Is cystic fibrosis autosomal dominant?
NOPE… It’s autosomal recessive
What ethnicity does CF affect most?
White populations of northern European background
How many newborns are affected with CF?
1 in 2,500
What is the frequency of CF carriers?
1 in 25
Do heterozygotes display symptoms?
What is the chance of a heterozygote parenting a child with CF?
Are CF homozygotes infertile?
-But loss of the allele in the population is very slow, since most alleles exist in heterozygous carries who are unaware of their status
What type of glands and where does CF have it’s effect?
Epithelial glands in the respiratory and GI tracts
What is CF characterized by?
Excessively thick secretions
What is measured in the blood to screen newborns for CF?
Immunoreactive trypsinogen (IRT)
-But this isn’t 100% effective
What leads to the diagnosis of CF in children?
Recurrent respiratory tract infections and sometimes chronic malabsorption leading to failure to thirve
What % of CF patients suffer from pancreatic insufficiency?
What is the basis for the most common diagnostic test for CF?
High levels of chloride in sweat forms
What is the most serious problem in CF?
Obstruction of the airways by viscous mucus in the bronchioles and colonization by bacteria
What bacteria are most commonly seen in CF?
Pseudomonas aeruginosa and Staphlyococus aureus
What does CF lead to long term?
Lung destruction (bronchiectasis)
What do most patients with CF die from?
What is the result of the pancreatic ducts being obstructed by mucus in CF patients?
Deficient secretion of pancreatic enzymes and inadequate digestion of fats leading to a failure to thrive and production of smelly stools
What % of CF patients are pancreatically-sufficient?
What results from the thick secretions blocking the bile ducts in the liver of CF patients?
Why are male CF patients frequently infertile?
Congenital absence of the vas defrens
Females are occasionally infertile
What is the management for CF
- Regular chest PT
- Antibiotics for chest infections
- Pancreatic enzymes and fat-soluble vitamins
- Aerosol medications to loosen secretions
What recombinant human DNAase is used in CF patients to reduce the viscosity of mucous?
What surgical indications may be indicated in CF?
- Surgery for SBO
2. Lung, heart-lung, and liver transplants
What SE can be seen with long term use of high-dose antibiotics?
What is the average lifespan for CF?
What is the protein that produced by the mutated gene in CF?
Cystic fibrosis transmembrane regulator
That does CFTR function as?
A chloride channel that spans the cell membrane
Why do CF patients have a high chloride content in their sweat?
Chloride is secreted instead of being reabsorbed
This salt imbalance leads to an increased viscosity of mucous in the lungs as well
What is deleted in the CFTR gene to cause CF?
A single AA (phenylalanine) at position 508 is deleted due to a 3bp deletion
What is a NBF (nucleotide binding fold)
The folded part of the protein structure that specifically binds the ATP, which provides energy for the membrane transport process
Where is the phenlyalaine at position 508 normally located in CFTR?
In the first NBF
What % of cases of CF are caused by the deletion of Phe508?
What test can be used to detect the Phe508 deletion in DNA to show whether an individual is homozygous or heterozygous?
-Segment of DNA that spans F508 is amplified and the mutations is identified by electrophoretic analysis to indicate size difference
What % of CFTR mutations can PCR detect?
Can you do PCR on amniotic fluid to determine if the child of known carries has this mutation?
Where efforts in gene therapy directed for CF?
Replacing the defective gene
What is A1AT (or A1-Antiproteinase)?
A serine protease inhibitor
Where is A1AT synthesized?
In heptocytes and by macrophages
Where is A1AT found?
It is a major component of the A1 globulin fraction of human plasma
What is the major function of A1AT?
It protects lung tissues from digestion by inhibiting the activity of elastase
What is elastase?
A proteolytic enzyme produced by neutrophils
How does A1AT work?
It binds almost irreversibly to the enzymes active site and blocks the action of its target enzyme
What does absence of A1AT cause?
Chronic severe pulmonary disease (emphysema) and liver disease
How many different alleles are known for A1AT?
75- This is highly polymorphic
What is the most common allele in the European population?
PiM (90% of Europeans have genotype MM)
What are the 2 mutant A1AT alleles?
S and Z
Which is the worst genotype resulting in about 10-15% of normal A1AT activity and found in 1/2500 whites of Northern European descent?
What % of normal A1AT activity do SS individuals have?
50-60% (appear relatively normal)
What % of normal A1AT activity do SZ individuals have?
30-35% (may develop emphysema)
What chromosome is the gene for A1AT located on?
What is the mutation in PiZ?
Changes GAG to AAG, which substitutes a lysine for a glutamic acid
In PiZ mutation where does the protein aggregate?
In the ER- Only 15 % of normal amount is secreted by the hepatocytre
What is the mutation in PiS?
Changes GAA to GTA, which substitutes a valine for a glutamic acid
(This decreases stability)
What does A1AT normally do?
If protects the body against elastance which is produced by neutrophils to destroy foreign microorgnaisms
When A1AT is missing, what happens?
Damage to the lungs
What exacerbates the effect of a lack of A1AT and why?
Cigarette smoking because it oxidizes a methionine residue on A1AT which is crucial for binding of A1AT to elastase
Describe how A1AT normally protects against elastace?
The methionine in position 358 acts as a baid for elastance. Elasace cleabes the peptide bond on the carboxyl side of methionine, and when this bond is cleaved, the residues on either side spring apart and create “jaws” to trap the elastace
What happens in the rare Pittsburgh variant?
There is an arginine substituted for methionine which destroys the affinity for elastace and creates a bait for thrombin, which causes a lethal bleeding disorder
What happens to ZZ individuals?
They have significant lung damage and develop emphysema in their middle age (5% of all emphysema cases)
What makes the progression of this disease quicker and worse?
Cigarette smoking (develop emphysema sooner and don’t live as long as non-smokers)
What other organ does ZZ A1AT deficiency effect?
The liber…. the mutant inhibitor aggregates in the RER of heptaocytes
What % of non-alcoholic liver cirrhosis does A1AT deficiency account for in the US?
What can be used to diagnose A1AT deficiency (even pre-natal diagnosis)
ASO hybridization (because most cases are caused by one of 2 mutations…Z and S)