The Atypical HUS Foundation

Has anyone ever heard of the MTHFR mutation? We finally got the genetic testing results for Blake back in May and were told that this is the mutations he has but I have not been able to find any information on it at all.  I would really like to learn more about it and what to expect.  His Nephrologist told us that while he has this mutation there is one of his levels that should be off while he is sick but his levels (can't remeber the name) have been normal both times. She said they will do more testing the next time he is sick and see if they can come up with anymore answers.  Just trying to find out any info I can to make a little more sense out of everything. Thank you!

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Hello Vanessa

I personally never heard of it but below is a link that can maybe help you better understand.

If it involves insufficient vitamin B12 I do know this can be a trigger to AHUS.

Hope this helps


Hi Vanessa,


My name is Tara and I have been working to identify genetic causes that lead to aHUS for my PhD thesis for the past 5 years in Dr. Richard Smith's Lab. Linda Burke sent me a message about whether or not I know anything about (or am working on) MTHFR in our lab.  


So the quick answer is I have not heard of aHUS patients having variants that cause disease in this gene.  Thus far we only know of a few genes that lead to aHUS when they are not working correctly. These include: CFH, CFI, MCP, CFB, C3, and THBD. Other things that are known to lead to aHUS are deletions in the CFHR genes (CFHR1-5) as well as anti-FH autoantibodies.  When these variants are present they lead your alternative pathway (part of the complement cascade) to be overactive and attack your body’s healthy cells.


That is what we do know. Now to answer your question on what the variant in MTHFR may mean. I can’t say for sure. While I have never heard of mutations in this gene being a cause of aHUS I do know that common polymorphisms (changes in the DNA) in MTHFR can predispose to excessive clotting among other problems. If you are interested in this here is an informative link (including the connection between it and B12 levels):


The gene itself starts the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.  When it does not work this can lead to an increased amount of the chemical homocysteine in the blood, and when there is an excess of homocysteine this increases clotting. aHUS is a rare clotting disease which may be why your doctor ordered genetic testing of MTHFR, especially if testing of the other 6 genes was negative. 


I found one reported case of two sisters each with the same homozygous (two copies of the nonworking gene) mutation in MTHFR. They were diagnosed at first with HUS (not aHUS), then cblC disease.  One of the sisters also had a mutation in CFH and this sister had the more severe case.  Here is a link to the paper:

However, in another study they found that the three common inherited thrombophilia factors (factor V, F5 c.1691G > A; methylenetetrahydrofolate reductase, MTHFR c.677 C > T and prothrombin, F2 c.20210 G > A) were not susceptibility factors for the development of aHUS.


So while it is possible that the mutation found in your case is involved in aHUS at this point to my knowledge not enough is known about it to tell you what to expect.  I also don’t know what the mutation was that was found so I can’t be specific about what it may mean. This is one of frustrating things about genetic testing. We can test for mutations but then when it’s something we’ve never seen before we have to be careful about saying whether or not the mutation is disease causing.  It could just be one of the thousands of non-disease causing changes that we all have in our DNA. This is why further functional studies are typically done.


I hope this is helpful.  However, I am not an MD so there may be something different about your case which is why your doctor ordered this test. If you have any other questions let me know and if I can I will try and answer them.


Thanks to Tara for providing the information on this question.
Thank you all for the information.  Sorry it has taken me so long to respond.  We are in the processing of moving and won't be settled for another 2 weeks.  As soon as we get our things and are settled I will add some more of the information from the test results and see if it helps make more sense.  Thank you all again for the info it is greatly appreciated, every little bit helps understand this awful disease a little better.  Hope all is well.

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Did you know...

CFH (Serum Complement Factor H) is a regulatory protein. The secreted protein product of CFH consists of 20 repetitive units named "short consensus repeats" or SCRs (each approximately 60 amino acids). In patients with aHUS the last 5 "pearls" in the twenty pearl strand protein, SCR16 - SCR20, should bind to protect cells but do not- they are defective in one or more of the last 5 SCR locations. If they cannot bind or stick to the kidney to protect that tissue, the platelets clump into clots that affect the glomeruli of the kidney -potentially causing acute renal failure.
• • • • • • • • • • • •
It is estimated that there are about 2 cases of aHUS in the U.S. per 1,000,000 of population, and about 60% of aHUS patients are diagnosed as children. The condition is potentially life threatening, and either can be chronic or can recur at intervals.
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