Pathology P.462-471: Inborn Errors Of Metabolism And Cystic Fibrosis

Front 1

What is Mucoviscidosis?

Back 1

another name for cystic fibrosis

Front 2

How is cystic fibrosis inherited?

Back 2

autosomal recessive

Front 3

Cystic fibrosis occurs by a genetic defect in what gene?

Back 3

CFTR (cystic fibrosis transmembrane conductance regulator); allows chloride transport through the membrane

Front 4

The CFTR gene is activated by which signal transduction pathway?

Back 4

G-protein/cAMP pathway leading to protein kinase A opening the chloride channel

Front 5

What is the ENaC channel?

Back 5

epithelial sodium channel; CFTR defect leads to increased sodium absorption into respiratory cells = dehydrated mucus

Front 6

How does a defect in the CFTR gene lead to high sodium content in sweat?

Back 6

defective CFTR leads to decreases in ENaC channels in sweat ducts. sodium is now not reabsorbed into the cells and stays in the sweat

Front 7

How does a defect in the CFTR gene lead to thick mucus?

Back 7

normal CFTR gene inhibits ENaC, so in cystic fibrosis, there are more sodium channels open. Sodium enters the airway cells and water follows (out of the mucus). the mucus is now very viscous and blocks the airway

Front 8

Loss of normal CFTR function leads to (increased or decreased) sodium reabsorption in sweat ducts?

Back 8

decreased. sodium stays in the sweat duct and does not re-enter the epithelium

Front 9

Loss of normal CFTR function leads to (increased or decreased) sodium reabsorption in airway mucus?

Back 9

increased. sodium leaves the mucus/enters the epithelium. water follows and dehydrates the mucus

Front 10

How does CFTR damage affect bicarbonate/pH?

Back 10

CFTR mutant cells secrete acidic substances (due to decreased bicarbonate). luminal pH drops (acidic)

Front 11

What causes class 1 cystic fibrosis?

Back 11

defective protein synthesis of the CFTR channel

Front 12

What causes class 2 cystic fibrosis?

Back 12

Bad protein folding of the CFTR channel

Front 13

What causes class 3 cystic fibrosis?

Back 13

normal amount of CFTR channels, but defective regulation and they can't be activated

Front 14

What causes class 4 cystic fibrosis?

Back 14

decreased conductance (blockage of ion pore)

Front 15

What causes class 5 cystic fibrosis?

Back 15

reduced abundance of CFTR channels

Front 16

What causes class 6 cystic fibrosis?

Back 16

mutated regulation of other ion channels

Front 17

What other 2 proteins can reduce CFTR expression?

Back 17

MBL2 (mannose binding lectin 2) and TGFB1 (transforming growth factor B1)

Front 18

Why is alginate production bad in patients with infection?

Back 18

allows for biofilm production; biofilm= antibiotic resistance

Front 19

Why can cystic fibrosis lead to antibiotic resistant infection?

Back 19

stale mucus = hypoxia = alginate = biofilm = protection for bacteria

Front 20

What is meconium ileus?

Back 20

small bowel obstruction from dried mucus plugs

Front 21

Why are aeruginosa bacteria dangerous?

Back 21

they produce alginate = biofilm = antibiotic resistant

Front 22

Why might males with cystic fibrosis be infertile?

Back 22

mucus plugs of the vas deferens

Front 23

How does cystic fibrosis lead to malabsorption?

Back 23

Mucus covers the absorptive membrane of the intestine and may also plug pancreatic duct (digestive enzymes cannot enter intestine)

Front 24

Why might a patient with cystic fibrosis have edema?

Back 24

mucus plug in pancreatic duct = low peptidases in intestine = low protein absorption = low colloid pressure = edema

Front 25

Why might a patient with cystic fibrosis have abdominal pain or jaundice?

Back 25

bile duct occlusion or gallstones

Front 26

Patients with PKU have a defect in what gene/protein/enzyme?

Back 26

PAH (phenylalanine hydroxylase)

Front 27

Patients with PKU have a build-up of what amino acid in their blood?

Back 27

phenylalanine

Front 28

What is the function of phenylalanine hydroxylase?

Back 28

convert phenylalanine into tyrosine

Front 29

PAH converts phenylalanine into tyrosine in what organ?

Back 29

liver

Front 30

Why can PKU arise with a defect in Dihyrdropteridine reductase?

Back 30

this enzyme generates BH4 which acts as a cofactor for the conversion of phenylalanine into tyrosine; low BH4 = PKU

Front 31

"Classic" PKU is caused by ...

Back 31

defect in PAH

Front 32

Why does PKU have a "mousy" odor?

Back 32

lack of PAH leads to formation of alternative metabolites (phenylacetic acid) that accumulate in sweat

Front 33

Why is it important that pregnant mothers with PKU have a phenylalanine restricted diet?

Back 33

excess phenylalanine can cross placenta and cause neuro defects in the fetus

Front 34

Why does a dosage of BH4 help patients with PKU?

Back 34

BH4 can act as a chaperone for altered PAH to help increase enzyme function (prevent degradation of PAH)

Front 35

What is galactosemia?

Back 35

inability to degrade galactose; lack of glucose-1-phosphate uridyl transferase or galactokinase deficit

Front 36

In patients with a lack of glucose-1-phosphate uridyl transferase, what compound accumulates in patient's blood?

Back 36

glucose-1-phosphate; also galactitol and galactonate

Front 37

Why do patients with galactosemia have decreased vision?

Back 37

excess galactitol enters the lens and water follows = cataracts

Front 38

Defect in galactokinase leads to excess ...

Back 38

galactose

Front 39

Why does galactosemia lead to hyperaminoaciduria?

Back 39

galactose and glucose-1-phosphate accumulate and decrease AA reabsorption = AA stays in the urine