Predictors of deterioration of lung function in cystic fibrosis.

The severity of lung disease in cystic fibrosis (CF) may be related to the type of mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and to environmental and immunological factors. Since pulmonary disease is the main determinant of morbidity and mortality in CF, it is important to identify factors that can explain and predict this variation. The aim of this longitudinal study of the whole Swedish CF population over age 7 years was to correlate genetic and clinical data with the rate of decline in pulmonary function. The statistical analysis was performed using the mixed model regression method, supplemented with calculation of relative risks for severe lung disease in age cohorts.The severity of pulmonary disease was to some extent predicted by CFTR genotype. Furthermore, the present investigation is the first long-term study showing a significantly more rapid deterioration of lung function in patients with concomitant diabetes mellitus. Besides diabetes mellitus, pancreatic insufficiency and chronic Pseudomonas colonization were found to be negative predictors of pulmonary function. In contrast to several other reports, we found no significant differences in lung function between genders. Patients with pancreatic sufficiency have no or only a slight decline of lung function with age once treatment is started, but an early diagnosis in this group is desirable.

Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of the alpha-subunit of the epithelial sodium channel.

OBJECTIVE: To study patients with autosomal recessive pseudohypoaldosteronism type 1 and to relate pulmonary disease to gene mutations of the epithelial sodium channel (ENaC). STUDY DESIGN: Clinical and laboratory data were collected from 4 Swedish patients with pseudohypoaldosteronism type 1. The genes for ENaC and cystic fibrosis transmembrane conductance regulator were analyzed for mutations with methods including DNA sequencing. RESULTS: Three novel mutations were found in the alpha-gene of ENaC, 2 frameshifts (1449delC and 729delA) and 1 missense mutation resulting in the substitution of leucine for serine 562 in the alpha-chain (S562L). The 1449delC mutation was found in all patients in either homozygous or heterozygous form and seems to be the predominant cause of pseudohypoaldosteronism in Sweden. The allele coding for S562L also contained a transition converting tryptophan 493 to arginine (W493R), which seems to be a rare polymorphism. All patients had pulmonary symptoms to various degrees. The bacterial findings resembled, to some extent, those in cystic fibrosis, but development of chronic lung disease and progressive decline in lung function were not observed. CONCLUSIONS: Genetic deficiencies of the alpha subunit of the ENaC are associated with prominent lung symptoms, which are, however, clearly different from those in cystic fibrosis.

Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden.

Children with cystic fibrosis (CF) diagnosed by neonatal screening have a better nutritional development and other advantages compared with those in a nonscreened group. The two-tier immunoreactive trypsinogen (IRT)/DNA screening protocol has been found superior to the single-tier IRT approach, improving the positive predictive value and thus reducing the false-positive rate. However, variations of the DNA test are required for different populations. In this study we examined CFTR (cystic fibrosis transmembrane conductance regulator) mutations in 331 CF patients attending the centres in Stockholm, Lund and Uppsala, comprising about 75% of the CF population in Sweden. The frequency of deltaF508 among CF alleles was 68.3%. There were two other mutations, 394delTT and 3659delC, found to be fairly frequent, amounting to 8.5 and 7.9%, respectively. Other mutations were comparatively rare. A simple and effective method of analysing the three mutations from Guthrie cards has been developed. Assuming Hardy-Weinberg equilibrium, 90% of our CF patients will be expected to carry at least one deltaF508 allele and 97.6% to carry at least one deltaF508, 394delTT or 3659delC copy. Including the latter two in a screening programme would thus substantially reduce the risk of a false-negative outcome.

Mild cystic fibrosis mutations in Southern Sweden with special reference to S549I and T338I.

In this study of cystic fibrosis (CF) gene mutations in Southern Sweden we found missense mutations in 12 out of 110 patients. These patients, as a group, differed from deltaF508 homozygotes by a higher frequency of pancreatic sufficiency and an older age at diagnosis as has been indicated in previous studies. In addition, lung function (vital capacity (VC) and forced expiratory volume in 1 s (FEV1)) tended to be better although the difference did not reach statistical significance (p = 0.13 for FEV1). For two mutations, S549I and T338I, our results differed from earlier reports. In our experience, S549I confers a milder phenotype and T338I a more severe one than previously reported. We conclude that each mutation should be treated separately when trying to correlate genotype with phenotype.

Recurrent Pseudomonas bronchopneumonia and other symptoms as in cystic fibrosis in a child with type I pseudohypoaldosteronism.

We report a child with multiple target organ pseudohypoaldosteronism type 1 with frequent recurrent pulmonary infections caused by Pseudomonas aeruginosa and Pasteurella multocida and high levels of chloride in sweat, urine and nasal secretion. Repetitive faecal chymotrypsin samples have all shown pathological values in spite of no other sign of exocrine pancreas dysfunction. The similarities with cystic fibrosis and the importance of the salt content in bronchial fluid are discussed.

394delTT: a Nordic cystic fibrosis mutation.

In a systematic screening for mutations in the gene encoding the cystic fibrosis transmembrane regulator among Danish cystic fibrosis (CF) patients, we identified a mutation in exon 3 (394delTT); this mutation was found to be relatively common in Denmark. We therefore screened for 394delTT in Sweden and Norway, where it turned out to be the second most frequent mutation, accounting for 4% of all CF mutations. It also occurs with a high frequency in Finland, but has not been found in larger surveys of mutations in the CFTR gene. Thus, 394delTT seems to be a specific Nordic CF mutation.