Mucoviscidose

The mucoviscidose ( mucus + viscosity ) is a Genetic disease concerning the whole of the covered bodies of a glandular epithelium. It is the lethal genetic disease with recessive autosomic Transmission most frequent among Europeans of the type Caucasien, whereas it is very rare in the Noires populations. In France, it touches a newborn on: approximately 2500. The frequency of the healthy carriers of transferred gene is of 1 out of 25 is two million people in France. The Symptôme S of the disease are digestive and respiratory anomalies as well as a Infertilité at the man. Its demonstrations are invalidating and half of the treated patients die before the 30 years age. The only possible therapy is very heavy: double clerk's office heart/lung and rests on the availability of a donor of bodies.

Its first scientific description goes back to 1936, but this disease was known since more moved back times. With the Middle Ages already, one knows the disastrous fate of the newborn whose mother notices the “kiss salted” ^,. In 1938, it is recognized like a pathological entity reaching the Pancréas from where its historical name of cystic fibrosis of the pancreas . It preserves this English name: in '' cystic fibrosis ''.

There exist rough forms of late diagnosis since 10 % of the mucoviscidoses are diagnosed after the ten years age. There is no curative treatment but progress of the assumption of responsibility makes it possible to lengthen the life expectancy in the event of early diagnosis especially. In France, tracking became a priority of public health with its generalization at all the new born ones since 2002.

Description

The mucoviscidose is a disease of the epithelial fabric of the glands Exocrine S of the organization. This fabric is found in many bodies as the respiratory tracts (Bronche S, nasal cavities…), the Pancreas, the Liver and the biliary tree, the Small intestine , the vas deferenses of the Genitals male, the glands sudoripares of the Skin.

Pulmonary demonstrations

The pulmonary demonstrations remain the major cause of the Morbidité and the Mortalité. There exists a chronic Inflammation of the bronchi with superinfection Bactérie does not attend mainly by Staphylococcus aureus and especially Pseudomonas aeruginosa (pyocyanic). The patients present thoracic pains, a chronic Toux and permanent purulent Expectoration S. A expiratory Dyspnée occurs when the respiratory function worsens. Abscess and the pulmonary Kyste S are consequences of the chronic infection. Hémoptysie S are not rare. The post-inflammatory fibrosis leads to a respiratory Insuffisance major.

With the examination of the patient, there exists often a digital Hippocratisme testifying to a Bronchectasie and the sounding is generally normal but can detect bronchial rails with type of sibilants.

The Pneumothorax can worsen the respiratory state of the patients.

Digestive demonstrations

Intestinal demonstrations

The demonstrations occur as of the néo-native period in the form of a Iléus méconial which occurs at 10 with 20 % of the children carrying the disease. This iléus méconial corresponds to the absence of emission of méconium of new born and to a low obstruction of the bowels. It can be diagnosed at the time of the morphological echography showing the existence of an intestinal hyperechogenicity. The rectal injection allows the evacuation of a viscous obstructive méconium.

The syndrome of the distal obstruction of the bowels (SOID) which touches more readily the child is a occlusion small intestine which MIME the appendicular crisis .

The Reflux gastro-œsophagien is frequent in the infant, sometimes raised by the operations of respiratory Kinésithérapie and chronic cough. This backward flow is not amended with the age of the child contrary to the majority of the RGO.

The rectal prolapsus is also more frequent in the infants mucoviscidosic, because it is supported by a volume of more important saddle, the malnutrition and the increase in pressure will intra abdominal at the time of the efforts of cough and defecation.

A sténose colic can be seen at the time of an overdose of the treatment by pancreatic enzymes. A digestive hemorrhage complicates the biliary demonstrations hépato.

Biliary demonstrations hépato

The biliary attack hépato of the mucoviscidose results in a rise in the viscosity of the bile then by an obstruction with the evacuation of the latter in the hepatic channels into the gall bladder. The consequence is the appearance of a Cholestase néonatale evolving sometimes to a biliary Cirrhose multifocale.

The cholestase reached 6 % of the patients and appears by a Ictère which is the reflection of the rise in the Bilirubine not combined in blood. Biologically one notes rise concomittante Transaminase S and γGT.

The biliary Cirrhose multifocale becomes complicated same manner as a common cirrhosis with the appearance of a Hypertension portale, digestive hemorrhages and of a hépato-cellular Insuffisance. It is the second cause of death among sick patients of the mucoviscidose.

One can sometimes also find a lithiasis vésiculaire being able to worsen a pancreatic pathology under unclaimed.

Pancreatic demonstrations

The pancreatic demonstrations are present in 90% of the cases. The patient presents a lubricating chronic diarrhea characterizing stéatorrhée, a distension and a preserved appetite.

The pancreatic insufficiency exocrine reaches the large majority of the patients involving a defect of absorption of greases (essential fatty-acids), proteins and vitamins liposoluble (has, D, E, K, and sometimes water-soluble like B12). The disorder of the absorption of the vitamin D involves a bad mineralization of the bones and a risk of rickets and fracture.

Among the other manifestations of the malabsorption one finds an insufficiency of growth, a puberty delay, a Anémie, deficiency disorders (in vitamins, trace elements and minerals).

Sometimes one can see the appearance of a pancréatite. A diabetes insulinodépendant reaches approximately 20% of the patients and an adult on two.

Genital demonstrations

The genital demonstrations of the mucoviscidose are characteristic only at the man with a bilateral sterility of the vas deferenses . This anomaly discovered during the investigation of a Infertilité of a couple must make seek this pathology systematically.

They reach the man by atrophy or hypoplasy of the ways excrétrices of the Spermatozoïde S: Vas deferens and seminal blisters involving a Azoospermie or severe Oligospermie (less than 5 million spermatozoa per ml).
the composition of the Sperme is also modified:

Other demonstrations

The affections rhino sinusiennes are frequent. The quality of mucus in the sines is the same one as that of the bronchi. An ignition and a chronic infection involve a chronic Sinusite and secondarily a polypose nasale'.

The electrolytic hydro disorders with Déshydratation by salt loss can apparaîtrent at the time of efforts or strong heat. The diagnosis of mucoviscidose in front of a table of dehydration with Hyponatrémie, Hypochlorémie and metabolic Alcalose is not rare in particular the summer.

A myocardiopathy probably of deficiency origin can be described as well as a pulmonary arterial Hypertension consecutive in a chronic pulmonary heart.

Etiology

The gene responsible for the mucoviscidose

The gene CFTR, Cystic fibrosis transmembrane conductance regulator , code a Protein whose function is essential at the organization. The change S in this gene are responsible for the mucoviscidose. The gene is localized on the Locus q31.2 of the Chromosome 7. It codes the synthesis of a membrane Protéine of: 1480 amino-acid with: 300000 pairs of bases divided into 27 Exon S.

Protein CFTR

The molecular weight of the cystic fibrosis transmembrane conductance regulator is of 168 kD, and, when it is glycosylée, of 180 kD. The molecule is located at the apical pole of the epithelial cells

Functional deterioration of the CFTR

The change of gene of the mucoviscidose involves a defect in the synthesis of the protein cystic fibrosis transmenbrane conductance regulator or CFTR (family ATP Binding Cassette), which is a membrane protein entering the formation of a ionic Canal selective with the Anion S and mainly Chlorure S. plasmic membrane apical of the epitheliums exocrines of many fabrics whose role is to evacuate chlorine will intra cellular towards the outside of the cell. -->

The defect of synthesis prevents the correct integration of protein in the membrane, it results an extracellular chlorine deficit from it and thus a defect of hydration of mucus, a hyperviscosity of epithelial secretions related to an exaggerated reabsorption of secondary water to the cellular retention of the ion chlorinates.

There exists more: 1200 indexed changes. The most frequent change is the change Delta F508 consists of the délétion of an amino-acid, a phenylalanine in position 508, due to a change relating to the tenth Exon of gene. This change is found in nearly two thirds of the cases with variations according to the studied populations

Among the other changes, a small number exceeds the threshold of 1 % in the French population. There exists a certain relationship between the change (the Génotype) and the clinical demonstrations of the disease (the Phénotype). The very great variability of the demonstrations and the gravity of this disease is in connection with the multiple changes responsible for the CFTR.

The changes are gathered in 6 classes according to the functional consequences which they cause. Certain changes involve quantitative protein anomalies, classify 1 (complete absence of manufacture of protein) or classify 5 (lowers number of proteins manufactured), or qualitative, class 2 (difficulty of manufacture of protein) or classes 3,4 and 5 (dysfonction of protein).

Physiopathology of the demonstrations

The insufficiency of operation of the glands exocrines is noticed especially on the level of the Poumon, the Pancréas and the Foie. The digestive attacks are earliest and the historically described first.

On the level of the pancreas

Enzymes of the pancreas, like the lipase and the trypsin, which are used for digestion are badly excreted in the intestinal light because the pancreatic channels are stopped because of a too thick secretion. The enzymes then attack directly pancreatic fabric and of the cysts can be formed. When the pancreas is destroyed, one speaks about pancreatic insufficiency. The pancreas is reached in its function exocrine and endocrine.

reached function exocrine: the reduction or the absence of arrival of enzymes of digestion in the intestinal light leads to a Syndrome of malabsorption which can have a repercussion on the staturo-ponderal and puberty development of the children.

reached endocrine function: the destruction of the cells beta of the small islands of Langerhans leads to the absence of secretion of insulin and a diabetes insulinodépendant appears.

On the level hépatobiliaire

The viscosity of the bile is increased by the dysfunctions of protein CFTR of the biliary epithelial cells. The channels which transport the bile will be stopped because of this liquid too thick. The repetition of these obstructions leads to localized phenomena of cirrhosis and hepatomegaly.

The usual consequences of the biliary cirrhosis are the same one at the patient mucoviscidosic that in the remainder of the population. Hypertension carries, the digestive hemorrhages and the hépatocellulaire insufficiency can lead to the hepatic Clerc's Office.

On the level of the lung

The bronchial liquid of surface is composed of water and mucus. Channels CFTR are used for active secretion of chlorine towards this liquid, they interact with the channels of absorption of sodium to limit their work. This chlorine movement involves a water and sodium movement. This water secretion makes it possible to hydrate the bronchial liquid of surface and to maintain to him adequate rheological properties for an effective clearance muco-ciliaire. The clearance muco-ciliaire is the flow of liquid of surface transported by the ciliées cells of the bronchial tree. The evacuation of this liquid allows the elimination of dust and the infectious agents towards the digestive system.

The functional deterioration of channels CFTR involves a disorder of hydration of the bronchial liquid of surface. The Viscosité of the Mucus becomes too important and the lashes cannot move it at a suitable speed.

This attack of the function of water secretion has a major repercussion at the pulmonary level by secretion of a Mucus abnormally thick and Hypertonique, which leads to the chronic obstruction of the Bronche S like with nonthe evacuation of dust and bacteria.

With the wire of time, bacteria of the different types and profile can evolve/move at the same patient. Initially banal bacteria such as Staphylococcus aureus or Haemophilus influenzae colonize and infect the lungs. Thereafter germs such as Pseudomonas aeruginosa or Burkholderia cepacia occupy the place. The repeated use of antibiotics but also of other factors still unspecified and dependant on the disease itself, support the colonization of the bronchial tract by bacilli pyocyanic generally resistant to antibiotics of current use. These bacteria are exceptional at the unscathed people of mucoviscidose.

There exists an ignition of the bronchial epithelium whose mechanisms are incompletely elucidated. It is not yet distinct that this ignition is directly consecutive with the bacterial colonization of mucus. The physiopathological studies concentrate on the other functions of the protein CFRT, which would have a role in the regulation of the ignition, even a role in the destruction of Pseudomonas Aeruginosa.

In the long term, the ignition and the chronic infection induce lesions of pulmonary fabric which lead to a table of obstructive chronic Broncho-pneumopathie.

Correlation genotype and phenotype

The importance of the symptoms and their severity depend on the class of change which gene CFTR undergoes. Certain changes involve more disorders functional calculuses than others thus the epidemiological studies show a different mortality in populations having different changes. The pancreas can present lesions different according to the changes from gene, which is less obvious for the lesions of the respiratory epithelium.

Epidemiology

The mucoviscidose touches a child who is born on 2500 in Europe and in North America. It is the recessive Genetic disease most frequent at the populations Caucasien born (i.e. of European origin). There exists in France 2 million operational carriers hétérozygotes; this amounts saying that approximately an adult on 25 is carrying a transferred gene. There exists very little of case at the Blacks and even less at the Asian ones.

The Prévalence varies according to the area in France: it is about 1/5 000 births, with important regional differences. Thus, in Celtic Brittany the prevalence is of 1/1 600. In Paris region and in the south of France, it is about 1/10 000.

The relative importance in the Caucasian populations of the frequency of the allele of the mucoviscidose can surprise. This allele would have undergone a Natural selection because it confers a certain resistance with respect to digestive infections diarrheal, like the Typhoid fever. Indeed, the cells carrying transferred protein CFTR (ΔF508) are penetrated by the agent of this disease ( Salmonella enterica typhi ). The individuals Hétérozygote S would have been favoured in the reproduction, compared to the healthy Homozygote S and carrying the changes.

Survival

The mucoviscidose equally touches the men and the women. For still unexplained reasons, the men have a Life expectancy longer than the women.

The life expectancy of the patients depends largely on the access to the care and increase regularly. In 1959, the median age of survival for the mucoviscidosic children was 6 months. To the international level, the median age of the death passed from 8 years in 1974 to 21 years in 1994. In the United States, for the newborns in 2006, the life expectancy is now 36.8 years, that is to say 5 years more compared to the figure of 2002. In the developed countries, the patients have an about comparable life expectancy. Nevertheless, in the countries in the process of development, the majority of the patients do not exceed 10 years of life.

In Canada, a study relating to the period 1970-1989 shows that median survival improves among the men and sick women of the mucoviscidose. It is carried out in many centers in the world. The results are standardized and reproducible.

The individuals reached of mucoviscidose compared with unscathed individuals have:

a negative potential difference reflecting an increased absorption of sodium
a more important variation of the potential difference under inhibiter of sodic absorption
Of the tiny variations of the potential difference under perfusion of substance acting on the CFRT.

Genetics

The research of the change depends on the studied population. The most frequent changes in the white populations are:

The found genotypes are:

At a man with azoospermy or oligospermy

the search for a hypoplasy of the seminal blisters and/or the deferent ones by an urologist or medical imagery is the first stage. If this one is positive the search for change of gene CFTR is realized.

Differential diagnosis

Is posed especially in the presence of repeating respiratory affections:

bronchopulmonary Asthma
Dysplasie
Deficit in alpha-1-antitrypsin
Passive smoking
Disease of Kartagener

Assumption of responsibility of the disease

The disease is currently incurable, but the treatments to mitigate the effects made it possible to improve considerably the life expectancy of the patients passing 7 years in 1965 to 39 years today to France; although an important part of the patients does not reach the 30 years.

It is also necessary to treat the complications (chronic respiratory insufficiency, cardiac problems, cirrhosis of the liver, diabetes…)

Curative treatment

Genic therapy

The mucoviscidose being a monogenetic disease, i.e. relating to one gene, it is naturally that great hopes of cure were born with the appearance of the concept of the genic Thérapie. Analyzes of the quantity of ARN messenger (ARNm) in the healthy cells revealed an extremely low number of ARNm coding CFTR, between two and three copies per cell. In theory, even with a very low rate of transfer, it would be possible to restore a function of normal secretion in the pulmonary cells while bringing one or two copies of healthy gene integrated in a vector. The restored function, mucus should flux and allow a satisfactory clearance muco-cilliaire. Indeed, the infections of the pulmonary ways by the pathogenic ones and the Inflammation which follows is one of the cause of the loss of the respiratory function.

The vector chooses was the repugnant Adénovirus because in a selective way the pulmonary cells. One carries out an infusion of viruses transformed directly in the bronchi of the patient. In spite of a relatively simple principle, the genic therapy butts against several points '. The Immune system of the patient fights against the vector adénoviral and destroys it. Moreover the cells having integrated transgene express proteins of the virus and thus are identified then eliminated by the cellular immune system. From the presence of a thick bronchial mucus, the penetration of the adénovirus in the target cells is slowed down considerably. In addition, the transgene is not integrated in a final way in the target cells and it is rather quickly eliminated.

Proteinic therapy

The knowledge of the physiopathological mechanisms in the mucoviscidoses leave the possibility of a pharmacological treatment aiming at intervening to mitigate their failure.

Activation of protein CFTR

Many molecules seem to be able to intervene on the maturation of protein ΔF508-CFTR and to prevent its premature blocking by the Appareil of Golgi, thus increasing the number of molecule transmembrane CFTR reaching the apical wall of the ciliées cells and providing a work of transfer of chlorine.

Among them, there were tests with the butyrate and its compounds; in vitro, of high N-oxide trimethylamine or glycerol concentrations, the myoinositol and the taurine can partially neutralize the defect of transfer of protein ΔF508 CFTR towards membrane surface.

Miglustat is tested since September 2007 in a clinical trial of level II like inhibiter of the enzyme of glycosylation of the F508del-CFTR protein. The glycosylation involving an accelerated degradation of protein by the endoplasmic Reticulum, its inhibition makes it possible to leave the even transferred CFTR, to take its functions on the apical membrane of the ciliée cell.

Activation of alternative ways of secretion

In front of the failure of the genic therapy, other therapeutic strategies are considered; one among it consists of the activation of healthy ways of secretion.

The channel chloride CFTR is not the only channel apical chloride present in the epithelium S. the idea under unclaimed of this therapeutic strategy is to activate using specific drugs of the channels already present in the apical membrane. The studies are made difficult from the difficulty which obtaining an epithelium of functional lung represents. This is why the large majority of work are made on the epithelium colic, another epithelium which presents a sodium chloride secretion dependant on the AMPc. Using this tool, several alternative ways were described by the researchers. Among those, one can quote the attempt to activate the calcium chloride secretion depend on calcium by activating channels purinergic P2X using ATP. The treatment tested thus consisted of the injection using an inhaler of a agonist of receivers purinergic P2X. The connection of the agonist on these receivers causes an intracellular calcium increase, calcium which will activate the calcium chloride secretion by activating a channel chloride depend on apical calcium. With the difference of the calcium secretion passing by CFTR, secretion thus induced is not constant but transitory, of the phenomena of rétroinhibition stopping rather quickly the activation of this way.

Palliative treatment

Respiratory tracts

Kinesitherapy

The bronchi are often blocked by a mucus damning up and prone to permanent bronchopulmonary infections, the Kinésithérapie tries to mobilize and evacuate bronchial secretions. Initially, the kinesitherapist practices techniques of respiratory acceleration of flow. He rehabilitates also cough so that it becomes more effective. Then, the patient will learn the techniques from postural drainage and bronchial toilet which should be practiced several times per day. This bronchial drainage perhaps helped by the use of thinners or aerosol which increase the hydration of the mucosities and allows their best mobilization. (see Aérosolthérapie)

Techniques used by the kinesitherapist:

increase in respiratory flow, and its alternative:
the slow expiry, total open glottis in latéro-ulna,
education with cough,
drainage of posture,
etc

The kinesitherapist can make use of instrumental techniques:

exercises of inciting spirometry,
mechanical vibrations,
etc

Antibiothérapie

The infections and bronchial superinfections acute or chronic are treated by a antibiothérapie determined by the bacteriological examinations. The setting in culture of spittles (ECBC) or taking away of blood (hémoculture) makes it possible to determine the principal germ in question, to evaluate the importance of colonization, and of knowing which antibiotics will be effective. The two principal germs (Staphylococcus aureus and Pseudomonas aeruginosa) develop usually and quickly resistances to antibiotics. It is thus not rare that one uses doubles antibiothérapies by intravenous way being able to be accompanied by an inhaled antibiothérapie maintenance.

Are generally useful:

the Penicillin S and Beta-lactam antibiotic S (Cephalosporine S),
the Aminoside S by way IV in partnership with other antibiotics against Pseudomonas (see the tobramycin used in atomizing),
the Fluoroquinolone S on Pseudomonas even in the children,
the Fosfomycine on Pseudomonas multirésistant,
the fucidic Acid on Staphyloccoques,
etc

Pulmonary Clerc's Office

In the desperate cases of serious attacks of the respiratory tract, the Clerc's Office of lung (even heart/lung in certain cases) makes it possible to prolong the life, but mortality after 3 years of Clerc's Office is of 50 %. The Clerc's Office does not cure the disease, it just makes it possible to find a correct respiratory function.

Techniques of Clerc's Office of a pulmonary Lobe with a donor resulting from the same family developed.

System oto-rhino-laryngologic

Attack ORL is almost constant in the mucoviscidose with in particular chronic sinusitis and polypose nasal. The therapeutic one of these disorders is not the subject of a consensus. The surgery generally suggested vis-a-vis a polypose, does not avoid an early repetition (repetition at 4 years on average) of this polypose, a surgery by endoscopic way thus developed to improve the continuations post-operative. A antibiothérapie by local instillation, associated with the endoscopy, would also decrease the repetitions of sinusitises and the recourse to a conventional surgery .

A fall of hearing, even a hearing impairment (rare) can be caused by the use of certain antibiotics (Aminoside S) necessary in pulmonary period of superinfection.

Nutritional and digestive assumption of responsibility

The Nutrition is a major stake in the mucoviscidose. If, until the beginning of the year 1980, the patients were to observe a strict mode without greases (the pancreatic extracts per bone were less powerful than nowadays), today they can eat of all and follow a mode hyperprotéiné (150 % of a normal ration, 180 % in period of superinfection). In the event of denutrition and of failure of the hypercaloric oral supplémentations, one sets up a parenteral nutrition (by perfusion) or entérale (by naso-gastric probe or Gastrostomie).

The mucoviscidose involves the difficulty of assimilation of greases but one should not let the subjects thin down itself nor to present a deficiency in essential fatty-acids. Powders of “gastro-protected” pancreatic enzymes make it possible to improve the digestive functions.

An adapted mode, hypercaloric equitably divided into protein/glucid/lipid, privileging oils vegetable (the such sunflower) and triglycerides with average chains, rich in iron, vitamins (7500 to 10000 UI/jour of vitamin has, 1200 to 1500 UI/jour of vitamin D, 5 to 10 mg/kg of vitamin E, K and sometimes B12), out of salt, zinc and selenium must be followed.

The backward flow gastro-œsophagien must be treated to avoid the aggravation of the respiratory symptoms.

Other therapeutic and hygiene of life

The patients of the mucoviscidose must have a good hydration and a supplementation out of salt during the periods of efforts and strong chaleur'. The heat wave of August 2003 in France saw the increase in the number of cases of dehydration in the population of the patients mucoviscidosic

The sport, even high level, is strongly advised.

Anti-flu vaccination is advised in addition to obligatory vaccination (Diphteria-Poliomyelitis-Tetanus).

Fertility among women

The disorders of the cycle are frequent more in the event of severe attack in connection with the disorders of the nutrition of the disease than by the disease itself.

Although the cervical glaire is thicker among these women their fertility seems little touched. An oral contraception is possible in spite of a reduction in the absorption of the sexual steroids which are liposoluble in these patients whose absorption of greases is disturbed.

Average additional contraceptives are desirable during the antibiotic treatments by venous way.

Pregnancy at a person reached of mucoviscidose

The first pregnancy, described in 1960, at a woman reached of mucoviscidose leads to the death of the patient six weeks after her childbirth whereas the median of survival was 10 years.

In 1992,4% of the mucoviscidosic women in the United States are pregnant. The pregnancy should be planned and a research of the most frequent changes must be made in the future father. The diagnosis by taking away of the chorion is made if the father is carrying a change since the fetus has a risk on two to be reached in this case.

In the event of severe attack, the woman must be informed of a possible death during the pregnancy or in the post partum. The general anesthesia is complicated by the attack of the lungs. Nevertheless the available data on the exact risks of the pregnancy at a mucoviscidosic woman are weak. A reduction of 60 % of forced expiratory volume should be an absolute counter-indication with a pregnancy.

Although pregnancies proceeded without complication after a transplantation artificial heart-lung, that Ci are disadvised because of an increase in the rejection of the graft and because of the teratogenic risks of the drugs anti rejection.

The genetic Council

The systematic tracking of the people at the risk is in force in several countries, and in France since the middle of the years 1990.

Risk for the members of a family of a mucoviscidosic child

Parents of an ill child

So that the child develops the disease, it is necessary that his/her parents are both carriers of sick gene
In certain very rare cases the child can develop the disease even if only one of his/her parents is healthy carrier
the research of the change must be carried out in the parents
It is rare that on this occasion the disease is diagnosed at one of the parents
In the event of new pregnancy, the probability that the child is reached is of 25 %, that the child is healthy and not carrier of gene is of 25% and that the child is healthy and carrying gene is of 50 %

Brothers and sisters of an ill child

They must profit from the research of the changes of gene. Failing this, the test with sweat must be carried out.

Descendant of a woman reaches mucoviscidose

the women are fertile, but it is difficult for them to have a child
Each one of these descendant will be carrying a gene of the disease
the risk of the disease will depend on the genetic statute on the procreator
tracking on the changes on CFTR at the procreator depends on its family history and its religious convictions and personal

Descendant of a man reaches mucoviscidose

Because of infertility, the men must have recourse to the techniques of Procréation médicalement assisted
Each one of its descendants will be carrying a gene of the disease
the risk of the disease will depend on the genetic statute on procreative the
tracking on the changes on CFTR at the procreative one depends on its family history and its religious convictions and personal

Tracking of the carriers hétérozygotes

So that the child presents the disease, it is necessary that the 2 parents are healthy carriers hétérozygotes of a change of embarrassment CFTR (or more rarely than a relative is reached disease and the other healthy carrier hétérozygote). Approximately 2 million people is healthy carrier of a change of embarrassment CFTR. If the 2 parents are healthy carriers of a change of the embarrassment then the child has a chance on 4 to carry the disease, if none of the 2 parents or only one are carrying a change of embarrassment CFTR, it does not have no chance there that their children to be born has the disease. The tracking of an healthy carrier cannot be made that by analysis of its DNA using molecular test since it does not present a symptom. To determine if the parents of a couple are healthy carriers, in particular at the time of a pregnancy, a tracking of the woman can be proposed (because it is it which generally consults and in the event of positive test, a test can be made thereafter on the father.

However, this method does not prevent the eradication of the disease. Indeed, even if a antenatal test is carried out on the 2 parents, and that one of these tests is negative, that does not guarantee that the child will not have the disease since analysis DNA of gene CFTR can give negative forgeries, all the changes of the embarrassment not being known (the principal change gF508del representing only 70 % of the cases).

Tracking at the time of the sperm donation

Diagnosis anténatal

A consultation of genetics, before the beginning of the Grossesse, is desirable to explain the limits of the diagnosis anténatal if the change is not known in a family or a person is sick

Diagnosis préimplantatoire

High-risk pregnancy

the Diagnostic préimplantatoire is possible at the couples high-risk and having to resort to a Procréation médicalement assisted. The pre-implantatoire diagnosis is not authorized in all the countries; it is it in France.
the diagnosis is possible by study of DNA collected by Biopsie of trophoblaste or Amniocentèse
the proportioning of the Isoenzyme S of the alkaline Phosphatase in the Amniotic liquid is possible if the changes are unknown.

Pregnancy at the intermediate risk

One of the parents is carrying the change and the other relative has a negative tracking of change of the CFTR. No complementary examination is available to test the fetus.

Pregnancy with bottom risks

the tracking of mucoviscidose is possible on the hyperechoic aspect of the fetal intestines (correspondent with a illéus méconial) or on the observation of an intestinal dilation. The sensitivity and the specificity of this sign for the mucoviscidose are very low.
the absence of visualization of the Gall bladder during fetal echography is also regarded as a sign of call.

Tracking

Pre native systematic

Proposed in France by some with all the expectant mothers, this tracking was not recommended by the National Advisory committee of Ethics for the health and life sciences in its opinion n° 83 of the March 25th 2004.

Néo-native systematic

The arguments in favor of a systematic tracking are:

the existence of a reliable test
the sometimes late diagnosis of the disease because of the forms frustrate
the benefit of an early assumption of responsibility of the children reached

It is carried out since 2002 in France.

It is held in two stages

This test consists in proportioning immuno-reactive trypsin, Proenzyme secreted by the Pancréas circulating in blood. It can be carried out three days after the birth of the child. It is carried out starting from one blood drops dried at the same time as the tracking of the Phénylcétonurie, the Hypothyroïdie and the congenital Hyperplasie of the suprarenals.
the detection of an abnormal trypsin level results in carrying out a molecular diagnosis (30 changes are required accounting for 84% of the whole of the changes). The children in whom a change of gene CFTR will have been highlighted will undergo in the month following their birth a test with the sweat whose results are in a certain number of cases difficult to interpret. This test being a genetic test requires the agreement written and signed parents. Only 30 changes of gene CFTR on more than 1.500 known are the subject of tracking néonatal. These 30 changes are present in 86% of the cases, which means that 14% of the implying case of other known changes are not currently detected by the genetic test.
the complexity of the genetic information transmitted at the conclusion of the tests is included/understood sometimes with difficulty by the parents thus one cannot predict the evolution of the disease according to the detected changes.

Nearly 110 new-born babies are thus detected each year as being Homozygote S. In same time, one knows that are born: 26000 “healthy carriers”. But, for complex statistical reasons, only 400 of them will be identified, via systematic tracking.

April 26th, 2007, the national Advisory committee of ethics gave an opinion being opposed to information parents children Hétérozygote S:

“ that the systematic revelation of the statute of healthy carrier of a newborn is not encouraged, taking into account the absence of direct interest for the child ”

“ It acts not to transform an human being into a being locked up in its genetic statute, with the risk of sacralization of gene that comprises ”

Information concerning the hétérozygotie should be delivered only on one request of the child detected and sometimes happened in age to procreate but knowing that these children hétérozygotes and their parents are convened for a test of sweat, it is difficult not to reveal this information as of the birth. In the same way, the parents of children considered as hétérozygotes, are in right to wonder about their clean hétérozygotie in particular if it would intend to have children within the framework of an other union.

History of the mucoviscidose

Turkey and Iraq whereas this genetic disease touches mainly only the European populations. It is estimated that the disease appeared there, approximately 5000 years ago. It would have then extended to the west, to finally cover the Europe, the North America and the Australia. As of the 17th century, the literature mentions this disease. Indeed, one finds accounts reporting the history of children “to the salted kiss”. ---> Described for the first time in 1936, at the time of a thesis written in German and chaired by the professor Guido Fanconi, under the coeliaque term of disease with pancreatic anomalies which worked as doctor with the Babies' Hospital New York. It described the characteristics clinical and histological of the disease which it connected with a deficit in vitamin A. Although this theory was never confirmed, it persisted in supporting it during many years.

The term of mucoviscidose was created in 1943 by Doctor Sydney Farber: Mucus, viscous and of the suffix dares. The hereditary feature and the recessive mode of transmission were suggested in 1945.

It is in 1953 that the professor Di Sant Agnese discovers the electrolytic anomalies in the sweat of the patients allowing to consider a diagnosis specific to the disease: the test of sweat. The defect of water secretion induces a hypertonic sweat indeed (salted). In spite of the technical difficulties (children being literally wrapped in bandages) and a considerable rate of false-positive, this test was during years the test diagnosis of this disease which until was based there only on the private clinic. But 20 years after the insulation of this disease, the assumption of responsibility does not allow a prolonged survival: half of the children reached dies before ten years.

The realization of the jejunal Biopsie finally makes it possible to distinguish the coeliaque Maladie from the mucoviscidose. Later, this biopsy will make the diagnosis of intolerances with milk proteins.

In 1989, the team of professor Lap Chee Tsui highlights the genetic anomaly at the origin of the disease '': a change of a gene located on the long arm of the Chromosome 7. This gene named cystic fibrosis ( CF ) code a Protein called cystic fibrosis transmenbrane conductance regulator ( CFTR ).

Genetics of the populations

As of 1990, geneticists French of Unit 155 of INSERM proposed an assumption, daring for the time, but confirmed by later work. They made go up the origin of the pathological change at the time Neolithic era and perhaps even paleolithic, at populations of the the Middle East. The carriers of this terrible disease are thus the downward distances of tribes coming from this area of the world. This study can appear contradictory since she hardly explains the reasons of the European character of this disease.

Personalities reached of the mucoviscidose

Sources and references of the article

Sources

Samuel Mr. Moskowitz, Ronald L Gibson, Darci L Sternen, Edith Cheng, Garry R Cutting, CFTR-Related Disorders in GeneTests: Medical Genetics Information Resource (database online). Copyright, University off Washington, Seattle. 1993-2007

References

See too

Donation of organs

External bonds and documents

Orphanet
NCBI kystic fibrosis
Vaincre the mucoviscidose
has bottom for OJ, Fight association against the mucoviscidose

Simple: Cystic fibrosis

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