Cystic fibrosis 11/10/22 Flashcards
What is cystic fibrosis and its symptoms?
Cystic fibrosis is an inherited disease characterized by the build-up of thick, sticky mucus. Affected areas are the respiratory system and the digestive system. Symptoms include problems with breathing and bacterial infections in the lungs, some affected babies have meconium ileus (a blockage of the intestine that occurs shortly after birth), other digestive problems result from a build-up of thick, and sticky mucus in the pancreas.
The pancreas is an organ that produces insulin and helps digest food. Mucus often damages the pancreas, impairing its ability to produce insulin and digestive enzymes. Problems with digestion can lead to diarrhoea, malnutrition, poor growth, and weight loss. In adolescence or adulthood, a shortage of insulin can cause a form of diabetes known as cystic fibrosis-related diabetes mellitus (CFRDM). Most men with cystic fibrosis have congenital bilateral absence of the vas deferens (CBAVD), a condition in which the tubes that carry sperm (the vas deferens) are blocked by mucus and do not develop properly. Men with CBAVD are unable to father children (infertile). Women with cystic fibrosis may experience complications in pregnancy.
Primary ciliary dyskinesia is also caused by different genes (DNAI1 and DNAH5) but patients present with similar symptoms.
What inheritance is cystic fibrosis?
This condition is inherited in an autosomal recessive pattern.
Is cystic fibrosis a loss or gain of function?
This is a loss of function mutation.
How common is cystic fibrosis?
Prevalence is 1 in 2,500 newborn infants and a carrier rate of 1 in 25.
Different ethnicities have different prevalence so it’s important to design the screening test for the population. More common in caucasian populations. Affects males and females equally.
What genetics causes cystic fibrosis?
It is a mutation in the CFTR gene. The most common one is the delta F580 mutation which is a 3-base deletion in one amino acid (phenylalanine) at position 580 in the CFTR gene. The delta F580 accounts for 70% of cystic fibrosis and is a class II mutation. There are 1700 different disease-causing mutations that have been found for cystic fibrosis.
What causes cystic fibrosis?
The CFTR gene provides instructions for making a protein called the CF transmembrane conductance regulator (CFTR). This protein is a member of the ATP binding cassette transporter family and functions as a gated Cl- channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports 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.
Disease-causing mutations in the CFTR gene alter the production, structure, or stability of the chloride channel. All of these changes cause defects in the channel causing impairments to the transport of chloride ions and the movement of water into and out of cells and causes the mucus to have a less osmotic potential and is thicker. As a result, cells that line the passageways of the lungs, pancreas, and other organs produce mucus that is abnormally thick and sticky. In the delta F580 variant the small amount of delta F508 that makes it to the cell membrane has defective channel function due to the misfolding of NBD1 (part produced by delta F508 gene) and the altered structure of the mRNA also leads to a reduction in translation efficiency.
How is cystic fibrosis diagnosed?
The heel prick test and the sweat test.
Heel prick. This is when a small amount of blood is gotten from the heel of a baby used in the UK and uses an immunoreactive trypsinogen test as a preliminary test for CF. This also tests for sickle cell and congenital hypothyroidism (CHT). The most 5 common CF mutations in England are the ones that are screened for at birth. Delta F508, R117H, G551D, 621+1G>T, G542XX.
Sweat test. This tests the chloride levels in sweat as the chloride ion transport defect causes an abnormally high concentration of chloride in the sweat as chloride cannot be reabsorbed from the lumen of the sweat duct. Chlorine below 30 mmol /L means CF is unlikely, chlorine between 30-59 mmol /L means CF is possible and additional testing is needed, and 60 mmol /L or above means CF is likely to be diagnosed.
If this is the case, then confirmation via genetic screening needs to be done.
What are the different classes of cystic fibrosis?
Depending on the mutation that the person has this can change how severe the symptoms of cystic fibrosis are as this will determine the activity of the CFTR protein.
Class I mutations result in no synthesis of the gene product.
Class II mutations produce a defective protein product that cannot fold correctly and that is destroyed in proteasomes.
Class III mutations produce a protein that gets to the cell surface but is abnormally regulated which results in a channel defect.
Class IV mutations result in defective chloride ion conductance.
Class V mutations are typically promoter or intron-exon splicing mutations that reduce the number of mRNA transcripts, allowing some normal but decreased protein products.
Class VI mutations result in increased rates of turnover of the chloride channel at the cell surface meaning decreased half-life of the protein.
What is segregation testing?
This when only the person with the disorder is tested.
What is cascade screening?
This is when someone has the disorder and so the whole family is offered screening to test for carriers.
What is the grantham score?
Grantham score is a prediction of the effect of substitutions between amino acids based on chemical properties, including polarity and molecular volume, characterised into classes of increasing chemical dissimilarity.
What is conservation?
The preservation of highly similar DNA sequences among different organisms. Conserved sequences are usually found in functional genes.
How can the Grantham score predict the severity of a mutation?
The Grantham score compares amino acids, therefore, if there was a genetic disorder that causes an amino acid change the Grantham score would indicate how conserved this change was (how similar or not the amino acids were). The scoring system is - conservative 0-50, moderately conservative 51-100, moderately radical 101-150, radical ≥151.
How is cystic fibrosis treated?
*Medicines for lung problems - antibiotics to prevent and treat chest infections, control of airway inflammation (NSAIDs), mucus thinner, bronchodilators, and steroid medicine
*Exercise
*Airway clearance techniques such as positive expiratory pressure (PEP) device, or a high-frequency chest wall oscillation device
*Dietary and nutritional advice
*Lung transplants
*Pancreatic insufficiency can be treated with pancreatic enzyme replacement therapy and checking and providing electrolytes, vitamins, and minerals
What is cosegregation?
The tendency for closely linked genes and genetic markers to segregate (be inherited) together.
