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Test your knowledge #9! (Genetics/Pathology)

2K views 10 replies 5 participants last post by  mahwish 
#1 ·
An infant presents with neonatal hepatitis. Screening indicates a deficiency in a serine protease inhibitor that protects pulmonary function. The diagnosis is confirmed by genetic screening. What is the most probable genotype in this patient?
  • Hemizygous for the ΔF508 allele at the CFTR locus
  • Hemizygous for the M allele at the PI locus
  • Homozygous for the ΔF508 allele at the CFTR locus
  • Homozygous for the Z allele at the PI locus
  • Homozygous for the M allele at the PI locus
 
#4 ·
D) Homozygous for the Z allele at the PI locus

D) Homozygous for the Z allele at the PI locus

DX
Alpha-1-antitrypsin (AAT). AAT deficiency is an inherited genetic abnormality in the AAT protein that impairs its activity in the pulmonary alveoli and causes it to accumulate in hepatocytes.

Px can develop COPD, emphysema and cirrhosis.

Note: there are two genes involve such as S-gene and Z-gene

The S gene is more frequent among individuals of Spanish or Portuguese descent and the Z gene is highest in patients of Northern or Western European descent.

Tx
Replacing enzymes

Ref:http://emedicine.medscape.com/article/295686-overview
 
#6 ·
Tx: Replacing enzymes
This is the major medical treatment for presentation as an adult with the COPD - this of course wouldn't help the cirrhosis :(. (The yearly cost is also 2X to 4X the average individual income in the U.S.! :eek:) The major surgical treatment is b/l lung transplant.
(low-yield note: I knew a man who had a lung transplant - he was on the waitlist for more than three years, and had to pay a lot of money, so I think that neither treatment is for normal people. Not that that sort of thing is on Step 1!)

For children, the main treatment is liver transplant.

I did read a recent article that was positing that mTOR inhibitors could speed up the degradation of misfolded proteins and help protect the liver, so we'll see how that goes in clinical trials...
 
#5 ·
D is correct!

You all are too smart - I should have said: "Infant presents in distress..." in the stem or added "Hemizygous for the Z allele at the PI locus" to the answer choices. But you probably would still have gotten it. Well done! :happy:

There are three main alleles of the PI gene (also called SerpinA1):
  • PI*M - normal, full-function allele.
  • PI*S - minor deficiency allele
  • PI*Z - major deficiency allele
People deficient in antitrypsin are at increased risk for:
  • Panacinar emphysema: AAT is the major antiprotease in the alveoli
  • Cirrhosis: misfolded AAT collects in the ER of hepatocytes and provokes the Unfolded Protein Response and apoptosis (only in PI*Z/Z and some variants of PI*S/S or PI*S/Z)
So when alleles are combined:
  • Heterozygotes with one normal allele (PI*M/Z, PI*M/S, PI*M/null) are carriers, likely at no increased risk of either cirrhosis or emphysema
  • PI*S/Z heterozygotes and PI*Z/null hemizygotes have an increased risk of emphysema but not cirrhosis
  • PI*Z/Z homozygotes have an increased risk of emphysema and cirrhosis (because there is so much misfolded Z-type protein)
  • PI*null/null homozygotes have an absolute risk of emphysema and no increased risk of cirrhosis

95% of AAT-deficient individuals are PI*ZZ homozygous. Incidence is similar to CF. Actually, CF can also cause an obstructive jaundice and also involves the lungs, which is why I used it as a distractor. I was also trying to demonstrate Rasheed's "two similar answers are wrong" rule.
 
#9 ·
@Mondoshewan

a very stupid question...my brain is not working right now..:sleepy:
in ur post u mentioned that if u had changed the question to:
You all are too smart - I should have said: "Infant presents in distress..." in the stem or added "Hemizygous for the Z allele at the PI locus" to the answer choices. But you probably would still have gotten it.
u mean for this genotype?

PI*S/Z heterozygotes and PI*Z/null hemizygotes have an increased risk of emphysema but not cirrhosis,
 
#10 ·
@Mondoshewan
a very stupid question...my brain is not working right now..:sleepy:
in ur post u mentioned that if u had changed the question to:... [hemizygous for the Z allele].. u mean for this [PI*Z/null] genotype?
Precisely - such a patient would be likely to develop emphysema in their 30's or 40's because of their severe lack of antiprotease activity. However, they would not be making enough of the misfolding PI to cause such early hepatitis, so that wouldn't be the answer for our baby. :) Sleep well! :sleepy:
 
#11 ·
hemizygous for the Z allele]
.. u mean for this [PI*Z/null] genotype? Precisely - such a patient would be likely to develop emphysema in their 30's or 40's because of their severe lack of antiprotease activity. However, they would not be making enough of the misfolding PI to cause such early hepatitis, so that wouldn't be the answer for our baby. :) Sleep well! :sleepy:
lol.. that was really stupid question..haha
thanks for explaining :)
 
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