Drépanocytose

The drépanocytose , also called hémoglobinose S , sicklemy , or weakens with sickle-shaped cells , is a hereditary Maladie concerning approximately a newborn on 6 000 and is characterized by the deterioration of the Hémoglobine, Protéine ensuring the transport of the Oxygène in the Sang.

Although rare, it is the first Genetic disease in France.

History

Since several thousands of years, the drépanocytose is known and described under various terms (in bond with the pain or the bones), in Africa, where it initially appeared.

In 1904, James Herrick, doctor with Chicago, makes the first medical description of the drépanocytose: it examines a black student 20 years old, hospitalized for cough and fever. The subject is weak, the subject has giddinesses and suffers from headaches. For one year, it has felt palpitations and breathlessness like certain members of its family. The examination of the Blood watch which the patient is very feeble, the number of its Hématie S reaching only half of the normal value. The observation of a blood smear shows Hématie S unusual in form of Faucille or breaks into leaf of Acanthe.

The drépanocytose is not a rare disease. It reaches the populations of African origin particularly (each year 300 000 African children are born reached from this genetic anomaly).

Pathogenesis

The Gène S is an abnormal allele of gene governing the structure of the chain beta of the Hémoglobine. It is responsible for the synthesis of chains beta of which one of the residues of Glutamic acid in position 7 is replaced by a residue Valine. The hemoglobin which results called HbS from it (hemoglobin S for Sickle-concealment disease ) thus has the structure " alpha2ß2S". It is distinguished from hemoglobin has, normal, by its slower electrophoretic mobility and especially by the marked insolubility of its deoxygenized form, which crystallizes easily of its solutions.

The gene responsible for sickle-shaped anemia is recessive: it is necessary that the two copies of this gene (carried by the Chromosome 11) are abnormal so that the individual is sick. Thus, an individual can thus be reached only if his/her two parents transmit responsible gene to him; he is then known as homozygote .

The red globules of the Homozygote, which contain practically only of HbS, acquires the property thus to be polymerized when they are deoxygenized. This explains why the falciformation of red blood corpuscles is started by the lack of oxygen in blood (Hypoxie):

in vivo , in venous and capillary blood: from where prolonged sequestration, formation of Thrombosis S and easy Hémolyse of the red globules in the fine capillaries where the drépanocytes have evil to clear a passage, being given their lengthened form, as in the Rate where the slowness of circulation creates the requirements for the formation of the drépanocytes, which will be there phagocytes by SRE.
in vitro , during the examination of fresh blood between blade and plate, when a reducing body is added (Métabisulfite).

At the Hétérozygote, the red globules contain a mixture in equal proportions of HbA and HbS. At the time of the test of deoxygenation between blade and plate, these red globules does not take the shape of sickles, but of sheets of houx.

Geographical distribution

The high presence of this disease in Africa seems to be a genetic case of Polymorphisme balanced pulled by a Natural selection: indeed, the carrying people healthy Hétérozygote S (A/S) or reached drépanocytose Homozygote S (S/S) are protected from the neurologic affections of Plasmodium , the parasite responsible for the Paludisme also called malaria.

The gene S, person in charge of the anomaly, are largely widespread in the African continent (reaching in certain populations the frequency of 30%); one also finds it in other areas inhabitants the edge of the Mediterranean, in particular in Italy (especially in Sicily), in Greece and Anatolia (only one century ago hardly that the Malaria disappeared from several Mediterranean regions).

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Symptoms

The affection is announced in the infant, but is usually not manifest with the birth because the red globules of the newborn contain 50-90% more of fetal hemoglobin. The Symptôme S of this disease can appear as of the six months age. The usual acute demonstrations of the drépanocytose are of three orders:

vaso-occlusive Crises : clots stop an artery, which involves intense and brutal pains in part of the body (frequently hands, feet, hips, abdomen). These crises can be very painful.
haemolytic Anemia : the red globules of the drépanocytaires are of abnormal form (hemoglobin S is indeed less soluble than normal hemoglobin (hemoglobin A)), it precipitates, and deforms the Hématie S. Those takes the shape of sickles, and is stopped by the filter which the Rate represents, where they are destroyed. This destruction involves a fall of the number of Hématie S and thus a regenerative anemia.
Infections : they are more frequent at the drépanocytaires. They can also worsen anemia in the event of infection by the Parvovirus B19.

The chronic demonstrations of the drépanocytose associate a delay of size and weight, nutritional deficits (in particular in folates, because this vitamin is essential to the creation of the red blood corpuscles which are renewed very quickly at the time of the crises of anemia, thus exhausting the stock of folates), a frequent puberty delay, cardiopulmonary disorders (cardiomégalie, respiratory insufficiency), a Rate hypertrophied (but which with time will become on the contrary atrophic), of the anomalies retain (Hémorragie S), etc

The destruction of red blood corpuscles on the level of spleen involves an occlusion of the splenic vessels responsible for a splénomégalie. With the wire of time, the spleen cannot fill any more are lymphoid role of body (one speaks about asplénie functional), which involves a sensitivity increased to certain germs, in particular the méningocoque one ( Neisseria meningitidis ) and the pneumococcus ( Streptococcus pneumoniae ).

Today tests make it possible to detect the healthy carriers (people which have the responsible Allèle but which is not sick); they are then informed that the child designed by two healthy carriers presents a risk on four to be reached of sickle-shaped anemia.

The gene is more frequent in the paludic zones because the deterioration of hemoglobin constitutes a selective advantage: Plasmodium falciparum being destroyed with red blood corpuscle, then too deformed, the hétérozygotes (carrying the genes Hémoglobine has and Hemoglobin S) resist the Paludisme better that the healthy homozygotes.

Tests of laboratory and diagnosis

Separately the consatations common to all the haemolytic states, research will relate especially to the description of hemoglobin S. This can be done:

by the observation of fresh blood preserved between blade and plate, with or without addition of a reducer (Métabisulfite of potassium, Ascorbic acid): one will see the red globules of the homozygote being transformed into sickles and those of the hétérozygote in sheets of houx
by the electrophoresis of the hemolysate of red globules which will show, at the homozygote, a single band of an abnormally slow Hb, and at the hétérozygote the presence of two bands of Hb, of which fastest will be hemoglobin has and the other hemoglobin S.

Treatment

The treatment of the drépanocytose rests on:

treatment of the vaso-occlusive crises: analgesics (being able to go to opiates)
to avoid the factors starting the crises (cold, altitude, infections, dehydration)
supplementation in folates
preventive medication of the infections with pneumococcus and méningocoque
transfusion in the event of major anemia or of infection engraves

Research

The results published in December 2001 in the Scientific magazine Science obtained thanks to a Franco-American collaboration coordinated by Philippe Leboulch, director of the unit Inserm 111, person in charge of a laboratory to the Massachusetts Institute off Technology and professor with Medical Harvard School, mark a big step towards the genic Thérapie of the drépanocytose, which is one of the most frequent genetic diseases in the world. In collaboration with Yves Beuzard (unit Inserm 111, Academic institute of Hematology, Hospital Saint-Louis, Paris), Philippe Leboulch succeeded in curing mice drépanocytaires by introducing in these animals a gene producing a hemoglobin " anti-drépanocytaire" in high quantity. This research received the support of the French Association against the myopathies (AFM), organizing of the Telethon.

Simple precautionary measures

to frequently drink water
to air the parts well, in order to oxygenate
well to remain with the heat
not to take a weight
to eat rich foods in iron, or which facilitate the assimilation of iron (spinaches, oranges.)
not to catch cold, or more generally to avoid to the maximum the respiratory infections
wearing clothing which does not cut blood circulation
not to blow

A discussed drug

Until, put here aside the Hydroxyurée the simple and precautionary measures, there exists little of means of limiting the symptoms. June 3rd, 2007, the French institute of the industrial property (INPI) granted to a doctor Bénin ois, Jerome Fagla Médégan, a patent of discovered for a remedy against the drépanocytose. The drug is called VK 500 . A French laboratory agreed to put in manufacture this drug which could save the life with: 200000 patients who die each year because of this affection. However, no serious clinical study proved the real effectiveness of this drug in the fight against the drépanocytose.

External bonds

Federation S.O.S GLOBI: Federation of the Patients Drépanocytaires and Thalassémiques;
AFDPHE: the drépanocytose on the site of French association for the tracking and the prevention of the handicaps of the child;
CHU of Lyon: the drépanocytose, a name complexes for a particularly painful polysymptomatic disease, by Dr. C. Pondarré;
Drepanosite.free.fr: cerebral vasculopathy drépanocytaire by Dr. S. Verlhac and F. Bernaudin;
INRP: synthesis of knowledge on the drépanocytose;
Inserm: the research and the study of the diseases of the red globule in Creteil;
DREPAVIE: Fight association against Drépanocytose;
NCBI (NIH) : Sickle Concealment links ;
SCA ''clinical trials'' ;
'' University off Maryland Medical Center: Sickle Cell Weakened ;

'' Sickle Concealment Information Center '';

'' Sickle Cell Weakened Research: recent primary literature one sickle concealment weakened .
LCDM: Fight association against Drépanocytose in Madagascar;
DORYS: Fight association against the drépanocytose;

References

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