Inherited Disorders

Question 1

what is the most common fatal autosomal recessive disorder in Caucaisna children (1:2000)?

Answer 1

CF

Question 2

what causes CF?

Answer 2

mutation in the gene for ‘cystic fibrosis transmembrane conductance regulator’ (CFTR

Question 3

what is CFTR?

Answer 3

membrane protein that acts as a cholride channel

Question 4

what type of transporter is CFTR?

Answer 4

ATP binding cassette (ABC) transporter

Question 5

what does CFTR contain

Answer 5

• 2 membrane spanning domains
• 2 ATP binding domains
• regulatory domain that can be phosphorylated by PKA

Question 6

what does phosphorylation of the cytoplasmic regulatory domain by PKA activate?

Answer 6

the channel - providing regulated Cl- and fluid secretion

Question 7

what are the changes in the respiratory system with CF?

Answer 7

the mutant CFTR does not transport Cl- into the airway lumen!

Question 8

what does mutant CFTR in respiratory system lead to?

Answer 8

-Na+ and H20 in luminal surface is low
= thickened and viscous mucous secretions
leads to bacterial infections!

Question 9

what are the most common causes of mortality and morbidity in patients with CF?

Answer 9

respiratory infections

Question 10

what major change in the pancreas is found with CF?

Answer 10

exocrine pancreatic insufficiency

Question 11

a loss of CFTR function leads to thicker acinar secretions which leads to?

Answer 11

duct obstruction and tissue destruction

Question 12

what types of tissues replace the pancreatic parenchyma?

Answer 12

fibrotic tissue and fat - “CF”

Question 13

is there a defiency of pancreatic enzymes in CF?

Answer 13

yes - lipase, trypsin, chymotrypsin

Question 14

why is there steatorrhea with CF/

Answer 14

defieincy of fat soluble vitamins

Question 15

what is commonly found in some children right after birth with CF?

Answer 15

meconium ileus and intestinal obstruction

Question 16

more than 95% of males with CF are what?

Answer 16

infertile

because they lack a vas deferens - a phenotype known as CONGENITAL BILATERAL ABSENCE OF TEH VAS DEFERENS (CBAVD)

Question 17

what is CFTR function in sweat glands?

Answer 17

reabsorption of NaCl - defective in CF - high salt content in skin!

Question 18

the presence of what is diagnostic of CF?

Answer 18

excessive salt in sweat

Question 19

where is the CFTR mutation located?

Answer 19

long arm of chromosome 7

Question 20

what is the most common mutation of CFTR?

Answer 20

A F508
deletion of 1 aa = 3 bp deletion that eliminates the phenlylalanine residue of CFTR at position 508

NBD1 - defective processing!

Question 21

what does the F508 mutation prevent?

Answer 21

protein from maturing properly and reaching the plasma membrane

Question 22

what is pilocarpine?

Answer 22

a drug that stimulates sweating

Question 23

what are some molecular diagnostic tests to diagnose CF?

Answer 23

ASO - if mutation is known
PCR
Southern blot
Allel specific PCR

Question 24

the carriers for CF are _____ wheras the affected children are ____ for the mutation?

Answer 24

heterozygous

homozygous

Question 25

what sickle cell due to?

Answer 25

point mutation of the beta globin chain of Hb

Question 26

what is replaced in sickle cell anemia?

Answer 26

glutamic acid (glutamate) is replaced with valine at the 6th position of the beta glob in chain of Hb

Question 27

the acidic aa that was ____ is replaced with a _____ aa?

Answer 27

``` hydrophilic branches chain (hydrophobic) ```

Question 28

where is glutamate normally present?

Answer 28

exterior of the Hb molecule

Question 29

what does the replacement of valine in sickle cell disease result in?

Answer 29

creation of a hydrophobic pocket on the exterior of the Hb molecule

Question 30

what happens to Hb in sickle cell in deoxygenated state

Answer 30

Hb aggregates to form long filament like structures - results in distortion of the structure of RBC = sickling!

Question 31

when is HbS less soluble?

Answer 31

in deox state - this is why sickling is seen more in periphery - deox Hb levels are higher in limbs

Question 32

a single aa change in Hb is what?

Answer 32

critical for solubility of Hb

Question 33

how are sickled and distorted RBC removed ?

Answer 33

spleen - this is why they have anemia/splenomegaly

Question 34

how can sickling crisis result?

Answer 34

excessive removal of sickled RBCs from the circulation - resulting in worse anemia and jaundice (hyperbilirubinemia) during the crisis

Question 35

what type is hyperbilirubinemia in sickle cell?

Answer 35

pre-heptic (hemolytic type)

Question 36

what is hyperbilirubinemia in sickle cell characterized by?

Answer 36

increase unconjugated (indirect) bilirubin - bound to albumin increase in total bilirubin urine is normal color

Question 37

why may people with sickle cell anemia develop pigmented gall stones?

Answer 37

due to excessive loss of conjugated bilirubin in bile

Question 38

HbS has fewer _____- than HbA

Answer 38

number of negative charges - HbS moves slower than HbA towards the anode (+)

Question 39

what are molecular diagnostic tests for detection of sickle cell disease and carriers?

Answer 39

ASO test - dot blot test | RFLP analysis

Question 40

DMD and BMD are mutations of what?

Answer 40

dystrophin gene

Question 41

the dystrophin gene is the largest gene located on what chromosome?

Answer 41

X

Question 42

what id DMD due to?

Answer 42

almost complete absence of functional dystrophin

Question 43

what is BMD due to ?

Answer 43

production of abnormal dystrophin or less amounts of dystrophin

Question 44

what does DMD prevent the production of?

Answer 44

dystrophin - muscle protein

Question 45

what is the most common MD resulting in 1:3,000 boys?

Answer 45

DMD

Question 46

which MD is more severe?

Answer 46

DMD - severe with early onset! | BMD is milder - with later onset

Question 47

on what level can DMD and BMD deletions be distinguished from eachtoehr?

Answer 47

codon level

Question 48

almost all deletions causing DMD involve what?

Answer 48

frameshift mutations | abolishing translation of dystrophin protein

Question 49

BMD deletions are mostly?

Answer 49

``` in frame some dystrophin (although truncated) is translated! ```

Question 50

what tool is needed to diagnose DMD?

Answer 50

multiplex PCR

Question 51

what are the clinical features of DMD?

Answer 51

weakness in muscles - pecs, trunk, upper and lower legs | pseudohypertrophy of calf - due to replacement of normal muscle with CT and fat

Question 52

what is Gower's maneuver?

Answer 52

DMD boys distinct way of getting up from floor

Question 53

what is the function of dystrophin?

Answer 53

anchors the cytoskeleton of msucle cells to the ECM links actin filaments to TMP of the muscle cell plasma memrbane

Question 54

what does the dystrophin anchor do?

Answer 54

stabilize the PM and enables the cell to withdtand the stress of muscle contraction

Question 55

function loss of dystrphin leads to what?

Answer 55

ocidative cellular injury and myonecrosis

Question 56

what can immunofluorescence staining indicate with Md?

Answer 56

increase in CT between myocytes

Question 57

what is western blot used for in MD?

Answer 57

can show protein size and quantity of protein - BMD = in frame DMD = complete absence - frame shift deletion

Question 58

what are other useful tests used in DMD?

Answer 58

CKMM - elevated with MD (indicated muscle damage) females are carriers - have higher CKMM multiplex PCR is used to Id specific mutation