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CRRAB 2 Week 5 and 6 > cystic fibrosis > Flashcards

cystic fibrosis Flashcards

1
Q

What is the inheritance pattern for CF?

A

autosomal recessive

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2
Q

What is the general mutation in CF?

A

inactivating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

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3
Q

What is the CFTR actually? Where is it found?

A

a chloride ion channel found on the apical surface of epithelial cells lining airways, pancreatic ducts, intestine and other tissues

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4
Q

Although CF can affect multiple organs, where are the most serious consequences?

A

pulmonary

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5
Q

What causes death in 90% of CF patients?

A

progressive lung disease

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6
Q

What are some non-pulmonary effects of CF?

A

pancreatic enzyme insufficiency
CF-related diabetes
malabsorption in the intestines
male infertility

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7
Q

What is the median survival for CF today?

A

37.4 years - a huge improvement form the past where it was largely a pediatric disease only (now almost half are adults)

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8
Q

The CFTR gene is found on what chromosome?

A

the long arm of chromosome 7

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9
Q

What ethnic group has the highest incidence of CF?

A

caucasians - especially northern european caucasians (1:2500)

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10
Q

How many mutations have been identified for CF? Why is this not bad news?

A

1900!

actually not bad news because only 5 mutation are found in over 1% of cases and only 160 mutations account for over 95% of cases

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11
Q

What is class 1 of CFTR mutations?

A

class 1 occurs when no protein is produced due to a nonsense mutation causing a stop codon

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12
Q

What is the example allele for class 1? What percentage?

A

G542X - (x for stop)

5% of CF alleles

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13
Q

What is class 2?

A

defective protein folding activates ER quality control, leading to degradation of the protein

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14
Q

What is the example allelef or class 2? What percentage?

A

F508del (deletion at 508)

THIS IS THE MOST COMMON - 70% of alleles and 90% of people who have CF have at least 1 allele like this

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15
Q

What is class 3?

A

defective gating or regulation of channel opening

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16
Q

What’s the example of class 3? Percentage?

A

G5510D

4%

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17
Q

What’s class 4?

A

defective in ion transport

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18
Q

What is class 5?

A

normal CFTR protein, but decreased amounts

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19
Q

What are the “severe” mutations and what are the “less severe” mutations?

A

severe = 1, 2, and 3 (the most common unfortunately)

less severe = 4 and 5

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20
Q

How do the severe and less severe mutations differ in terms of diagnosis, % CFTR function, extrapulmonary effects and survival?

A

severe: less than 1% of CFTR function, diagnosed first year, median survival 37.4, pancreatic insufficient and at risk for CF-related diabetes and liver disease

less severe: about 5% of CFTR function, may have later presentaion, survival to about 50 yrs, pancreatic sufficient and less risk for other effects

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21
Q

Describe the structure of the CFTR?

A

its membrane spanning domain forms a pore for the chloride ion channel

there are two nucleotide binding domains and an T domain that provide regulatory sites that promote opening of te channel (NBD binds ATP and R has phosphorylation sites for PKA)

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22
Q

What aspect of CF can be totally predicted based on what alleles you have?

A

if you have two severe alleles, you will definitely have a defect in the pancreatic ducts leading to pancreatic enzyme insufficiency.

everything else is multifactorial and difficult to predict

23
Q

Where does synthesis of the CFTR take place? WHat does it require?

A

in the endoplastic reticulum membrane

requires intra-domain folding and inter-domain interactions mediated through interaction with a series of chaperone proteins

24
Q

Describe the folding defect created by the F508del mutation

A

you have incorrect foling of the NBC1 domain so you have incorrect interactions of the NB1 and the other domains since the chaperones can’t interact with it

25
Q

Again, what happens to that misfolded protein?

A

it stays in the ER and activates the quality control pathways, leading to degradation by the proteosoe

26
Q

Again, what are the three most frequent mutations in the US?

A

F508del - most common, misfolding
G542x - stop codon = non-functional protein
G551D - ion channel cosed too much

27
Q

What happens in the G551D mutation in more specific terms?

A

the ion channel is usulaly moving between open and closed conformation based on signals

this mutations makes the CFTR unable to response to an ATP opening signal, so it spends most of its time in the closed formation

28
Q

What is the normal function of CFTR?

A

when the channel is open, it allows chloride ions to flow thoruhg it to the apical side

this movement of Cl pulls H20 out of the cell into the apical side of the epithelium

if the CFTR is not functional or not regulated, insufficient water is delivered to the cell surface

29
Q

How does the water move to follow Cl?

A

via a paracellular route - through tight junctions

30
Q

What ion follows Cl- to balance the negative charge that would create an unfavorable gradient?

A

Na - also via the paracellular route with water

It then flows back into the cell via ENacs on the apical side

31
Q

Opening of the CFTR channel requires what two signals?

A
  1. protine kinase A needs to phosphorylate the R domain (linked to cAMP activity)
  2. 2 ATP need to bind the NBD domains
32
Q

What key parameter is depending on the CFTR?

A

airways surface liquid volume

33
Q

Why is the airway surface liquid volume essential?

A

essential for clearance of mucus via the activity of cilia

also hydrates the mucous - keeps it rfom getting too viscous

34
Q

What happens if you have a decrease ASL layer?

A

you get a buildup of viscous mucous that’s too thick for the cilia to move

this leads to a failure of bacteria clearance, colonization, infection, inflammation and mucous plugging

35
Q

What are the long term structural damages that can occur with the frequent infection seein in CF?

A

bronchiolectasis and bronchiectases

36
Q

What are the major organisms causing infection in CF?

A 
haemophilus influenzae
staphylococcus aureus
pseudomonas aeruginosa
Burkholderia cepacia
Aspergillus fummigatus
37
Q

What are the mainstays of treatment for CF?

A

chest physiotherapy to improve drainage and aggressive treatment of infection with antibiotics

can also give hypertonic saline or DNase aerosols to make mucous less viscous and anti-inflammatories to help control inflammation

38
Q

What does the CFTR do in the pancratic duct and how does this lead to a decrease in pancreatic enzymes?

A

it secretes HCO3 which recruits luminal H2O and neutralizes secretion to prevent the formation of protein plugs

without it, you get those protein plugs blocking the duct which damages the cells, causing leakage of proteolytic enxymes and destruciton of tissue, leading to pancreatic insufficiency

39
Q

WHat does pancreatic exocrine insuffiency lead to?

A

malabsorption of lipids and fat-based vitamins - need supplementation

40
Q

What is the other consequence of th epancreatic damage?

A

CF-related diabetes (has characteristics of both T1D and T2D - loss of pancreatic beta cell mass and also insulin resistance)

41
Q

What happens to the intestine in CF?

A

you lose the ability to secrete H20 into the intestina lumen, leading to viscous mucous, obstruction (meconium ileus in 15% of newborns with CF, distal intestinal obstruction syndrome in adults), inability to absorb protein and fats, susceptibility to GI cancers

42
Q

Why are males infertile in CF?

A

the vas deferens is absent in virtually all male CF patients due to obstruction and reabsorption in utero

43
Q

What is the effect on sweat glands?

A

in sweat glands, the CFTR normally promotes the uptake of Cl ions from the extracellular space with Na following

without it means the Cl is not absorbed from the skin, so you have increased NaCl in sweat

44
Q

Who should be screened for CF mutations?

A
  1. carrier screening by genetic testing - all individuals who are planning a pregnancy or seeking prenatal care. also family of those with CF
  2. prenatal testing when there’s a 25% chance of the fetus having CF
  3. screening of all newborns required in all states!
  4. diagnostic testing with symptoms
45
Q

What is the carrier frequency in northern european caucasian ethic groups?

A

1 in 25!

46
Q

So what is the CF risk in the nortn european caucasian ethic background?

A

1/2500

47
Q

What’s the risk of having a CF baby if you’re both carriers?

only 1 a carrier?

neither carriers, but caucasian?

A

1/4

1/1000

1/250,000

48
Q

How do we do prenatal testing for CF?

A

chroionic villus sampling 10-12 weeks for DNA mutation testing

amniotic fluid 16-17 weeks for DNA mutation testing

also ultrasound for echogenic bowel (meconium building up as ileus)

49
Q

Why does early detection make a difference in CF?

A

nutrition - you can start pancreatic enzyme replacements early to avoid malnurition

pulmonary function - can start aggressive prophylactic antibiotics

50
Q

What’s the typical screening protocol for newborn screening?

A
  1. IRT immunoreactive trypsin (test of pancreatic function(
  2. if positive, check DNA mutation analysis
  3. If positive, sweat test - this is the definitive
51
Q

What are two newer strategies for CF treatment?

A

lung transplant - but not really helpful

drugs to target pecific deficiencies of CFTR mutations

52
Q

What drug has been developed against he G551D mutation?

A

This is the one with the gating issue - Ivacaftor keeps the channel in the open conformation for a higher percentage of time even without ATP gating

53
Q

What drug combination is in the works for the F508del mutation?

A

Ivacraftor and Lumacraftor

lumacraftor promotes traffic to the cell surface instead of degradation despite being misfolded

54
Q

What drug was not really helpful for the G542x premature stop codon mutation?

A

Ataluren - was supposed to make the ribosome less sensitive to stop codons

CRRAB 2 Week 5 and 6 (6 decks)

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