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NBME 22 Answers

nbme22/Block 3/Question#23

A 45-year-old woman comes to the physician for a ...


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submitted by bubbles(45),

Can someone explain properly how we know that this trait follows Mendelian genetics and is autosomal recessive and furthermore how the parents were heterozygous?

I guessed a lot on this question and got lucky :(

niboonsh  Autosomal Dominant disorders usually present as defects in structural genes, where as Autosomal Recessive disorders usually present as enzyme deficiencies. P450 is an enzyme, so we are probably dealing with an autosomal recessive disorder. furthermore, the question states there was a "homozygous presence of p450.....". In autosomal recessive problemos, parents are usually heterozygous, meaning that 1/4 of their kiddos will be affected (aka homozygous), 1/2 of the kids will be carriers, and 1/4 of their kids will be unaffected. +10  
nwinkelmann  Is this how we should attack this probelm?: First clue stating endoxifen is active metabolite of Tamoxifen should make us recognize this undering first pass hepatic CYP450 metabolism? Once we know that, the fact that the metabolite is decrease suggests an enzyme defect, which is supported by patient's homozygous enzyme alleles. Then use the general rule that enzyme defects are AR whereas structural protein defects are AD inheritance patters. Once we know the pattern, think that most common transmission of AR comes from two carrier parents. So offspring alleles = 25% homozygous normal, 50% heterozygous carrier, and 25% homozygous affected, thus sister has a 25% of having the same alleles as patient (i.e. homozygous CYP450 2D6*4)? +6  
impostersyndromel1000  we had the exact same thought process, so i too am hoping this is the correct way to approach it get reasoning friend +  
ajss  thanks for this explanation, I totally forgot about AR patterns are most likely enzymes deficiencies, this kind of make the question easier if you approach it that way, thanks +  

 +2  upvote downvote
submitted by dentist(18),
  • enzyme deficiencys = AR

  • homozygous presence of CYP..."

QED: homozygous + AR = 25%

Tamoxifen has to be metabolized via first pass metabolism to an active metabolite (endoxifen). The patient has decreased concentrations of the metabolized product indicating that the patient’s pair of cytochrome P450 alleles aren’t metabolizing tamoxifen correctly. The question is asking what the chances are the sister has the same genotype, which would be 25% --> 1/2 * 1/2 = 1/4

medschul  How do we know the parents are not homozygous +2  
yotsubato  Chances are they are not unless they had or are incestuous +  

 +0  upvote downvote
submitted by g8427(0),

If some one can help me understand bc im a bit confused. I understand the thought process and I realized that this was an AR disease and I also got the 1/4 affected, 1/2 carrier and 1/4 unaffected. But I chose 0% bc I figured if it was an AR disease the 1 child already diseased was homozygous affected (1/4 affected). Which lead me to think that the other sister was either a carrier or not affected at all. Am I just over thinking this or am I not fully understanding whats going on?

rush  you have to think about each child individually, doesn't matter what the siblings have. The question states what are the odds of the child getting the disease. So regardless of the other siblings it still is Mom (1/2) dad (1/2) which makes it 1/4 AR +  
titanesxvi  But how do we know that the parents are heterozygous for the mutation +  
need_answers  we know that the parents have to be heterozygous Aa X Aa because on a 2x2 table, the only way the daughter could be homozygous for an AR is by having both parents be carriers (Aa) so the question was asking what are the chances the sister has the same alleles (aa) and there is only a 25% of having the same alleles. +