Cystic Fibrosis 1/9

Question 1

Genetic transmission

Answer 1

AR

Question 2

Name of affected gene and chromosome number

Answer 2

CF Transmembrane Conductance Regulator (CFTR) on Chromosome 7

Question 3

Effects of mutation in most tissues (Lungs and GI tract)

Answer 3

absorption of sodium increases due to lack of Cl secretion–>thickening of mucosal lining and disruption of cilial function

Question 4

Effects of mutation on sweat glands

Answer 4

No absorption of Cl leads to increase luminal negativity. Sodium will stay in lumen and sweat will be very salty

Question 5

Bicarb transport and pancreas

Answer 5

in some CFTR mutant variant, Cl transport is normal but bicarb transport is abnormal–>acidic fluid than can result in pancreatic insufficiency

Question 6

Class I mutation

Answer 6

Defective protein synthesis–> complete lack of protein at apical surface of epithelium

Question 7

Class II mutation

Answer 7

Abnormal protein folding, procession and trafficking: Most common CF mutation is deltaF508 (Phenylalanine)–>Complete lack of the protein on apical epithelium

Question 8

Class III

Answer 8

Defective regulation: No ATP binding and hydrolysis needed for ion passage–> Normal amount of CFTR protein on apical epithelium but is nonfunctional

Question 9

Class IV

Answer 9

Decreased conductance: mutation typically occurs in transmembrane domain of CFTR, which forms ion pore for Cl transport. Normal amount of protein but reduced function–>Milder phenotype of CF

Question 10

Class V

Answer 10

Reduced abundance: affects intronic splice site or the CFTR promotor–>reduced abundance of normal protein–>milder phenotype

Question 11

Class VI

Answer 11

Altered regulation of seperate ion channels: CFTR is involved in regulation of multiple distinct ion channels–>Mutation affects regulatory role of CFTR.

DeltaF508 mutation is both class II and VI

Question 12

Classic CF

Answer 12

Seen in two severe mutations in classes I,II,III–>pancreatic insufficiency, sinopulmonary infections and GI symptoms.

Question 13

Nonclassic or atypical CF

Answer 13

Pts who don’t demonstrate other features of CF, yet they harbor bi-allelic CFTR mutations. Important to identify these for the purpose of genetic counseling

Question 14

Manifestation of vit A deficiency in CF pt

Answer 14

squamous metaplasia of the lining epithelium of the ducts in pancreas, which are already injured by the inspissated mucus secretions

Question 15

meconium ileus

Answer 15

thick viscid plugs of mucus that are found in small intestines of infants and sometimes cause a small bowel obstruction

Question 16

3 most common organisms responible for lung infections in CF pts

Answer 16

S. aureus, H. influenzae, P. aeruginosa

Question 17

CBAVD

Answer 17

Congenital Bilateral Absence of Vas Deferens maybe the only feature suggesting an underlying CFTR mutation

Question 18

Clinical features of CF

Answer 18

1) Chronic sinopulmonary disease.
2) GI and nutritional abnormalities
3) Salt-loss syndrome
4) Male urogenital abnormalities resulting in obstructive azoospermia

Question 19

CF diagnosis criteria

Answer 19

One or more characteristic phenotypic features OR history of CF in a sibling OR positive new born screening test result

AND

Increased sweat chloride concentration on 2 or more occasions OR identification of 2 CF mutations OR demonstration of abnormal epithelial nasal ion transport

Question 20

Autosomal dominant disorders

Answer 20

1) Affects non-enzyme proteins involved in regulation of complex metabolic pathway: LDL receptor
2) Affect key structural proteins: Collagen, Spectrin

Question 21

Autosomal recessive disorders

Answer 21

1) Expression tends to be more uniform than AD
2) Often causes loss of function of enzyme protein
3) Includes nearly all inborn errors of metabolism

Question 22

Very few X-linked dominant disorders such as:

Answer 22

Vit. D resistent rickets

Question 23

CF classes image from NEJM

Answer 23