Frequency
- It is the most common genetic disorder among Caucasian children.
- The frequency varies between populations: the condition is considerably less common in Asian and African populations than in the white populations of Europe and North America, with variation within each country.
- The exact frequency in Europe is unknown, but estimates range between 1/8,000 and 1/10,000 individuals.
- In the United States cystic fibrosis affects at least 30,000 people ; between 900 and 1,000 new cases are diagnosed every year. One in 29 people of Caucasian ancestry is an unaffected carrier of the CF gene mutation. In the United States, cystic fibrosis occurs at a rate of 1 in 3,400 births. While it occurs in persons of all racial and ethnic backgrounds, it is most common in Caucasians of Northern European ancestry.
Symptoms
- The disease is chronic and generally progressive
- onset usually occurs during early childhood or, occasionally, at birth with meconium ileus. Meconium is the first stool of a newborn. This stool is very thick and sticky. Meconium ileus is a bowel obstruction that occurs when the meconium is thicker and stickier than normal meconium, creating a blockage of the small intestine. Most infants with meconium ileus have cystic fibrosis.
- Virtually any internal organ may be involved but the principle manifestations concern the breathing apparatus (chronic bronchitis), pancreas (pancreatic insufficiency, adolescent diabetes and occasionally pancreatitis) and, more rarely, the intestine (stercoral obstruction) or liver (cirrhosis).
- The most common form of cystic fibrosis is associated with respiratory symptoms, digestive problems (steatorrhea i.e excess fat in feces or constipation) and staturoponderal growth anomalies.
- Mortality and morbidity depend on the extent of bronchopulmonary involvement.
- Male sterility is a constant feature: Men who have CF are infertile because they're born without a vas deferens. The vas deferens is a tube that delivers sperm from the testes to the penis.
- Late-onset forms, which are usually only mild or monosymptomatic, have also been reported.
Genetics and mechanisms
- Cystic Fibrosis is characterized by alterations in the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) protein, which plays a role in the regulation of transmembrane hydroelectrolytic flux.
- The CFTR gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively charged particles called chloride ions into and out of cells. The transport of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucus. Mucus is a slippery substance that lubricates and protects the lining of the airways, digestive system, reproductive system, and other organs and tissues.
- The CFTR protein also regulates the function of other channels, such as those that transport positively charged particles called sodium ions across cell membranes. These channels are necessary for the normal function of organs such as the lungs and pancreas.
- Alterations in the protein lead to changes in the characteristics of exocrine excretions. An absence of functional CFTR in the epithelial cell membrane leads to the production of sweat with a high salt content (associated with a risk of hyponatremic dehydration) and mucus secretions with an abnormal viscosity (leading to stasis, obstruction and bronchial infection).
- Cystic fibrosis is a monogenic autosomal recessive disease caused by mutations in the CFTR gene (chromosome 7). Thus, to have symptoms of CF, an individual must have two defective CFTR genes, by inheriting a mutant copy of the CFTR gene from both mother and father (right). People with a single CFTR mutation are termed “carriers”, and do not have symptoms of CF.
- More than 1250 mutations have been reported. Nearly 70% of all cases are caused by the delta F508 allele, with 30 other mutations accounting for a further 20% of cases.
- There is no clear correlation between genotype (genetic make-up of cells) and phenotype (observable characteristics of the disease). In addition to the allelic heterogeneity and the occurrence of multiple mutations in the same gene, a wide range of other factors may influence the phenotype, including the environment and disease modifying genes.
The CFTR protein is a channel protein that controls the flow of H2O and Cl- ions in and out of cells inside the lungs. When the CFTR protein is working correctly, as shown in Panel 1, ions freely flow in and out of the cells. However, when the CFTR protein is malfunctioning as in Panel 2, these ions cannot flow out of the cell due to a blocked channel. This causes Cystic Fibrosis, characterized by the buildup of thick mucus in the lungs.
Diagnosis
- Diagnosis is suspected on the basis of sweat test results (chloride concentration above 60 mmol/L) and is confirmed by identification of a CFTR mutation.
- Neonatal testing has been widely available since the end of 2002 and leads to diagnosis in 95% of cases.
- Genetic counseling should be offered to couples carrying heterozygous mutations (identified through the birth of a first child with cystic fibrosis, a family history of the disease or following detection of a heterozygous mutation in an infant screened at birth).
- Antenatal testing is possible through mutation analysis of chorionic villus samples taken after the eighth week of gestation.
Treatment
- Treatment of cystic fibrosis remains purely symptomatic (treating only the symptoms), revolving around bronchial drainage, antibiotics for respiratory infections, pancreatic analysis and administration of vitamins and calorific supplements for digestive and nutritional problems.
- These cost-effective treatments have significantly improved the prognosis for cystic fibrosis patients: in the 1960's the majority of patients died before 5 years of age, whereas the current average life-span exceeds 35 years and life-expectancy is 40 years.
- Symptomatic treatment of the disease should improve with the development of etiological treatments (treating the cause of the disease) with complementary benefits (pharmacological approaches or gene therapy), neonatal testing and multidisciplinary management.