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Question 1

Is CF dominant or recessive?

Answer 1

Recessive

Question 2

Effect of CF on males

Answer 2

If 10% CFTR activity then vas deferens not formed, sperm made but can’t leave so infertile

Question 3

Clinical clues for CF

Answer 3

Meconium Ileus: neonatal, intestinal blockage

Failure to thrive: any age

Chronic respiratory disease with sinus disease

Rectal prolapse

Polyps (sinus disease)

Always do newborn screening if suspect since easy and cheap!

Question 4

Sweating for sweat test induced by

Answer 4

Pilocarpine Iontophoresis

Question 5

Approach to CF Newborn Screening

Answer 5

Do immunoreactive Trypsinogen, pancreatic enzyme precursor that’s elevated in CF patients

Mutation analysis

Sweat chloride testing when a few days old

Question 6

Complications from failure to diagnose CF during infancy

Answer 6

Hypochloremia (alkalosis)

Hyponatremia (dehydration, failure to thrive)

Vitamin E deficiency (hemolytic anemia)

Vitamin K and zinc deficiency

Vitamin ADEK deficiency since fat soluble and have less pancreatic enzyme delivery

Question 7

Main bacteria of CF

Answer 7

Pseudomonas aeruginosa

Also lung scan is blue cuz a lot of neutrophils

Use aerosolized antibiotics to treat, also use anti inflammatory one to break up bacteria biofilm to deliver

Question 8

Other complications of CF

Answer 8

Pneumothorax

Sinusitis

Question 9

CF Cure

Answer 9

Kalydeco (Ivacaftor):

Help with at least one copy of G551D and older than 2, class III mutation

Ion channel therapy, potentiator, unlocks gate for ion channel at membrane, take 3-4 times a day with fat

Cures sweat chloride test, improve lung function, help gain weight

Orkambi (Lumacaftor/Ivacaftor)

Help with 2 copies of F508del and 6 years old

Corrector and potentiator, rescuing deletion isn’t enough

Not pass sweat test but decrease hospitalizations, some improvement for lungs but results not that great

Both cost 300k a year

Question 10

Class I CFTR Mutation

Answer 10

Reduced or ABSENT transcription

Nonsense, frameshift, splice site mutations

Any mutation ending in X or * like Gly542*

Question 11

Class II CFTR mutation

Answer 11

Block in protein processing like misfolding, incorrect translational modification, error in protein trafficking

Missense mutation or AA deletion

Phe508del

Question 12

Class III CFTR mutation

Answer 12

Block in regulation of CFTR chloride channel

Missense mutations

Gly551Asp

Question 13

Class IV CFTR mutation

Answer 13

Altered conductance of chloride channel

Missense mutation

Question 14

Class V CFTR mutation

Answer 14

Reduced synthesis due to alternative splicing

Some missense mutations, some splice mutations

Question 15

Class VI CFTR mutation

Answer 15

Increased CFTR turnover at cell surface

Protein is unstable and quickly degraded

Multiple types of mutations

Question 16

Cis-acting variants of CF

Answer 16

No CFTR of miss exon 9

9T is good, 3T is bad (5T risk for male infertility if second CFTR mutation on other allele)

TG 9 is good, TG 13 is bad

Arg117His is known mutation but clinical symptoms likely only with 5T, unlikely with 7T (if have CFTR mutation present on second allele)

Need parental testing to see if cis or trans heterozygote

Question 17

CBAVD

Answer 17

Congenital bilateral absence of vas deferens

Causes male infertility

May be present even in the absence of pancreatic/lung findings

Question 18

CF Genetic testing

Answer 18

Targeted mutation testing: check one or two familial mutations, know what to look for

Mutation Panels: at least 23 mutations checked, detection rates differ amongst ethnic groups

Sequence analysis: read through to look for mutations or misspellings at exons, splice sites, and certain intron areas, 98% detection
Detects unclassified mutations, doesn’t detect large deletions or duplications

Deletion/Duplication testing: account for 2% of mutations, extra or missing exon alters protein

Sequence and duplication/deletion analysis: most thorough since two tests, slower and pricey

No perfect test and negative DNA result doesn’t eliminate the full risk of having CF or being a carrier, sweat chloride test is still best

Question 19

CF Newborn Screening

Answer 19

Do immunoreactive trypsinogen from a heelstick for pancreatic enzyme, top 4% of IRT each day get DNA test

Two mutations and from top 4% IRT has high risk, no mutations requires no follow up without symptoms but doesn’t rule out CF

90% false positives, 3% false negative like with meconium ileus

Question 20

CF incidence for non Jew Euro White?

Answer 20

1/2500