Flashcards in Inherited Disorders Deck (58)
what is the most common fatal autosomal recessive disorder in Caucaisna children (1:2000)?
what causes CF?
mutation in the gene for 'cystic fibrosis transmembrane conductance regulator' (CFTR
what is CFTR?
membrane protein that acts as a cholride channel
what type of transporter is CFTR?
ATP binding cassette (ABC) transporter
what does CFTR contain
-2 membrane spanning domains
-2 ATP binding domains
-regulatory domain that can be phosphorylated by PKA
what does phosphorylation of the cytoplasmic regulatory domain by PKA activate?
the channel - providing regulated Cl- and fluid secretion
what are the changes in the respiratory system with CF?
the mutant CFTR does not transport Cl- into the airway lumen!
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!
what are the most common causes of mortality and morbidity in patients with CF?
what major change in the pancreas is found with CF?
exocrine pancreatic insufficiency
a loss of CFTR function leads to thicker acinar secretions which leads to?
duct obstruction and tissue destruction
what types of tissues replace the pancreatic parenchyma?
fibrotic tissue and fat - "CF"
is there a defiency of pancreatic enzymes in CF?
yes - lipase, trypsin, chymotrypsin
why is there steatorrhea with CF/
defieincy of fat soluble vitamins
what is commonly found in some children right after birth with CF?
meconium ileus and intestinal obstruction
more than 95% of males with CF are what?
because they lack a vas deferens - a phenotype known as CONGENITAL BILATERAL ABSENCE OF TEH VAS DEFERENS (CBAVD)
what is CFTR function in sweat glands?
reabsorption of NaCl - defective in CF - high salt content in skin!
the presence of what is diagnostic of CF?
excessive salt in sweat
where is the CFTR mutation located?
long arm of chromosome 7
what is the most common mutation of CFTR?
deletion of 1 aa = 3 bp deletion that eliminates the phenlylalanine residue of CFTR at position 508
NBD1 - defective processing!
what does the F508 mutation prevent?
protein from maturing properly and reaching the plasma membrane
what is pilocarpine?
a drug that stimulates sweating
what are some molecular diagnostic tests to diagnose CF?
ASO - if mutation is known
Allel specific PCR
the carriers for CF are _____ wheras the affected children are ____ for the mutation?
what sickle cell due to?
point mutation of the beta globin chain of Hb
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
the acidic aa that was ____ is replaced with a _____ aa?
branches chain (hydrophobic)
where is glutamate normally present?
exterior of the Hb molecule
what does the replacement of valine in sickle cell disease result in?
creation of a hydrophobic pocket on the exterior of the Hb molecule
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!
when is HbS less soluble?
in deox state - this is why sickling is seen more in periphery - deox Hb levels are higher in limbs
a single aa change in Hb is what?
critical for solubility of Hb
how are sickled and distorted RBC removed ?
spleen - this is why they have anemia/splenomegaly
how can sickling crisis result?
excessive removal of sickled RBCs from the circulation - resulting in worse anemia and jaundice (hyperbilirubinemia) during the crisis
what type is hyperbilirubinemia in sickle cell?
pre-heptic (hemolytic type)
what is hyperbilirubinemia in sickle cell characterized by?
increase unconjugated (indirect) bilirubin - bound to albumin
increase in total bilirubin
urine is normal color
why may people with sickle cell anemia develop pigmented gall stones?
due to excessive loss of conjugated bilirubin in bile
HbS has fewer _____- than HbA
number of negative charges - HbS moves slower than HbA towards the anode (+)
what are molecular diagnostic tests for detection of sickle cell disease and carriers?
ASO test - dot blot test
DMD and BMD are mutations of what?
the dystrophin gene is the largest gene located on what chromosome?
what id DMD due to?
almost complete absence of functional dystrophin
what is BMD due to ?
production of abnormal dystrophin or less amounts of dystrophin
what does DMD prevent the production of?
dystrophin - muscle protein
what is the most common MD resulting in 1:3,000 boys?
which MD is more severe?
DMD - severe with early onset!
BMD is milder - with later onset
on what level can DMD and BMD deletions be distinguished from eachtoehr?
almost all deletions causing DMD involve what?
abolishing translation of dystrophin protein
BMD deletions are mostly?
some dystrophin (although truncated) is translated!
what tool is needed to diagnose DMD?
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
what is Gower's maneuver?
DMD boys distinct way of getting up from floor
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
what does the dystrophin anchor do?
stabilize the PM and enables the cell to withdtand the stress of muscle contraction
function loss of dystrphin leads to what?
ocidative cellular injury and myonecrosis
what can immunofluorescence staining indicate with Md?
increase in CT between myocytes
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