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Flashcards in Inherited Disorders Deck (58):
1

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

CF

2

what causes CF?

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

3

what is CFTR?

membrane protein that acts as a cholride channel

4

what type of transporter is CFTR?

ATP binding cassette (ABC) transporter

5

what does CFTR contain

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

6

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

the channel - providing regulated Cl- and fluid secretion

7

what are the changes in the respiratory system with CF?

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

8

what does mutant CFTR in respiratory system lead to?

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

9

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

respiratory infections

10

what major change in the pancreas is found with CF?

exocrine pancreatic insufficiency

11

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

duct obstruction and tissue destruction

12

what types of tissues replace the pancreatic parenchyma?

fibrotic tissue and fat - "CF"

13

is there a defiency of pancreatic enzymes in CF?

yes - lipase, trypsin, chymotrypsin

14

why is there steatorrhea with CF/

defieincy of fat soluble vitamins

15

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

meconium ileus and intestinal obstruction

16

more than 95% of males with CF are what?

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

17

what is CFTR function in sweat glands?

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

18

the presence of what is diagnostic of CF?

excessive salt in sweat

19

where is the CFTR mutation located?

long arm of chromosome 7

20

what is the most common mutation of CFTR?

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

NBD1 - defective processing!

21

what does the F508 mutation prevent?

protein from maturing properly and reaching the plasma membrane

22

what is pilocarpine?

a drug that stimulates sweating

23

what are some molecular diagnostic tests to diagnose CF?

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

24

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

heterozygous

homozygous

25

what sickle cell due to?

point mutation of the beta globin chain of Hb

26

what is replaced in sickle cell anemia?

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

27

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

hydrophilic
branches chain (hydrophobic)

28

where is glutamate normally present?

exterior of the Hb molecule

29

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

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

30

what happens to Hb in sickle cell in deoxygenated state

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

31

when is HbS less soluble?

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

32

a single aa change in Hb is what?

critical for solubility of Hb

33

how are sickled and distorted RBC removed ?

spleen - this is why they have anemia/splenomegaly

34

how can sickling crisis result?

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

35

what type is hyperbilirubinemia in sickle cell?

pre-heptic (hemolytic type)

36

what is hyperbilirubinemia in sickle cell characterized by?

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

37

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

due to excessive loss of conjugated bilirubin in bile

38

HbS has fewer _____- than HbA

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

39

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

ASO test - dot blot test
RFLP analysis

40

DMD and BMD are mutations of what?

dystrophin gene

41

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

X

42

what id DMD due to?

almost complete absence of functional dystrophin

43

what is BMD due to ?

production of abnormal dystrophin or less amounts of dystrophin

44

what does DMD prevent the production of?

dystrophin - muscle protein

45

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

DMD

46

which MD is more severe?

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

47

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

codon level

48

almost all deletions causing DMD involve what?

frameshift mutations
abolishing translation of dystrophin protein

49

BMD deletions are mostly?

in frame
some dystrophin (although truncated) is translated!

50

what tool is needed to diagnose DMD?

multiplex PCR

51

what are the clinical features of DMD?

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

52

what is Gower's maneuver?

DMD boys distinct way of getting up from floor

53

what is the function of dystrophin?

anchors the cytoskeleton of msucle cells to the ECM

links actin filaments to TMP of the muscle cell plasma memrbane

54

what does the dystrophin anchor do?

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

55

function loss of dystrphin leads to what?

ocidative cellular injury and myonecrosis

56

what can immunofluorescence staining indicate with Md?

increase in CT between myocytes

57

what is western blot used for in MD?

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

58

what are other useful tests used in DMD?

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