Almost all are point mutations or small deletions (1 to 84 pz). However, it is important to understand that most of them are rare, and the functional consequences of many of them are difficult to understand. In fact, fewer than 10 mutations (shown in Table 2) occur with a frequency greater than 1%, while the most common mutation in the world, characterized by a deletion of phenylalanine at position 508 (ΔF508 – Phe508del) (deletion of 3 base pairs from exon 10), occurs in approximately 30-80% of cystic fibrosis patients, depending on ethnicity.
Mutations in the CFTR gene can be divided into 6 different classes, divided according to their functional consequences at the cellular level (Figure 1):- class I: the protein is not synthesized;
Their accumulation over time results in a change in function
Class II: CFTR is inadequately processed in Golgi apparatus;- Class III: protein does not function;- Class IV: CFTR shows abnormal guidance;- Class V: CFTR has partial synthesis defect;- Class VI: CFTR is demoted, accelerated.Mutations in classes i, ii, iii are more common and associated with pancreatic failure, while mutations in Classes IV, V, and VI are rarer and patients have no pancreatic symptoms.The CFTR gene contains about 250-280 kilosasads, consisting of 27 exons.
It encodes a 1480 amino acid glycoprotein that forms five domains: 2 transbonary domains, each with 6 α-Helix holes, 2 nucleotide domains (NBD) in the cytoplasm linked to transbonary regions, and a regulatory domain (R) that binds transbonary domains among them. The ion channel only opens when the regulatory region has been phosphorylated by protein kinase a (PKA) and the nucleotide domain binds to ATP.
A consequence of genetic abnormalities is the lack or malfunction of chlorine channels at the cellular level, resulting in Altered chloride transport in the mucous and serous glands of most organs.
These secretions will have a low water content, be sticky, adhere to the epithelium of the excretory ducts and difficult to remove externally. Their accumulation over time results in a change in function and destruction of various organs (lungs, pancreas, liver, intestines, birth organs). At the skin level, there is a sweaty secretion with a high concentration of salt.Cystic fibrosis varies in severity depending on CFTR mutations and environmental factors and comes in several forms, some of which cause premature death in children as a result of progressive obstructive pulmonary disease with bronchiectasis, others are characterized by pancreatic failure and progressive obstructive pulmonary disease.
The clinical picture, age at diagnosis, severity of symptoms
In adolescence, with increased hospitalizations in adulthood, and others manifesting as recurrent sinus and bronchitis or infertility in young men.The clinical picture, age at diagnosis, severity of symptoms and rate of disease progression in the affected organs vary widely.Pulmonary symptoms. In the uterus of babies with cystic fibrosis at birth and immediately after birth, lung histology is normal (except for dilated ducts of the submucous glands). In a short period of time, however, pulmonary lesions appear, which are characterized by obstruction of the peripheral airway as a result of a build-up of secretions.
- Affected individuals then develop lower respiratory inflammatory syndrome, followed by chronic intracranial infections.
- Because elastase (NE) released by neutrophils at the site of inflammation causes cleavage of the CR1 receptor, complement component C3b, and immunoglobulin G (IgG), bacteria can no longer be opsonized and destroyed, which promotes their survival.
- A change in the anti-infective defence leads to the appearance of bacterial bronchitis and bronchitis (most commonly Staphylococcus aureus and Pseudomonas aeruginosa , but also Aspergillus fumigatus with fungal development), with intense neutrophil infiltration and airway obstruction.
This also causes an increase in elastase in IL-8 epithelial cells, which is a chemoattractant for neutrophils, destroys elastin and stimulates secretion, contributing to the maintenance of infection and inflammation, thus causing structural damage and disruption of gas exchange.Respiratory symptoms may appear in the first month of life in the form of coughing, rapid breathing or wheezing, and some children may even have severe respiratory failure associated with bronchitis.Since nasal polyps occur in 10-32% of patients with cystic fibrosis, their presence is an indication for a sweat test.
Hypoxemia occurs initially during sleep
Most children over 8 months of age (90%) have recurrent antibiotic-resistant sinusitis.In adults, the symptoms of cystic fibrosis are characterized by chronic coughing (initially dry, intermittent, consistent with infection, prolonged, seizure, night-time exacerbations, especially in the morning after waking, later productive), intermittent coughing with increased sputum production associated with discolouration, mild fever, dyspnoea exertion, pneumonia, recurrent bronchitis, hypodension, overactive airway with refractory asthma, and non-response to β-adrenergic therapy, bronchospasm, bleeding and swelling .
As lung disease progresses as a result of chronic infections, significant structural changes in the airways (cysts or abscesses) occur, accompanied by fibrosis of the adjacent lung parenchyma and the appearance of obstruction with hyperinflation and gas blockage. Hypoxemia occurs initially during sleep and exercise, while hypercapnia develops late and is part of a negative prognosis.
Also, the appearance of pulmonary hypertension and the development of the pulmonary heart with advanced parenchymal disease is a sign of an unfavorable prognosis, which is associated with survival of about 8 months.A recent study found that passive exposure to cigarette smoke adversely affects lung function in people with cystic fibrosis.Despite all therapeutic interventions, lung disease remains the leading cause of morbidity and mortality in cystic fibrosis.Gastrointestinal symptoms .
A diagnosis of cystic fibrosis
Mutations in the CFTR gene cause altered secretion of chlorides and water in the intestine, which can lead to tar obstruction at birth (more commonly in homozygotes 50F508) or distal bowel obstruction syndrome later in life. Meconium obstruction occurs in 15-20% of newborns diagnosed with cystic fibrosis, and can be a major symptom in the neonatal period.
Tar impact syndrome is defined by the build-up of a viscous mucous-alveolar mass in the terminal ileum and by adherence to the intestinal wall, which can sometimes become calcified.
Atresia often associated with torsion and peritonitis may also be a form of cystic fibrosis. A diagnosis of cystic fibrosis can be suspected during fetal life on the basis of ultrasound results indicating intestinal obstruction, such as the hyperechogenic appearance of the fetal intestine.The cause of distal bowel obstruction syndrome is unclear and may be related to dehydration, fever, decreased levels of enzyme supplementation, liver disease or the use of antiperistaltic drugs (opioids, anticholinergics).