Homocystinuria vs Hyperhomocysteinemia

[JingleChips]

Kind of confused here. The concepts discussed here are from 2 similar questions on UWorld but no question details will be posted.


One UW question (in the explanation) states that homocystinuria is most commonly caused by cystathionine beta synthase mutations and presents with marfanoid habitus, ectopia lentis, developmental delay, and thromboembolic complications.

Another UW question states that the most common genetic cause of hyperhomocysteinemia is methylene THF reductase (MTHFR) mutations and presents with thromboembolic complications, but also can be caused by mutations in methionine synthase, B12 deficiency, or folate deficiency.


I realize you can distinguish the causes of elevated homocysteine with low methionine by looking at other sx :
- MTHFR defect or folate deficiency MAY show megaloblastic anemia but there will be normal MMA levels and no periph neuropathy
- Methionine Synthase defect will show no anemia
- B12 deficiency will show megaloblastic anemia with elevated MMA / neuropathy

But I am just so confused at the naming. Why are they named differently (e.g. one elevated in the urine vs one in the blood), and are there any other differences (such as presentation) obviously besides buildup of Methionine + cysteine becoming essential AA in CBS mutations/B6 deficiency vs lack of Methionine and need for its supplementation in MTHFR mutations/Methionine Synthase Mutations/B12 deficiency? Like, does one just have elevated homocystiene in the urine and one in the blood?

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[Rahas]

This is an excellent discussion since I have some confusions about it as well.

My impression right now is that homocysteinemia and hyperhomocysteinemia are the same thing. I remember checking uptodate and they used the term hyperhomocysteinemia (even if I searched for homocysteinemia)

Furthermore, I believe I've read in Kaplan that vitamin deficiencies will cause homocysteinemia but not homocystinuria, so that latter points towards an enzyme defect.

I've also noted MTHFR deficiency is the most common as well as the mildest, and treatment is with folate replacement. I can't remember where I got this information from, it might have been uptodate but my subscription has expired.

Cystathionine defects make cysteine essential, methionine synthase deficiency doesn't "make" methionine essential since its essential to begin with.

Furthermore, after a lot of confusion, I sort of concluded that methionine synthase = homocysteine methyltransferase (this enzyme is mentioned in Kaplan) although I failed to find a source that explicitly stated so.

I think you should approach this similar to RPGN ie its a histological diagnosis where you find crescents in glomeruli and you know theres certain conditions that can do so and go about diagnosing which one. Similarly, homocysteinemia can result from a variety of issues, since there are multiple pathways to dispose it and multiple enzymes and vitamins involved, so once the blood tests are in, you need to be able to diagnose which one it is.

 

[JingleChips]

This is an excellent discussion since I have some confusions about it as well.

My impression right now is that homocysteinemia and hyperhomocysteinemia are the same thing. I remember checking uptodate and they used the term hyperhomocysteinemia (even if I searched for homocysteinemia)

Furthermore, I believe I've read in Kaplan that vitamin deficiencies will cause homocysteinemia but not homocystinuria, so that latter points towards an enzyme defect.

I've also noted MTHFR deficiency is the most common as well as the mildest, and treatment is with folate replacement. I can't remember where I got this information from, it might have been uptodate but my subscription has expired.

Cystathionine defects make cysteine essential, methionine synthase deficiency doesn't "make" methionine essential since its essential to begin with.

Furthermore, after a lot of confusion, I sort of concluded that methionine synthase = homocysteine methyltransferase (this enzyme is mentioned in Kaplan) although I failed to find a source that explicitly stated so.

I think you should approach this similar to RPGN ie its a histological diagnosis where you find crescents in glomeruli and you know theres certain conditions that can do so and go about diagnosing which one. Similarly, homocysteinemia can result from a variety of issues, since there are multiple pathways to dispose it and multiple enzymes and vitamins involved, so once the blood tests are in, you need to be able to diagnose which one it is.

What I bolded in the quite I know to be true (and most of my original post I'm pretty sure on). Curious as to others thoughts, especially since UWorld makes the distinction in names. I guess my main questions are:

1. Does homocystinuria have elevated levels of homocysteine in the blood too? (I'm assuming yes, unless there was a reabsorption defect in the kidney I don't know how you would otherwise have elevated levels in urine without elevated levels in blood)
2. Does hyperhomocystinemia / homocystinemia (as above poster calls it) have elevated homocysteine in the urine?
3. Does hyperhomocystinemia present with marfanoid/ectopia lentis/developmental delay like homocystinuria? (This I have no idea, I would imagine NO if it was a B12/Folate deficiency (since this wouldn't be present @ birth), but MAYBE if it was an enzyme deficiency. )

 

[Reperfused]

Hyperhomocysteinemia and Homocystinuria are two different things.

Homocysteinuria is a genetic disease that presents in childhood. The most common cause is Cystathionine synthase deficiency. Increased homocysteine in urine. You get all the features you mentioned above.

Now, Hyperhomocysteinemia is a medical condition (simply meaning increased homocysteine in the blood). This is not by name a genetic disease. It's just a medical condition that can be the result of genetic or acquired causes. Acquired causes for example, B12 deficiency etc. Out of its genetic causes, the most common is MTHFR deficiency.
MTHFR deficiency is caused by many different mutations. If it's mild, it can present as hyperhomocysteinemia in adults. This will cause the complications of thromboembolism etc only (not those marfanoid habitus etc stuff).
Only if MTHFR deficiency is "severe" then it will present as Homocystinuria in childhood (this is the reason MTHFR can be a cause of Homocystinuria, but not a common one). In such a patient you will find all the typical symptoms of increased homocysteine in urine and marfanoid habitus etc



I really hope I was able to put the concept into words that it made some sense. Correct me if I am wrong anywhere. Or just take the discussion forward.

 

[Reperfused]

So to answer your qs:

1. Yes homocysteinuria will always have increased homocysteine in blood as well as in urine.

2. Not always. In the mild form and adult presentation there will be increased homocysteine in blood only (not in urine). However, in severe MTHFR deficiency, which then becomes the disease homocysteinuria---> answer 1 will be applied (increase in both blood and urine).

3. Again, not always. Please apply the same concept as #2 (as I'm tired of typing now and also feeling hungry lol)

 

[JingleChips]

YAY You are awesome. Thanks!

 

[Rahas]

Hyperhomocysteinemia and Homocystinuria are two different things.

Homocysteinuria is a genetic disease that presents in childhood. The most common cause is Cystathionine synthase deficiency. Increased homocysteine in urine. You get all the features you mentioned above.

Now, Hyperhomocysteinemia is a medical condition (simply meaning increased homocysteine in the blood). This is not by name a genetic disease. It's just a medical condition that can be the result of genetic or acquired causes. Acquired causes for example, B12 deficiency etc. Out of its genetic causes, the most common is MTHFR deficiency.
MTHFR deficiency is caused by many different mutations. If it's mild, it can present as hyperhomocysteinemia in adults. This will cause the complications of thromboembolism etc only (not those marfanoid habitus etc stuff).
Only if MTHFR deficiency is "severe" then it will present as Homocystinuria in childhood (this is the reason MTHFR can be a cause of Homocystinuria, but not a common one). In such a patient you will find all the typical symptoms of increased homocysteine in urine and marfanoid habitus etc



I really hope I was able to put the concept into words that it made some sense. Correct me if I am wrong anywhere. Or just take the discussion forward.

This post has cleared a couple of things that were the missing links in my understanding. Thanks!

 

[HyperHarmonyCysteinemia]

Hi.
I am a new member. I am not a med student. I have hyperhomocystienemia. I was diagnosed in 2011. It is not being treated at all. I live in rural SE TN, and my health has deteriorated greatly the past 2 years. I came to this site for knowledge because I scared I am going to die. I hope that is OK. I just wanted to say Hi, and I will just be reading, not participating unless you want to ask me about my health or something. Thankyou for studying this illness. It means the world to me.

 

[Fewa Fibroblast]

So we can say that : a) Severe hyperhomocysteinemia can cause homocystinuria
b)Most common cause of Homocystinuria is Cystathione synthase defeciency
c)Most common genetic cause of Hyperhomocystenemia is Methylene THFR defeciency, other causes including folate,vit b12 defeciency, Pyridoxine defecincy etc.
Correct me if i am wrong