Cystathione synthase deficiency

[Enzymes]

So one of the causes of homocystinuria is this enzyme deficiency. Treatment is to decrease methionine, yet increase B12. This is sort of counterintuitive since B12 is a cofactor for producing methionine from homocysteine. Anybody understand this treatment?

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[Apoplexy__]

It's just to get the homocysteine levels down, since that's what's going to give them the strokes/MI's. Apparently that's more important than risking a buildup of methionine.

Ironically, FA mentions the B12, but fails to mention B6, which UWorld says is the single most important treatment for homocystinuria (since the most common homocystinuria is cystathionine deficiency).

 

[Handinhand]

This is standard general chemistry/ reaction equilibrium. You want to lower your dietary consumption of methionine and give them a lot of B12 so you can push the reaction in favor of Homocysteine ---> Methionine. If you have a high level of Methionine already from your diet, this reaction is not going to occur as much.

Kirby: FA definitely mentions B6 supplementation if the cause of homocysinuria is because of decreased affinity for B6 by Cystathionine Synthase. If the cause is because of a mutation in CS, then overloading them on B6 is going to do them jack squat, and instead you want to encourage the Metionine synthesis mentioned above. (FA pg. 111)

 

[dyspareunia]

So one of the causes of homocystinuria is this enzyme deficiency. Treatment is to decrease methionine, yet increase B12. This is sort of counterintuitive since B12 is a cofactor for producing methionine from homocysteine. Anybody understand this treatment?

Homocysteine can go one of two ways. One is to methionine via the methyltransferase that requires B12. The other is to cystathionine (and then cysteine) via cystathionine synthase, which requires B6. If your pt is lacking cystathionine synthase the only way homocysteine can go is methionine, which means you have to load them up with B12 for the methyltransferase to be able to handle the increased reactant (homocysteine) load. And sure now you'll increase methionine, but methionine is used for so many anabolic reactions that it won't matter.

It's just to get the homocysteine levels down, since that's what's going to give them the strokes/MI's. Apparently that's more important than risking a buildup of methionine.

Ironically, FA mentions the B12, but fails to mention B6, which UWorld says is the single most important treatment for homocystinuria (since the most common homocystinuria is cystathionine deficiency).

The most common cause of homocystinuria is cystathionine synthase deficiency and B6 supplementation won't help in that situation. You would need to give them cysteine.

 

[Apoplexy__]

The most common cause of homocystinuria is cystathionine synthase deficiency and B6 supplementation won't help in that situation. You would need to give them cysteine.

My understanding is you do both. There is residual enzyme activity that can be improved with supplementation. I'm only arguing the point because I feel B6 supplementation should be a knee-jerk reaction to homocystinuria.

I'm getting most of my info from UWorld QID #1504.

 

[Handinhand]

I believe you've skipped the Educational Objective at the end of that question Kirby, as it clearly states only about half of affected individuals will responds to high dose B6 therapy.

My understanding of Homocystinuria is that you will initially treat with B6 and B12 therapy, because you could simply have a deficiency in either vitamin leading to the excess levels. If vitamin replacement doesn't work, then you set them on a low methionine diet, and possibly increase their B12 supplementation even more.

 

[Enzymes]

This is standard general chemistry/ reaction equilibrium. You want to lower your dietary consumption of methionine and give them a lot of B12 so you can push the reaction in favor of Homocysteine ---> Methionine. If you have a high level of Methionine already from your diet, this reaction is not going to occur as much.

Kirby: FA definitely mentions B6 supplementation if the cause of homocysinuria is because of decreased affinity for B6 by Cystathionine Synthase. If the cause is because of a mutation in CS, then overloading them on B6 is going to do them jack squat, and instead you want to encourage the Metionine synthesis mentioned above. (FA pg. 111)

Thank you very much! Love you guys.

 

[Apoplexy__]

I believe you've skipped the Educational Objective at the end of that question Kirby, as it clearly states only about half of affected individuals will responds to high dose B6 therapy.

My understanding of Homocystinuria is that you will initially treat with B6 and B12 therapy, because you could simply have a deficiency in either vitamin leading to the excess levels. If vitamin replacement doesn't work, then you set them on a low methionine diet, and possibly increase their B12 supplementation even more.

Ehh I didn't think the educational objective saying that disproves what I'm saying. The explanation says that it improves residual activity, which means it has merit in the enzyme deficiency form. Here's a paper I found that UWorld probably is referring to:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC322660/

I'm not trying to be anal/stubborn here, and I agree with you that dietary changes are key, but I think there's value in associating homocystinuria with B6 treatment -- especially since it's effective in treating the root of disease in 2/3 etiologies, unlike B12. In other words, I'm just saying it's a better answer than B12 supplementation if one had to choose.