Molecular Medicine - Cystic Fibrosis

4 categories of human genetic disorders

1) monogenic

2) chromosomal

3) complex multigenic

4) somatically acquired mutations

monogenic disorders

single gene disorders

also known as mendelian disorders

chromosomal disorders

change in structure or number of chromosomes

categories of gene mutations

point mutations with coding sequences

mutations with noncoding sequences

deletions and insertions

structural alterations in protein coding genes

trinucleotide repeat mutations

hereditary disorders

transmitted in germline; familial

congenital

born with

single gene disorders transmission patterns

autosomal dominant

autosomal recessive

x linked recessive

cystic fibrosis is an

autosomal recessive disorder of ion transport (chloride and bicarbonate ion)

mutations in cystic fibrosis are in

transmembrane regulator (CFTR) gene, codes for an anion channel

cystic fibrosis presentation

viscous secretions in exocrine glands and in the lining of the respiratory, GI, and reproductive tracts

cystic fibrosis prevalence

most common lethal genetic disease that affects people of northern european descent

carrier frequency of cystic fibrosis

1 in 20

Pathogenesis of cystic fibrosis

CFTR chloride channel defect leads to increased sodium chloride concentration in sweat

in airway, decreased cl- secretions and increased Na+ and H2O reabsorption leads to dehydrated mucus

most common CF mutation

Phe508del or deltaF508

class I

absent CFTR

class II

phe508del

retention of misfolded protein at ER, degradation in proteasome

class III

impaired channel opening

class IV

reduced conduction (flow of ions)

class V

reduction in mRNA or protein

class VI

plasma membrane instability

Henrys law

solubility of a gas in a liquid is directly proportional to the concentration of the gas above the liquid

respiratory pathway

Nares → nasal cavity → pharynx → larynx → trachea → bronchi → bronchioles → alveoli

inhalation requires

diaphragm and external intercostal muscles

exhalation uses

abdominal muscles and internal intercostals

surfactants

reduce surface tension at the air-liquid interface in the alveoli, preventing their collapse

vital capacity =

IRV + ERV + TV

when co2 levels become too low

brain can decrease respiratory rate to raise CO2

immune mechanisms in respiratory

vibrissae in the nares, lysozyme in mucous membranes, mucociliary escalator, macrophages in the lungs, mucosal iga antibodies, mast cells

bicarb equation

co2 + h2o = h2co3 = H + CO3-

respiratory failure, results in _ pH

lower

total lung capacity =

VC + RV

kalydeco class

potentiator

kalydeco generic name

ivacaftor

kalydeco MOA

binds to CFTR and opens anion channel, unlocks the gate and holds it open

indications for ivacaftor

CF aged 1 month and older who have 1 of 97 mutations

adverse effects of ivacaftor

elevated liver enzymes, anaphylaxis, intracranial HTN, cataracts

orkami generic

lumacaftor/ ivacaftor

lumacaftor is a

corrector

orkambi MOA

helps CFTR form the right shape, move to the cell membrane and stay in the membrane longer

ivacaftor opens gate and holds it open

orkambi indication

CF aged 1 yr or older who have 2 copies of F508del mutation in CFTR gene

adverse effects of orkambi

including ivacaftor + breathing problems, increase in BP

common: increase in CK, sob/ chest tightness, URI/ flu symptoms, irregular period/ increase in menstrual bleeding

symdeko generic name

tezacaftor/ ivacaftor

symdeko class

tezacaftor = corrector

ivacaftor = potentiator

symdeko MOA

helps CFTR form the right shape, move to the cell membrane and stay in the membrane longer

ivacaftor opens the gate and holds it open

indications for symdeko

CF ages 6 and older with 2 copes of F508 del mutation and

CF ages 6 and older with a single copy of one of 154 mutations

adverse symdeko

fewer than orkami

common: ha, nausea, sinus congestion, dizziness

trikafta generic name

elexacftor/ tezacaftor/ ivacaftor

class of medication for trikafta

elexacftor & tezacaftor = corrector

ivacaftor = potentiator

indication for trikafta

CF ages 2 and older who have at least 1 copy of F508 del mutation or at least 1 copy of 271 mutations

trikafta side effects

liver damage, serious allergic reactions, intracranial HTN, cataracts

HA, uri, abd pain, d/c, rash, elevated liver enzymes and bilirubin, increase in CK, flu, inflamed sinuses

alyftrek generic name

vanzacaftor/ tezacaftor/ deutivacaftor

class for alyftrek

vanzacaftor/ tezacaftor = corrector

deutivacaftor = potentiator

deutivacaftor moa

binds to defective CFTR and holds open chloride channel; deuterated form of ivacaftor, allowing for a longer half life allowing daily dosing

alyftrek indication

CF ages 6 and up who are eligible based on mutations for trikafta or 31 other rare mutations

alyftrek outcomes

improvement in lung function comparable to trikafta

reduction in sweat chloride greater than see with trikafta

obstructive lung disease

increase in resistance to airflow due to diffuse airway disease, any level of respiratory tract

restrictive disease

reduced expansion of lung parenchyma and decreased total lung capacity

difference between obstructive and restrictive disease based on

PFTs

restrictive defects occur in 2 broad kinds

1) chest wall disorders

2) chronic interstitial and infiltrative diseases

anatomic site of chronic bronchitis

bronchus

major pathologic changes for chronic bronchitis

mucous gland hyperplasia, hypersecretion

etiology for chronic bronchitis

tobacco smoke, air pollutants

signs/ symptoms of chronic bronchitis

cough, sputum production

anatomic site of emphysema

acinus

major pathologic changes of emphysema

airspace enlargement; wall destruction

etiology for emphysema

tobacco smoke

signs/ symptoms of emphysema

dyspnea

small airway disease anatomic site

bronchiole

major pathologic changes in small airway disease

inflammatory scarring/ obliteration

etiology of small airway disease

tobacco smoke, air pollutants, misc

signs/ symptoms of small airway disease

cough, dyspnea

alpha 1 antitrypsin deficiency is a

autosomal recessive of low levels of alpha 1 antitrypsin

alpha-1 antitrypsin

antiprotease made in hepatocytes which normally inhibits proteases

uninhibited neutrophil elastase causes

break down in alveoli, result in panacinar emphysema

COPD causes _ emphysema

centriacinar

genetic defect in alpha 1 antitrypsin

glutamic acid to lysine at position 342

PiMM

normal

PiZZ

10% normal alpha 1 antitrypsin

PiMZ

60% normal alpha 1 antitrypsin

risk factors for CF

smoking

misfolded PiZ polypeptide

builds up in ER (doesn’t get transported to Golgi) → unfolded protein response (signaling cascade) → apoptosis → hepatocyte injury/ cell death

clinical manifestations of alpha 1 antitrypsin deficiency

emphysema, liver disease

tx for alpha 1 antitrypsin

augmentation therapy, inhalers, o2, tx for cirrhosis

alpha 1 antitrypsin is most common in

northern european descent

potentiators

keep CFTR channel open

useful in class III, IV, V

correctors

proper folding of CFTR protein, increasing trafficking to cell surface
class II

amplifiers

increase amount of CFTR protein the cell makes

class V