Rare CFTR mutation 1525-1G>A in a Pakistani patient

Cystic fibrosis (CF) is rare in non-Caucasian populations, and in such populations little is known about the spectrum of mutations and polymorphisms in the cystic fibrosis transmembrane conductance (CFTR) gene. We report the detection of a very rare CFTR mutation 1525-1G>A in intron 9 in a 5-year-old Pakistani child with typical clinical features of CF. It remains to be seen whether mutation 1525-1G>A is characteristic of Pakistani ethnicity with CF or associated with severe phenotypic features.     

Cystic fibrosis in the year 2020: A disease with a new face

The autosomal recessive disease cystic fibrosis (CF) was once untreatable and deadly in childhood, but now most patients survive to adulthood. Many countries have instituted CF newborn screening because early diagnosis improves outcome. CF research has greatly intensified following the discovery of the CF transmembrane conductance regulator (CFTR) gene, which has more than 2000 different mutations. For patients with common mutations like F508del, CFTR modulators are life transforming and may even prevent major complications if started early in childhood. For some patients with rare CFTR mutations, a treatment path still needs to be developed. Conclusion: This review provides a general update on CF, including screening and current and future treatment.     

Therapeutic strategies to correct malfunction of CFTR

Cystic fibrosis (CF) is a systemic autosomal recessive inherited disorder that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although the gene was cloned 11 years ago, there still is no definitive treatment to correct the functional deficit. Current treatment strategies focus on pancreatic enzyme replacement and control of pulmonary inflammation and infection. This review examines novel strategies still in preclinical development or phase 1 clinical trials. Gene therapy is an evolving area of study that offers the potential for a cure for cystic fibrosis. CF lung disease is a significant barrier to effective gene delivery and transfer, but new vectors show promise in overcoming these limitations. There are also new pharmacological therapies aimed at correcting defects in CFTR processing and function. These are tailored to the specific class of mutation but may offer therapeutic benefit to many patients. They include phenylbutyrate, flavonoids, aminoglycosides and xanthines.     

Cystic fibrosis transmembrane regulator gene mutations in Bahrain

A genotypic study was undertaken to characterize the cystic fibrosis transmembrane regulator gene mutations (CFTR) in the Bahraini cystic fibrosis (CF) population using a polymerase chain reaction-based direct gene test to search for 15 common CF mutations amongst Arabs. During the period October 2000 to May 2001, 19 patients (12 males and seven females; aged at time of study between 4 months and 14 years with a mean age of 5.4 +/- 4.3 years) from 13 families were recruited in the study. Patients were diagnosed as having CF, based on a typical clinical picture and sweat chloride levels > 60 mmol/l and were screened for CFTR mutations. The rate of consanguinity among the families was 77 per cent. Eight mutations were detected in 21 of the 26 alleles examined. The overall detection rate was approximately 81 per cent. The allele frequency of the eight mutations was estimated to be approximately 73 per cent. There was no specific phenotypic pattern that correlated with a specific genotype. All families except two were of Bahraini origin. Of the eight mutations detected, four were common among Bahrainis (2043delG > 548A --> T > 4041C --> G = deltaF508, in order of decreasing frequency), accounting for 66 per cent of the Bahraini CF alleles. However, we also detected four different heterozygous mutations, namely: 1161delC, 1756G -->T, 3120 + 1G --> A, and 3661A --> T, accounting for 16 per cent of the Bahraini CF alleles.     

Radiological analysis of children with cystic fibrosis who are homozygous for cystic fibrosis transmembrane conductance regulator mutation S549R (T-->G).

Genotype-phenotype analyses in cystic fibrosis (CF) have shown that cystic fibrosis transmembrane conductance regulator (CFTR) genotypes can predict pancreatic status but that correlations with pulmonary status remain elusive. We investigated the extent and severity of lung disease associated with CFTR mutation S549R (T-->G). This mutation is localized in intron 11 (nucleotide-binding fold 1 of the CFTR protein) and had so far been described as a private mutation only. It is associated with an extremely severe overall CF phenotypic expression. Detailed radiological analyses were performed by a single observer in 12 children with CF from the United Arab Emirates who were homozygous for CFTR mutation S549R (T-->G). A diversity of pulmonary changes included marked hyperinflation in early infancy in conjunction with inflammation of the interstitium. After 2 years of age, signs of central airway involvement occurred in association with early signs of pulmonary hypertension. In conclusion, although there is some diversity in the radiological findings of these CF patients, R549 is a very severe allele associated with extreme lung disease and rapid pulmonary decline.     

Children with cystic fibrosis in South Africa: an improving nutritional picture

Nutritional status and growth play an important part in determining the prognosis in cystic fibrosis (CF). In South Africa, the median survival of patients with CF is 18 years. Using chart review, we studied the pattern of growth over time of a South African CF population. The percentages of expected weight-for-age, height-for-age and weight-for-height were determined for each patient in 1986 (n = 49) and 1996 (n = 63). Mean indices were the same in the two years. In 1996, mean weight-for-age of children aged 5-10 years was 94.2 per cent (SD 20.4), 14.3 per cent higher (p < 0.05, 95 per cent confidence intervals 3-25 per cent) than children of the same age in 1986. Improved growth of young children with CF has been achieved in a resource-poor country setting the scene for improved prognosis.     

Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V)

Twenty-nine subjects (17 families) with cystic fibrosis belonging to the same Bedouin tribe were screened for cystic fibrosis transmembrane regulator gene mutations (CFTR). Homozygous I1234V mutation in exon 19 was identified in all families with a relatively high rate of consanguinity (96.6 per cent). The homozygous I1234V mutation tended to present with a variable degree of pulmonary disease, pancreatic insufficiency and electrolyte imbalance. Homozygous I1234V was found to be a common mutation in the studied Bedouin tribe in Qatar.     

Changing paradigms in the treatment of gastrointestinal complications of cystic fibrosis in the era of cystic fibrosis transmembrane conductance regulator modulators

Cystic fibrosis (CF) – although primarily a lung disease – also causes a variety of gastrointestinal manifestations which are important for diagnosis, prognosis and quality of life. All parts of the gastrointestinal tract can be affected by CF. Besides the well-known pancreatic insufficiency, gastroesophageal reflux disease, liver disease and diseases of the large intestine are important pathologies that impact on prognosis and also impair quality of life. Diagnosis and management of gastrointestinal manifestations will be discussed in this review. Since optimisation of CF therapy is associated with a significantly longer life-span of CF patients nowadays, also gastrointestinal malignancies, which are more common in CF than in the non-CF population need to be considered. Furthermore, novel evidence on the role of the gut microbiome in CF is emerging. The introduction of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators gives hope for symptom alleviation and even cure of gastrointestinal manifestations of CF.     

What's new in CF airway inflammation: an update

Neutrophilic airway inflammation is a characteristic feature of cystic fibrosis (CF) lung disease and present in most patients with pulmonary manifestations of the disease. Here we discuss the ongoing controversy whether the CFTR mutation itself causes a pro-inflammatory milieu in the airways or whether inflammation is always secondary to infection. Since the presence of inflammation has been shown to be a risk factor for subsequent lung function decline, noninvasive tests to monitor airway inflammation are urgently needed. Induced sputum is currently being assessed as a clinical and research tool, but unfortunately is only feasible in cooperative children. While nonspecific treatment approaches that decrease infection or improve clearance of airway secretions were found to positively affect airway inflammation, specific anti-inflammatory treatment strategies have been less successful. Since any intervention that decreases inflammation may potentially have a detrimental effect by promoting airway infection, a better understanding of the factors regulating inflammation in the CF lung will form the basis for more targeted treatment strategies in the future.     

Hepatobiliary disease in cystic fibrosis

Cystic Fibrosis (CF) is an inherited, multisystem disease characterised by defective salt and water transport across the secretory epithelia of the respiratory and gastrointestinal tracts. Much of the morbidity and mortality in CF results from inflammation and infection of the airways. However, since the introduction of more intensive therapies and Centre-based care, life expectancy has increased significantly. This has led to the recognition of other life limiting conditions in CF including liver disease which is now the 2^nd commonest cause of death in CF patients. Defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) gene impairs bile secretion at the hepatocellular and cholangiocellular levels leading to cholestasis. However, this alone fails to explain the broad spectrum of hepatobiliary problems seen in cystic fibrosis, and why only a proportion of patients develop clinically significant liver disease. It is now believed that the development of CF-related liver disease may reflect the influence of modifier genes on CFTR function.The characteristic lesion is focal biliary cirrhosis, resulting from biliary obstruction and progressive periportal fibrosis. The focal fibrogenic process progresses in about 10% of patients to multilobular biliary cirrhosis, portal hypertension and eventually liver failure. Careful evaluation of all CF patients needs to be made to ascertain the presence of liver disease with the majority of patients developing liver disease by 10 years of age. Aggressive treatment of malnutrition and portal hypertension is required but some children may progress to liver transplant.     

Combined heterotopic liver–pancreas transplantation as a curative treatment for liver cirrhosis and diabetes mellitus in cystic fibrosis

Cystic fibrosis (CF) is an inherited disease with a defect in epithelial chloride transport that results in a multisystem disease. Although pulmonary disease remains the primary cause of morbidity and mortality, focal biliary cirrhosis and portal hypertension may develop in up to 8% of these patients. Liver transplantation (TX) is an accepted therapy and shows good results. We report on a patient with cystic fibrosis homozygous for the most common CFTR mutation delta F 508 who received a combined heterotopic liver and pancreas transplantation at the age of 18 yr. He suffered from CFRD, which untypically required high doses of insulin. In addition, the patient had pulmonary complications, was chronically colonized with multiresistant Pseudomonas aeruginosa (MBL) and had an allergic bronchopulmonary aspergillosis (ABPA). The patient remained in stable health for 54 months post‐TX and was able to live a nearly normal life. With a follow‐up of five yr, the function of the liver and pancreas allografts was excellent. However, and sadly, his pulmonary function continued to deteriorate from progression of his CF, and he died of respiratory failure due to a severe pneumonia and septicemia at the age of 23 yr and five months.     

Recent advances in cystic fibrosis

Considerable advances in cystic fibrosis (CF) research have translated into improved patient care, reflected by a continuing trend of improving life expectancy in CF patients. This review summarises some of the major findings of CF research that have occurred in the past year. The review specifically focuses on those developments that have direct implications for patient care or those in which clinical trials suggest benefits that may impact on the treatment of CF patients in the near future.     

Management of superior mesenteric venous thrombus in cystic fibrosis related liver disease

Abdominal pain is a common feature in patients with cystic fibrosis (CF) and CF related liver disease (CFLD). Superior mesenteric venous (SMV) thrombosis is an uncommon but important cause of abdominal pain. Management strategies are complicated by an underlying prothrombotic state and increased risk of bleeding from complications of CF and CFLD. This review addresses clinical presentation, detection and management options of an acute SMV thrombus in the context of CF.     

Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment

Cystic fibrosis (CF) is a multiorgan disease caused by mutation of the CF transmembrane conductance regulator (CFTR) gene. Obstructive lung disease is the predominant cause of morbidity and mortality; thus, most efforts to improve outcomes are directed toward slowing or halting lung-disease progression. Current therapies, such as mucolytics, airway clearance techniques, bronchodilators, and antibiotics, aim to suppress airway inflammation and the processes that stimulate it, namely, retention and infection of mucus plaques at the airway surface. New approaches to therapy that aim to ameliorate specific CFTR mutations or mutational classes by restoring normal expression or function are being investigated. Because of its sensitivity in detecting changes associated with early airway obstruction and regional lung disease, high-resolution CT (HRCT) complements pulmonary function testing in defining disease natural history and measuring response to both conventional and experimental therapies. In this review, perspectives on the genetics and microbiology of CF provide a context for understanding the increasing importance of HRCT and other imaging techniques in assessing CF therapies.     

Cystic fibrosis: basic science

Advances in the elucidation of cystic fibrosis transmembrane regulator (CFTR) function have resulted in a greater understanding of the relationship between the CF gene defect and clinical disease. The clinical phenotype is influenced by the class of mutation and possibly by other modifier genes. CFTR regulates the volume and composition of airways surface liquid, primarily by controlling chloride ion transport. However, CFTR also regulates other membrane channels and transports other molecules which may be important in mucocilary clearance and innate defence mechanisms. CFTR may also modulate the inflammatory response in respiratory epithelial cells and other inflammatory cells through a range of mechanisms. It is apparent that CFTR dysfunction results in a range of effects which may contribute to the clinical phenotype. These may contribute to the development of clinical disease at different stages of the natural history of cystic fibrosis. A greater understanding of the basic defect and its implications is likely to result in novel therapeutic approaches.     

Newer therapies for cystic fibrosis

Cystic fibrosis is the most common lethal inherited disease in Caucasians in the UK, with an incidence of approximately one in 2500 live births. It is a heterogeneous disease which reflects different mutations in the cystic fibrosis transmembrane conductance regulator gene, modifier genes and environmental influences. The median life expectancy of children with cystic fibrosis born in the UK is approximately 30 years. Longer survival is the result of improvements in basic therapies including airway clearance, aggressive use of antibiotics and optimizing nutrition. Care given in a specialist centre has also been shown to improve survival. Despite this progress, pulmonary disease still accounts for most of the morbidity and is the cause of death in over 90% of patients with cystic fibrosis. This review will focus on newer therapies aimed at pulmonary disease which are now being used in the clinical setting, and other novel therapies which are still at the research stage.     

Faecal elastase-1 concentration in cystic fibrosis patients with CFTR I1234V mutation

Aim: To assess the exocrine pancreatic function among cystic fibrosis patients with cystic fibrosis trans-membrane conductance regulator (CFTR) I1234V mutation. Methods: Cross-sectional study of 40 cystic fibrosis patients with homozygous CFTR I1234V mutation belonging to a large Arab kindred family and 25 healthy subjects as a control group over a period of 12 mo. Assessment of their exocrine pancreatic function was performed by measuring faecal elastase-1 (FE1) concentration with a commercial ELISA kit using polyclonal antibodies (BioServ Diagnostics) in CF patients compared to healthy subjects. The results were compared with those obtained from a second laboratory using another commercial ELISA (ScheBo; Biotech, Germany) that uses two monoclonal antibodies against different specific epitopes of human pancreatic elastase. Results: All CF patients with CFTR I1234V mutation had normal levels of faecal elastase 1. No significant difference was found between the two methods for the CF groups or between the CF patients with and without pancreatic enzyme replacement.

Conclusion: Cystic fibrosis with homozygous CFTR I1234V mutation is associated with pancreatic sufficiency. Assessment of exocrine function using polyclonal antibodies does not significantly differ from that using two monoclonal antibodies against different specific epitopes of human pancreatic elastase.     

Somatische Gentherapie der Mukoviszidose Aktueller Forschungsstand

Background. Numerous gene mutations associated with hereditary disorders have been identified. In cystic fibrosis the hereditary defect is attributed to mutations in one single gene, the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Conventional therapies of CF have dramatically increased the life expectancy of afflicted individuals. However, the ultimate incurability of this disease calls for novel and better therapeutic strategies. As cystic fibrosis is believed to be caused by mutations in one single gene, it has appeared to be the ideal candidate for one of the most tempting approaches in clinical therapy, namely gene therapy. Laboratory protocols for the introduction of genes into various tissues have been developed and applied over the last years. The ease of gene transfer under laboratory conditions gave rise to the hope that rapid advances in gene transfer protocols under clinical settings could be achieved as well. Clinical trials. 25 clinical trials of gene therapy for cystic fibrosis have been initiated using viral and non-viral vectors for gene transfer. The outcome of the CF gene therapy studies as well as of those for other diseases have clearly demonstrated that gene transfer and gene therapy in humans is a much more complex and challenging task than originally thought. Still, the encouraging results achieved in animal models and the rapid progress in vector technology justify the hope that the novel genetic therapies will be applied successfully to the benefit of patients suffering from cystic fibrosis.