Cystic fibrosis

Question 1

What is cystic fibrosis
- frequency
- mode of inheritance

Answer 1

• Fatal monogenic recessive disease => congenital disorder
• Frequently seen in caucasians: 1/1600-1/3000
• heterozygote/carrier frequ. 1/20

Question 2

Triad of clinical manifestations of CF (disease phenotypes) due to loss of CFTR function

Answer 2

• increased sweat Na & Cl
• pancreatic insufficiency
• pulmonary infections

Question 3

Genetic locus for CF & encoded protein

Answer 3

-Gene: chrom. 7 in region q31-q32
- Protein: Cl- ion channel on membrane of exocrine Epi. cells

Question 4

Mutations in CFTR: a) mutation classification
b) mutation spectrum

Answer 4

CF transmembrane conductance regulator (CFTR) > control the Cl- channel
b) mutation in caucasians: ∆F508 - 70% Freq.

Question 5

Define
a) monogenic
b) mutation spectrum
c) compound heterozygotes

Answer 5

a) strong genetic influence from 1 gene
b) the nature, frequency of mutations assoc. w/ a genetically determined trait
c) different mutations on each chromosome e.g 1 carrying mutation for CF and the other carrying anoth mutated gene

Question 6

Pathophysiology of CF in GIT & lungs

Answer 6

Defect in CFTR
-> dec Cl- channel activity
-> change reg. of ENaC = inc Na+ = water absorption -> dec water content of secretions
= thick mucous secretion = blockage in pancreatic ducts & poor clearance in lungs

Question 7

pathophysiology of CF in sweat glands

Answer 7

Defect in CFTR
-> dec Cl- channel activity
-> change reg. of ENaC = dec Na+ reabsorption = inc NaCl [ ]

Question 8

describe new born screening for CF

Answer 8

• blood spots: measure immunoreactive trypsinogen (IRT), 48-72hrs after birth. If raised = CF
• detect mutations:
  2 = CF
  1 = do sweat test
  0 = CF unlikely

Question 9

Sweat test interpretation
*for new born screening done after 1wk postnatal
a) Cl 60 mmol/L
b) Cl 30-59 mmol/L
c) Cl 29 mmol/L

Answer 9

a) CF
b) borderline
c) normal

Question 10

Molecular methods

Answer 10

• 1st screen: Elucigene CF29v2 (detects 29 common varients, version 2) multiplex ARMS PCR
• 2nd screen: multiplex ligation-dependent probe amplification (MLPA) for lrg del & dup of 1/+ exons, and genomic DNA sequencing of entire gene (NGS, sanger sequ.)

Question 11

What’s the correlation b/w CFTR genotype & CF phenotype regarding pancreatic involvement & pulmonary manifestations

Answer 11

highest for pancreatic involvement: & lowest for pulmonary manifestations

Question 12

Why might CF be an advantage towards diahorrhea e.g. from cholera

Answer 12

Cholera toxins won’t affect CFTR bc Cl- channels not respond to bacterial stimulant = may protect against diahorrea