Clinical and genetical studies in cystic fibrosis and pseudohypoaldosteronism

Abstract: Cystic fibrosis (CF) is the most common severe autosomal recessive disorder among Caucasians and is caused by mutations of the chloride channel, CFTR (cystic fibrosis transmembrane conductance regulator) gene. Despite a markedly improved median survival many CF patients still die at a young age. The chronic lung disorder is the main cause of mortality. Endogenous and exogenous factors, which may contribute to the severity of the pulmonary disorder, are partly unknown. The autosomal recessive form of pseudohypoaldosteronism type 1 (PHA1) is a rare salt-wasting disorder and is caused by mutations of the epithelial sodium channel (ENaC) genes. The pulmonary symptoms in PHA1 have been described as mimicking those in CF. Genetic and clinical studies of these two diseases were the focus of this thesis. Paper I extended clinical data for two CFTR mutations, T338I and S549I. T338I conferred a more severe and S549I a milder phenotype, than previously reported. In paper II and III the phenotype and origin of two novel CFTR mutations, Y109C and 175insT, are described. Y109C was associated with a milder form of CF. In study IV, examination of the mutational spectrum in the Swedish CF population was completed with the aim of preparing for a pilot study of neonatal screening. A third common gene deficiency, 3659delC, was identified. Inclusion of deltaF508, 394 delTT and 3659delC in a gene test after an initial test for immunoreactive trypsinogen (IRT), would theoretically have detected practically all CF patients. The aim of paper V was to identify risk factors for progression of the pulmonary disorder in CF. The severity was partly predicted by the CFTR genotype. Patients with pancreatic sufficiency could be expected to have an almost normal long-term lung function, but an earlier diagnosis in this group is important. Negative risk factors included pancreatic insufficiency, chronic pseudomonas colonisation and diabetes. In study VI, of PHA1 patients, mutations of the alpha-subunit of the ENaC were associated with prominent lung symptoms. However, no chronic lung disease with decline of lung function with age and development of bronchiectasis was observed as seen in CF.