A mild variant of cystic fibrosis

Background. Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Among Dutch patients with cystic fibrosis, Delta F508 is the most common mutation and A455E the second most common mutation of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7. A455E is associated with preserved pancreatic function and residual secretion of chloride across membranes. We investigated whether it is also associated with less severe pulmonary disease in patients with cystic fibrosis. Methods. A total of 33 patients with compound heterozygosity for the A455E mutation were matched according to age and sex with patients who were homozygous for the Delta F508 mutation. The pairs were analyzed with respect to the following outcome variables: age at diagnosis, pulmonary-function values, and the frequency of pseudomonas colonization, pancreatic sufficiency, and diabetes mellitus. Results. Cystic fibrosis was diagnosed at a later age in the patients with the A455E mutation than in the Delta F508 homozygotes (mean age at diagnosis, 15.0 vs. 3.1 years; P<0.001). Fewer patients with the A455E mutation had pancreatic insufficiency (21.2 percent vs. 93.9 percent, P<0.001) and none had diabetes mellitus (0 percent vs. 27.3 percent, P=0.004). Forced expiratory Volume in one second (FEV(1)) and forced vital capacity (FVC) were significantly higher in the patients with the A455E mutation (mean FEV(1), 73.9 percent of the predicted Value vs. 54.3 percent of the predicted value; P=0.002; mean FVC, 88.7 percent of the predicted value vs. 76.3 percent of the predicted value; P=0.04). Fewer patients with the A455E mutation were colonized with Pseudomonas aeruginosa (33.3 percent vs. 60.6 percent, P=0.02). Conclusions. A455E is a common mutation causing cystic fibrosis in The Netherlands. Although several mutations are known to be associated with less severe pancreatic disease, our findings demonstrate a correlation between the A455E mutation and mild pulmonary disease. Because mortality in this disease depends primarily on the progression of pulmonary disease, patients with the A455E mutation have a better prognosis than patients who are homozygous for the Delta F508 mutation.