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Cystic Fibrosis in the 21st Century

Nicholas J Simmonds, MD(Res), MRCP, BMBS

Cystic fibrosis (CF) is the most common genetic, life-shortening disease in white populations [1]. It has a predilection for the lungs and gastrointestinal tract, and classically manifests as chronic suppurative lung disease and malabsorption, although significant variability in disease expression is well recognized. More than 70 years have passed since CF was identified as a separate disease entity when post mortem examinations of malnourished infants distinguished mucus plugging of pancreatic exocrine tissue from patients with celiac disease with normal pancreatic tissue [2]. At that time, life expectancy was very poor, with >70% of affected infants dying in their first year of life. Since then, major advances in our understanding of the disease have vastly improved the outcomes of individuals with CF. The median survival age is now approximately 38 years in most developed countries (Figure 1) [3], and infants born with CF in the 21st century are expected to live beyond 50 years of age [4]. An increasing number of middle-aged or older individuals with CF are also being recognized [5]. Identifying factors responsible for their longevity and improving our understanding of the mechanisms underpinning variable disease expression are important areas of ongoing research, as this survival advantage could potentially be extended to the general CF population. The present article provides an up-to-date review of CF, with a focus on survival trends, disease variability, and future treatment options, including the delivery of effective care to a changing CF population.The molecular basis of CFThe Mendelian autosomal recessive trait of CF was recognized in the 1940s, but it was much later, in 1989, when the gene mutation responsible for CF was identified [6]. The gene is on the long arm of chromosome 7, comprising 27 coding exons and spanning 250 kb with a transcript of 6.5 kb. It encodes a 1480 amino acid polypeptide – the CF transmembrane conductance regulator (CFTR). This functions as a cyclic adenosine monophosphate-regulated Cl– channel, which is expressed in the apical membrane of many epithelial cells, including those of the sweat ducts, lungs, pancreatic duct, intestine, biliary tract, vas deferens, kidneys, and bone. Over 1800 mutations have been described thus far [7], with the deletion of phenylalanine at position 508 (∆F508 or F508del) being the most common in white populations, accounting for approximately 70% of mutations [8,9]. CFTR mutations are classified by their functional capacity, with five different subgroups recognized (Table 1):

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