Fibrosis quistica del adulto. Correlacion genotipo-fenotipo pulmonar.

Abstract

Cystic fibrosis (CF) is the most common recessively-inherited disease in white people, occurring in approximately 1 in 5,532 live births in our area. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a protein expressed in the apical membrane of exocrine epithelial cells. Since the CFTR was cloned in 1989, over 1,000 mutations and 200 sequence variations in this gene have been identified so far. The CFTR functions principally as a cAMP-induced chloride channel and appear capable of regulating other ion channels. Mutations in the CFTR gene cause inspissated secretions leading to disease in the affected organs. With reference to chloride transport dysfunction, the CFTR mutations can be grouped into five classes: (I) CFTR not synthesised, (II) defective processing, (III) defective regulation, (IV) defective conductance, (V) partially defective production or processing. This classification makes it possible to predict the likely effect of a known mutation on the CFTR function, although the effect of a given mutation on cell function may not be known in full. While the CFTR protein does not reach the epithelial cell surface in presence of class I and II mutation, it is present on the cellular surface in class III, IV or V CFTR mutations, and a certain residual function could be found. This genotypic variation provides a rationale for phenotypic effects of the CFTR mutations. The relationship between genotype with congenital bilateral absence of the vas deferens (CBAVD) and pancreatic insufficiency (PI) has been established in several publications. In them, it was pointed out that the pair of CFTR mutations is closely linked to the development of CBAVD and PI. However, attempts to link mutations in CFTR to severity of lung disease have not been successfully demonstrated. Methods. A prospective cohort of adult CF patients, in whom it was possible to detect two CFTR mutations, was analysed. Patients were classified according to the CFTR mutation classes. Then, patients were grouped based on the CFTR molecular position on the epithelial cell surface and the type of molecular dysfunction (I-II/I-II, I-II/III, I-II/IV, I-II/V, I-II/III-V). The demographic characteristics as well as the spirometric values, the progression of lung disease, the probability of survival and the clinical characteristics were analysed and compared. Findings. Seventy four patients, in whom two CFTR mutations were detected, were included in the study. Patients with genotype I-II/I-II had significantly lower current FVC and FEV1 predicted values than patients with genotype I-II/III, I-II/IV and I-II/V. Moreover, the progression of lung disease (p Interpretation. CF can also be diagnosed in adult age. Those patients diagnosed in adulthood have less digestive affectations, better lung function and different genetic mutations. Sweat test can be negative or indeterminate. Moreover, they had a higher mean age and higher weight, less incidence of initial digestive abnormalities, pancreatic insufficiency, malnutrition, hepatic disease, chronic bronchial colonization of Pseudomonas aeruginosa, hospitalizations, lung transplantation and deaths due to CF. On the contrary, these patients had a higher incidence of pancreatitis, allergic bronchopulmanary aspergillosis at diagnosis and better respiratory function test parameters. There is a correlation between genotype and progression of lung disease. Patients with class I or II mutation on both chromosomes are associated with worse respiratory disease and lower probability of survival.

Date of Award	26 Sept 2006
Original language	Undefined/Unknown
Supervisor	Ferran Morell Brotad (Director) & Javier de Gracia Roldan (Director)