8/17/17 Flashcards
Is CF dominant or recessive?
Recessive
Effect of CF on males
If 10% CFTR activity then vas deferens not formed, sperm made but can’t leave so infertile
Clinical clues for CF
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!
Sweating for sweat test induced by
Pilocarpine Iontophoresis
Approach to CF Newborn Screening
Do immunoreactive Trypsinogen, pancreatic enzyme precursor that’s elevated in CF patients
Mutation analysis
Sweat chloride testing when a few days old
Complications from failure to diagnose CF during infancy
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
Main bacteria of CF
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
Other complications of CF
Pneumothorax
Sinusitis
CF Cure
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
Class I CFTR Mutation
Reduced or ABSENT transcription
Nonsense, frameshift, splice site mutations
Any mutation ending in X or * like Gly542*
Class II CFTR mutation
Block in protein processing like misfolding, incorrect translational modification, error in protein trafficking
Missense mutation or AA deletion
Phe508del
Class III CFTR mutation
Block in regulation of CFTR chloride channel
Missense mutations
Gly551Asp
Class IV CFTR mutation
Altered conductance of chloride channel
Missense mutation
Class V CFTR mutation
Reduced synthesis due to alternative splicing
Some missense mutations, some splice mutations
Class VI CFTR mutation
Increased CFTR turnover at cell surface
Protein is unstable and quickly degraded
Multiple types of mutations
Cis-acting variants of CF
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
CBAVD
Congenital bilateral absence of vas deferens
Causes male infertility
May be present even in the absence of pancreatic/lung findings
CF Genetic testing
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
CF Newborn Screening
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
CF incidence for non Jew Euro White?
1/2500
