermédiaires par an pour une prévalence globale d'environ 500 malades pour lesquels la généralisation des traitements chélateurs du fer a permis d'augmenter de façon très importante l'espérance de vie depuis une vingtaine d'années. Au niveau moléculaire, environ 90 % des allèles bêta-thalassémiques sont représentés par des mutations ponctuelles caractérisables facilement par séquençage Sanger ou par des techniques dédiées. Les 10 % restants sont des délétions plus ou moins larges détectables par MLPA ou par CGH Array. La détermination du génotype alpha est capitale dans l'exploration génétique d'une bêta-thalassémie puisqu'une alpha-thalassémie améliore la clinique tandis qu'une triplication alpha l'aggrave. Le génotypage additionnel d'autres polymorphismes inducteurs d'HbF permet même, au moyen d'un algorithme dédié, de prévoir l'âge de la première transfusion, faisant de la bêta-thalassémie l'une des premières applications potentielles de la médecine prédictive. Thérapie génique, diagnostic pré-implantatoire et nouveaux traitements médicamenteux (Sotatercept®, agonistes de l'hepcidine) achèvent de placer la ␤-thalassémie au-devant de l'actualité scientifique.Abstract. Beta-thalassemia is one of most common autosomal recessive disorders worldwide. In France, 5 to 10 new major or intermedia forms are diagnosed annually and the global prevalence is about 500 cases. Since 20 years and thanks to the generalization of iron chelator treatments, the life expectancy has dramatically increased. Nearly 90% of the ␤-thalassemic alleles are point mutations easily identified by Sanger sequencing or dedicated methods. The remaining 10% are deletions detectable by MLPA or CGH Array. The alphaglobin genotype is also essential in the exploration of beta-thalassemia because an alpha-thalassemia improves the clinical state whereas an alpha triplication worsens it. The additional genotyping of a few HbF inducer polymorphisms allows to predict the age of the first transfusion, thanks to a recent dedicated algorithm, making beta-thalassemia one of the first potential application of predictive medicine. Gene therapy, pre-implantatory diagnosis and new drugs (Sotatercept®, hepcidin-like molecules) have also recently contributed to make beta-thalassemia a main scientific topic again.

The correlation between cardiac magnetic resonance T2* and left ventricular global longitudinal strain in people with β‐thalassemia

“…Age β-thalassemia is a chronic disorder, in which affected individuals require frequent blood transfusions throughout their life. 14 Several imaging techniques including T2* CMR have emerged to predict an increased risk of heart failure and monitor the efficacy of iron chelation therapy in people with β-thalassemia. 7,18 Although in some studies, no correlation was found between specific iron concentration levels in heart and liver tissue, T2* CMR is a highly sensitive, reproducible, and noninvasive method for determining iron overload in heart.…”

Thalassemia review: features, dental considerations and management

“…In β thalassemia, the synthesis of normal α globin chains from the unaffected α globin genes continues as normal, resulting in the accumulation within the erythroid precursors of excess unmatched α globin (2, 8, 27). The free α globin chains are not able to form viable tetramers and instead precipitate in the red cell precursors in the bone marrow, forming inclusion bodies, which are responsible for the extensive intramedullary destruction of the erythroid precursors and hence the ineffective erythropoiesis that underlies all β thalassemia (3, 10, 27). Causes of the anaemia in β thalassemia occur in the presence of two phenomena: the first one is infective erythropoiesis and the second is the destruction of circulating red blood cells (haemolysis) (5, 8, 10).…”

“…Thalassemia is a genetic disorder that involves abnormal haemoglobin formation (1–3). Haemoglobin comprises of alpha and beta ‘chains’ which, in a patient with thalassemia, are faulty as a result of which the haemoglobin produced is faulty.…”

“…However, individuals who inherit this gene from their parents need to be very cautious when they have children of their own as the chances of their children inheriting more severe forms of thalassemia, increase significantly (7). The three types of thalassemia minor include alpha plus thalassemia trait which involves one of the four alpha genes to be missing, alpha zero thalassemia trait which involves two missing alpha haemoglobin genes, and beta thalassemia trait which involves the absence of one out of two beta haemoglobin genes (2, 3, 5). However, there are a number of types of thalassemia that are more dangerous and severe than the aforementioned types.…”

“…The best option while dealing with thalassemia is to ensure that it is prevented, which can be done by checking both parents for the presence of any gene mutations before the couple decides to have a child (5, 8). Patients with thalassemia usually experience a loss of appetite, jaundice, an enlarged spleen or liver and several bone problems (3). Since thalassemia is most commonly treated with blood transfusions, this causes excess iron to build up in an individual’s bloodstream (6).…”