Cystic Fibrosis

Question 1

Define monogenic

Answer 1

strong genetic influence by 1 gene.

Question 2

define autosomal

Answer 2

gene on one of the 22 autosomes there is 2 copies of each per cell/

Question 3

define recessive

Answer 3

need two defective copies to be affected by the disease.

Question 4

define carriers

Answer 4

heterozygotes who aren’t affected

Question 5

define dominant

Answer 5

inherited just one copy of the mutated gene, from either parent, is sufficient for the person to be affected.

Question 6

define congenital

Answer 6

inherited (present from birth)

Question 7

how is Cystic Fibrosis (CF) defined by these terms

Answer 7

(congenital) fatal monogenic recessive disorder.

Question 8

what is CF caused by

Answer 8

mutations in the gene for the CF transmembrane regulator gene “CFTR” gene. It is a Cl- channel.

Question 9

what population is CF most common in

Answer 9

caucasians.

Question 10

what is the inheritance pattern for CF

Answer 10

autosomal recessive.

Question 11

referring to the phenotype of CF what are the “classic triad of clinical manifestations”

Answer 11

1. Increased sweat Na and Cl
2. pancreatic insufficiency
3. Pulmonary infection

Question 12

the pathophysiology of CF is due to

Answer 12

the production of thick mucus

Question 13

male infertility caused by CF is due to

Answer 13

congenital bilateral absence of the Vas deferens

Question 14

Those with CF are at risk of recurrent infections with

Answer 14

Pseudomonas aeruginosa.

Question 15

those with CF are at risk of developing which metabolic disorder

Answer 15

diabetes mellitus.

Question 16

Detail the classic investigation of CF

Answer 16

There a range of causative mutations for CF so DNA testing in not the frontline of testing.
Investigation of clinical and family history
Newborn screening: Measure the IRT (immunoreactive trypsinogen), it is increase in CF.
Genotype: for more common mutations,
2 mutations =CF
1 mutation= sweat test
no mutation= not CF
Sweat test: tests electrolytes in the sweat. CF patietns secrete a normal volume of sweat but they cannot reabsorbed NaCl from the sweat resulting in increased levels.

Question 17

Describe the interpretation of a sweat test.

Answer 17

Sweat Cl- (in mmol/L)
60: CF
30-59: borderline
29: normal

Question 18

Describe CFs impact on the Lungs.

Answer 18

Cl and Na transport across the epithelia is affected
Theres a decrease in the Cl- channel activity
this leads to a change in ENaC (epithelial Na Channel)
this leads to an increase in Na (and h2o) absorption.
This leads to a decreased water content in secretions, this causes mucus to become thicker and further causes impaired flow, plugs and obstructions.
This leads to a decrease in pericillary volume, the thick mucus leads to poor cilary clearance of pathogens and results in recurrent infections.

Question 19

Describe the impact fo CF on the GIT.

Answer 19

Cl and Na transport across the epithelia is affected
Theres a decrease in the Cl- channel activity
this leads to a change in ENaC (epithelial Na Channel)
this leads to an increase in Na (and h2o) absorption.
This leads to a decreased water content in secretions, this causes mucus to become thicker and further causes impaired flow, plugs and obstructions.
The blockage of pancreatic ducts leads to aloss of water from the GIT, this leads to constipation, renal prolapse ad meconium ileus (blockage of the intestine)

Question 20

Describe the impact of CF on sweat glands

Answer 20

these is a decrease in Cl- channel activity
there is a change to the regulation of ENaC this leads to a DECREASE in Na absorption (vs an increase in the airways and GIT). this results in an increased sweat NaCl concentration.

Question 21

What are some possible heterozygote advantages to CF

Answer 21

CF mutations could be protective against diarrhoea

Resistance to typhoid fever.

Question 22

where is the CFTR gene located

Answer 22

Chromosome 7 (7q31-q32)

Question 23

What is the most common mutation associated with CF

Answer 23

delta F508
(others include: G542X, G55ID, 621 + 1 G>T)

Question 24

what do mutations in the CFTR gene result in

Answer 24

alternative splicing produces alternative (non functional) proteins.

Question 25

What are the types of mutations that could cause CF

Answer 25

missense, nonsense (truncation), deletion, insertion and frameshift (due to insertion or deletion)

Question 26

describe the classic phenotype of CF

Answer 26

complete loss of CFTR function as a Cl channel, this results in:

• Pancreatic insufficiency
• COPD
• Abnormal sweat electrolyte concentrations
• Absence of vas deferens in males

Question 27

CF can be mono-organ, what does this mean.

Answer 27

Mono-symptomatic/mono-organ forms of CF effect only one organ, the most effected is the pancreas the least is the lungs.