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Path 19.03 > 20.03.08 Cystic Fibrosis > Flashcards

20.03.08 Cystic Fibrosis Flashcards

1
Q

Mode of inheritance in CF

A

Autosomal recessive

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2
Q

Prevalence

A

1 in 2600 affected individuals in UK population

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3
Q

Carrier frequency

A

1 in 25 in UK. Lower in other populations

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4
Q

What is CFTR

A
  • Cystic fibrosis transmembrane conductance regulator
  • Cyclic AMP-acticated chloride ion channel
  • Located in plasma membrane of secretory epithelial cells in sweat ducts, vas deferens, intestine, lungs, kidney, pancreas
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5
Q

What phenotypes arise from CFTR mutations

A
  • Classical CF
  • Mild CF
  • CFTR-related disease
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6
Q

What is the most common UK mutation

A
  • p.(Phe508del)

- 75% of mutations in UK

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7
Q

What causes CFTR channel to open

A

R (regulatory) domain is phosphorylated by protein kinase A and when ATP is bound to NBD (nuclear binding domain)

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8
Q

Phenotype of CF (remember as CF PANCREAS)

A 
C= chronic cough
F= failure to thrive
P= pancreatic insufficiency
A= alkalosis and hypotonic dehydration
N= neonatal intestinal obstruction (meconium ileus)
C= clubbing of fingers
R= rectal prolapse
E= electrolyte elevation in sweat (salty skin)
A= Absence of vas deferens
S= sputum with staph or pseudomonas
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9
Q

What is fetal echogenic bowel

A

-Bright bowel on antenatal ultrasound imaging

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10
Q

What proportion of echogenic bowels are due to CF

A

3%

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11
Q

What are other causes of fetal echogenic bowel

A
  • Fetal aneuploidy
  • Intra-amniotic hemorrhage
  • infection (Cytomegalovirus CMV)
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12
Q

How can mild CF manifest

A

Pancreatic sufficiency, variable lung disease, lower salt chloride (still higher than normal)

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13
Q

How can CFTR-related disease manifest

A
  • Mild dysfunction of one organ system.

- Disseminated bronchiectasis, CBAVD, chronic idiopathic pancreatitis

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14
Q

Methods used to detect CF mutations

A
  • ARMS (amplification refactory mutation system)
  • OLA (oligonculeotide ligation assay)
  • Sanger
  • MLPA
  • NGS methods
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15
Q

What proportion of CFTR mutations are copy number changes

A

10%

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16
Q

What could be a possible reason for finding a homozygous CFTR variant in a non-consanguineous couple

A
  • UPD7

- Deletions

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17
Q

What 9 diseases are tested in the newborn screening program in UK

A
  • CF
  • Congenital hypothyroidism
  • Glutaric aciduria type 1
  • Homocystinuria
  • Isovaleric acidaemia
  • phenylketonuria
  • MCADD (medium-chain acyl-CoA dehydrogenasae deficiency)
  • Maple syrup disease
  • Sickle cell disease
18
Q

How old are babies when blood spots are taken

A

1) 5 days old

2) 28 days (if first is raised)

19
Q

What is the indicator used in CF newborn screening

A
  • Immunoreactive trypsinogen (IRT)

- Elevated (above 99.5th centile)

20
Q

What is IRT

A

Precursor to proteolytic enzyme trypsin.

21
Q

Where is IRT produced

A

Pancreas

22
Q

Where is IRT converted to trypsin

A

Small intestine

23
Q

Why is IRT elevated in newborns with CF

A

Mucous plugs block pancreatic ducts, preventing IRT reaching intestine.

24
Q

Other reasons for elevated IRT in newborns

A

Stressful delivery, premature

25
Q

Which common 4 CFTR mutations are examined in newborn screening

A

Phe508del, Gly551Asp, Gly542Ter, c.489+1G>T

26
Q

Other biochemical tests for CF

A
  • Sweat test (quantitative pilocarpine iontophoresis). People with CF lose more salt in sweat that unaffected people. Two abnormal readings above 60mmol/L are indicative of CF (90% of CF patients have positive sweat test).
  • Transepithelial nasal potential difference. Assess ion conductance in upper respiratory epithelium. Measures chloride and sodium ions.
27
Q

Are there genotype phenotype correlations

A
  • Yes
  • Severe mutations (leading to no CFTR protein, class 1-2) are associated with pancreatic insufficient CF.
  • Mild mutations (some functional CFTR, class 3-5) result in pancreatic sufficiency, lower sweat chloride levels, less severe respiratory disease.
28
Q

Give example of partial penetrant alleles

A

-5T allele of intron 8
-c.3850-2477C>T
Both alleles lead to leaky splice sites and the proportion of normal and truncated transcripts correlates with disease severity.

29
Q

What is the significance of the intron 8 polyT and poly TG tract

A
  • Length of polyT at the splice acceptor site of intron 8 has an effect on the splicing of exon 9.
  • 5T allele causes exon 9 to be skipped in 90% of transcripts
  • 5T with TG12 or TG13 causes increased exon 9 skipping.
30
Q

Which poly T allele is associated with CBAVD when found in trans with a path variant

A

5T12TG (5T13TG more associated with mild CF)

31
Q

Which allele is modified by the presence of 5T in cis

A

p.Arg117His

32
Q

What is the significance of R117H/7T when seen in trans with a pathogenic allele

A

Associated with a variable presentation or can even be benign.

33
Q

What is the significance of 5T/5T

A

Phenotype is highly variable and more likely to be associated with CFTR-RD

34
Q

When is 5T reflex testing recommended

A
  • Males with infertility caused by obstructive azoospermia
  • Patients with bronchiectasis/ pancreatitis, where 1 pathogenic mutation is detected
  • Patients with R117H
35
Q

Which polyT allele is exclusively seen in cis with p.Phe508del

A

9T

36
Q

What are possible treatments in CF

A
  • Daily airway clearance
  • Mucolytic enzymes
  • Antibiotics
  • Lung transplantation
  • Pancreatic enzyme replacement therapy (in PI CF)
  • CFTR modulators
  • DNA editing (CRISPR-Cas9, to remove mutated CFTR, then homologous recombination with WT)
  • RNA editing (antisense oligonucleotides to replace deleted segments of RNA)
37
Q

3 types of CFTR modulator drugs

A
  • Read through therapy

- Corrector therapy

38
Q

An example of read through therapy

A
  • Gentamicin.
  • An aminoglycoside antibiotic that can correct for nonsense mediated decay of truncated CFTR.
  • However issues with ototoxicity (toxic to ear).
39
Q

An example of corrector therapy

A
  • Lumacaftor
  • Facilitates maturation of CFTR and delivery to the membrane
  • Corrects proteins that cause misfolding (e.g. F5008del)
40
Q

An example of potentiator therapy

A
  • Ivacaftor
  • Improves CFTR channel function
  • Corrects for proteins that reduce gating efficiency (e.g. G551D)
41
Q

How do aminoglycoside antibiotics reduce the fidelity of translation

A

By inhibiting ribosomal “proofreading”, allows transcription past stop codon to yield full length protein

42
Q

What is orkambi

A
  • A combination of Lumacaftor and Ivacaftor.

- Used for hom F508del patients.

Path 19.03 (27 decks)

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