I. Disease
Cystic fibrosis (CF) is the most common inherited fatal disease in Caucasians. It is a hereditary disease, with recessive autosomal transmission, due to an alteration in the CFTR protein, provoking an anomaly in the transportation trans-epithelial of chloride and water. This alteration leads to secretion of thicker mucus than usual and salted sweat. Typically, the clinical expression involves the respiratory apparatus and the gastrointestinal tract, as well as the liver, the pancreas and the reproductive apparatus.
II. Epidemiology
In European Caucasian population, the average frequency of the disease is estimated to 1/2500 births, that is 1 heterozygote out of 25. It is less frequent in North Europe (1/ 10000) and especially on black individuals (1/90 000). In France, the frequency could be estimated to 1/3 500 births.
III. Clinical Signs
CF is considered as a typical monogenic disease, with recessive autosomal transmission. Nevertheless, the lack of direct relation between mutations of CFTR gene et the clinical expression of the disease suggests that other risk factors influence the phenotype at different levels (gastrointestinal, pulmonary and hepatic).
The clinical signs can appear right after birth or later. It is a progressive disease.The main symptoms concern :
- Respiratory apparatus: responsible of 95% of CF patients’ death, the severity of the respiratory affections is very heterogeneous among patients.
- Classically, we observe a secretion of thick and viscous mucus, more difficult to be transported out of the lungs. This thick mucus cumulates in the airways, obstructing them. This will lead to, little by little: air retention, obstruction of airways and repeated infections which will damage the lungs.
- The pancreas : the exocrine pancreatic insufficiency is present in 85 to 90% of the affected. It is due to the progressive obstruction of the channels by fibrosis. The reduction in the secretion of pancreatic enzymes disturbs the digestion of fats and lipids, leading to a steatorrhea and malabsortion.
- The liver : the liver affection, present in 20 to 25% des patients, will sum up in 30% of cases to hepatomegalia and in 9% of cases to hepatic insufficiency. This affection is linked to the obstruction of bile ducts by compression at pancreas level.
- Gastrointestinal apparatus: constipation is frequently observed, and could be revelatory of the disease on newborn by a meconium ileus (intestinal occlusion due to an abnormally thick meconium).
- The genital apparatus: male sterility is observed in 98% of cases, while normal sexual function is preserved, by absence or agenesis of spermiducts(obstructive sterility).
IV. Genetics
CF is due to a mutation in the gene coding the protein CFTR (CF Transmembrane regulator), located in the long arm of chromosome 7. The transmission of the disease is recessive autosomal.More than 1250 mutations have been listed, but mutation ΔF508 (deletion of a phenylalanine in position 508 of the protein) is by far the most frequent, representing nearly 70% of the mutations.There is no real correlation genotype – phenotype. Several factors are added to the heterogeneity of the mutations: environmental, modifier genes. It is therefore difficult to predict the evolution of the disease depending only on the genotype.
V. Diagnostic
The sweat test (also known as the sweat chloride test), is the most common test used to diagnose CF. This test measures the concentration of chloride in the sweat, which is significantly high in the affected people. This test has to be repeated and obtain figures superior to the average when doing several successive test to be able to establish a diagnostic. The test is painless, rapid and positive in almost the totality of cases of CF. High quantities of chloride in the sweat will bring to find confirmation for a CF diagnostic by the search of mutations in the CFTR gene.Since 2002, a neonatal screening is systematically performed in many countries to all the neonates. This screening is done by measurement of immunoreactive trypsine. The measurement of this pancreatic enzyme is done on the 3rd day of life and, in case of high quantity, a search of CFTR gene mutations will be done.
VI. Prenatal Diagnosis
A prenatal diagnostic should be proposed to couples having already an affected child and couples considered at-risk (family history, echographic signs).The diagnostic is done by sampling on chorionic villi (from throphoblast) from 11 weeks of amenorrhea or by amniocentesis (fetal amniotic cells) from 14 weeks of amenorrhea.
VII. Genetic Analysis – Technique
Biological sample: saliva on FTA cardAnalysis of the following mutations: Gene CFTR – analysis of exons 3,4,7,10,11,19,20 and 21Analysis description: PCR + sequencing of exons
VIII. Traitement
At the moment, there is no remedial treatment. Only preventive mesures can be taken. The current treatments are symptomatic. Lung problems (such as bacterial infections, inflammation and airway blockage) can be treated with pharmaceutical and non-pharmaceutical methods:: Respiratory phisiotherapy: bronchial drainage or chest physiotherapy daily. Chest physiotherapy (chest PT) consists of bronchial (or postural drainage), done manually or mechanically.Administration of antibiotics, to treat bacterial infections of the lung. Antibiotics may be taken orally, by injection or inhaled (via an aerosol form).Administration of protease inhibitors for treating the pulmonary affections.Administration of pancreatic substitution enzymes and vitamins for treating the pancreatic insufficiency.Administration of nonsteroidal anti-inflamatory drugs or steroids, for treating inflammation.For the treatment of airway blockage due to mucus buildup, the doctor may prescribe dornase alfa which is used in an inhalant machine, called a nebulizer.It is therefore very important to perform early diagnosis of the disease.