Thalassaemia

Etiology

Alpha-thalassaemia S

Alpha-thalassaemias are characterized by a deficit of chain of globine-alpha in hemoglobin. They thus affect the synthesis of the 3 kinds of Hémoglobine: HbA, HbA2 and HbF, since all contain the chain alpha; in these cases the life is not possible that thanks to the formation of significant amounts of abnormal hemoglobins being composed only of the chains whose synthesis is not blocked: the HbH and the Hb Bart' S. These diseases are rare and with localized racial distribution.

Beta-thalassaemia S

Β-thalassaemias are characterized by the absence of the chain β of hemoglobin. Only the synthesis of HbA is blocked.

We will study only the most frequent variety, which is the traditional Thalassémie or Mediterranean Anémie of Cooley

Description

Alpha-thalassaemias

Alpha-thalassaemias are frequent in the endemic areas for the malaria because they offer a partial protection against this disease. They correspond has a deficit of chain of globine-alpha in the Hb = Hémoglobine. This defect is expressed as of the fetal life because under-unit-alpha constitute fetal hemoglobin (alpha 2 gamma2). Each chromosome carries 2 genes alpha (= 4 alleles on the whole); the classification of alpha-thalassaemias is thus more complex than for beta-thalassaemias. If no allele-alpha is functional, the fetus dies in utero. If 2 or 3 alleles are functional, the patient will suffer from a Anémie Microcytaire and Hypochrome (alpha1 or alpha2-thalassaemia). If only one allele is functional, this genotype will confer to the patient a Hémoglobinose H. This alpha-thalassaemia has as a symptom an anemia chronic Hémolytique without néccessiter for as many transfusions. Lack globine-alpha, from tetramer-gamma (fetal life) or beta (after the birth) will accumulate and induirent damage with the red Globules which transport them, those will die in circulation after approximately 45 days. These red globules abysses will be recovered by the Macrophage S. The treatment is made by supplementation in Vitamine B9 or Folic acid and Vitamine B12 and dealt with fast of the infections (and all other factors precipitants).

Beta-thalassaemias

The genes of hemoglobin are carried by the Chromosome S 11 (chains of the type B, G and d) and 16 (chains of a) type. In the normal érythroblaste, there is a perfect balance of synthesis of the chains of globine between these 2 chromosomes. At the fetus, the fetal Hemoglobin (HbF) made up of 2 chains alpha and 2 chains gamma (2a2g) is majority. With the birth, its rate is of 85%. This rate decreases gradually to reach less than 1% at the age from 6 to 12 months. The molecular formula in the adult comprises 97 to 98% of Hémoglobine has (a2b2) and 2 to 3% of Hémoglobine A2 (a2d2). Thalassaemias are the consequence of changes of genes leading to a stop (a0 or b0- thalassaemia) or a reduction of synthesis (a+ or b+- thalassaemia) of a chain of globine. In beta-thalassaemia Hétérozygote, there is a reduction in synthesis of hemoglobin at the origin of the Microcytose and the Hypochromie. The small size of red blood corpuscles is compensated by their number from where a Pseudo-polyglobulie (6 to 7 million hématies/mm ³). In addition, the relative increase in synthesis of the chains leads to the rise in the rate of A2 hemoglobin (> 3.5%).

In beta-thalassaemia Homozygote, the relative excess of the chains has precipitates in the érythroblaste and involves its lysis by membrane toxicity what is at the origin of an ineffective érythropoïèse. The érythroblastes able to synthesize hemoglobin F manage to produce Réticulocyte S and GR. (red globules) mature. The GR. circulating are microcytaires i.e. of small size, deformed (Poïkilocytose) and have one shortened lifespan.

Anemia in the major Thalassémie i.e. Homozygote is due to 2 mechanisms: the ineffective érythropoïèse and hyperhémolyse. Major anemia induced a hypersecretion of Érythropoïétine inducing a stimulation of the érythropoïèse. The expansion of this sector can reach 30 times the normal. This has as a consequence of the osseous deformations interesting the bones of cranium, the area malaire, the jawbones and the ends of the long bones mainly. In addition, the hyperhémolyse and the metaplasy myéloïde are at the origin of the Splénomégalie and the Hépatomégalie. Finally these patients often present an overload Martiale in connection with the digestive hyperabsorption of Fer and especially the iterative transfusions; martial overload which can lead to a Hémochromatose with its complications endocrinienne, cardiac and hepatic.

Incidence and prevalence

Frequent in the endemic areas for the Malaria because they help to protect the carriers against the malaria (often Létal E in the countries in the process of development).

Diagnosis

Anemia < 7 g/l, microcytaire and hypochromic. Sometimes more moderate.
the electrophoresis of hemoglobin makes the diagnosis showing a percentage of HbF constantly increased and majority while the percentage of HbA2 is normal or high.
the free Hyperbilirubinéme is the witness of the Hémolyse.
For minor beta-thalassaemia: there is no clinical Symptomatologie. It can however exist light a Splénomégalie. Biology shows a Microcytose without anemia or only moderated, a pseudoglobulie with red globules > 5 to 7 millions/mm ³, a Hypochromie and HbA2 > to 3,5%.

Treatment

Transfusion of red globules according to the proportioning of hemoglobin, approximately once a month.

The transfusional treatment maintaining a rate of hemoglobin in the neighborhoods of 12 g/l avoids the appearance of the clinical signs. It is maintained with life if a Allogreffe of marrow is impossible.

The genetic Council

The diagnosis genotypic of the responsible molecular lesions, established by the Molecular biology, is not necessary to the diagnosis, but essential to the prenatal diagnosis .

Mode of transmission

recessive autosomic Transmission

Sources

Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MANDELEVIUM. MIM Number: 604131 * GeneTests: Medical Genetics Information Resource (database online). Copyright, University off Washington, Seattle. 1993-2005
thalassaemia medsante.

Traditional thalassaemia or weakens Mediterranean of Cooley

Geographical distribution

The gene thalassemic is largely widespread in the white Race, among the populations occupying the edges of the Mediterranean (Thalassa = the Mer in old Greek), in Corsica and Italy and in particular in the delta of the Po, in Sardinia, Sicily ; in Greece, in Crête, Cyprus, in Syria and Turkey.

Other hearths (perhaps due to a different allele) exist in Thailand, in India, China, with the Filipino and by places in Africa.

One also suspects the Malaria of having played a part in these distributions. (The malaria was eliminated from Italy only recently under Mussolini.)

Pathogenesis

the situation is entirely normal before the birth , because the synthesis of HbF is not affected. Normally, little time before the birth, the synthesis of the chains Beta and Delta is started, while that of the Gamma chains arrète almost completely. At this time thus the progressive replacement of HbF in the G.R. with HbA and of Hba2 starts. At the time of the birth , HbA accounts for already 10 to 40% of total globular hemoglobin.
At thalassemic the Homozygote, the synthesis of HbA does not start and that of HbF continuous during all the postnatal life. The G.R. are thus deprived of HbA and contain in the place of HbF. However the rate of synthesis of HbF after the birth is not enough, by far, to meet the needs for the Hématopoïèse, so that it occurs an extremely hypochromic anemia. This anemia is moreover Hémolytique, because the G.R. low in Hb are structurally abnormal (Microplatycytose) and have a very shortened mean length of life. The table thus made up is indicated under the name of major Thalassémie.
At thalassemic the Hétérozygote (carrying the " trait"), the synthesis of HbA is done, though with a slightly insufficient flow. The disease is consequently described as minor Thalassémie.

Tests of laboratory

The hematologic examination shows an extremely hypochromic anemia and Microcytaire: it is in this affection that the discordance between the number of G.R. (generally 2 to 3 X 10 exhibitor 6/mm ³) on the one hand and the rate of Hb and the hématocrite on the other hand is most marked. With the blood smear, among the bizarreries of the form which one can observe, most characteristic is that of red blood corpuscle out of target (target concealment), where the hemoglobin of the globule is collected in a ring with the periphery like in a central bulge. The osmotic resistance of the G.R. is increased, owing to the fact that their thinness allows them an important swelling before the bursting. The analysis by the combined methods of electrophoresis and alkaline denaturalisation shows that HbA is absent, HbA2 usually misses also, while HbF is only present in the globular Hémolysat.

Treatment

Transfusions, the Splénectomie is sometimes useful, without giving spectacular results.

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