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MFN2 -- Charcot Marie Tooth disease

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8
Interested to know if anyone with ME/CFS have any pathogenic SNP's in the MFN2 gene (some cause Charcot Marie Tooth Disease). As some of the symptoms between CMT and CFS overlap, I was curious if, before getting a ME/CFS diagnosis, anyone was checked for CMT.
 
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15,786
Interested to know if anyone with ME/CFS have any pathogenic SNP's in the MFN2 gene (some cause Charcot Marie Tooth Disease). As some of the symptoms between CMT and CFS overlap, I was curious if, before getting a ME/CFS diagnosis, anyone was checked for CMT.
1 of the 39 ME patients I have 23andMe data for has a heterozygous mutation at rs138382758 on MFN2. It is pathogenic when heterozygous, but "only" mild or moderate, and with a relatively late onset.
 
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8
Thanks,

I have the mutation in rs119103264. Have not yet gone down the metabolic disorder diagnosis path yet, and wanted to ask if others had checks.
 
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Sea

Senior Member
Messages
1,286
Location
NSW Australia
Thanks,

I have the mutation in rs119103264. Have not yet gone down the metabolic disorder diagnosis path yet, and wanted to ask if others had checks.
I am heterzygous for this mutation. (Listed in my results as i5008699) Interesting thanks imdcout. A quick look at the symptoms of CMT and I can see several that my grandfather and my father both suffered with. My father's hammer toes and peripheral neuropathy caused him significant difficulties in his later years. My grandfather retired early from the police force because of his 'bad legs'. I remember him shuffling like a frail old man even in his 60's.

Never has CMT been mentioned before as a possibility.
 
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8
Hi Sea,

Similar correlations with my mothers family. Same i5008699 result (via 23andme). I know about all the perils of sharing genetic data, but if others who google this thread would like to know, my anonymous profile is at:

https://my.pgp-hms.org/profile/hu4DB380

At some point, in the next few months or so, full genetic data should be available. Please note, the i5008699 result, is shown in the "insufficiently evaluated" table. Also please note this question, was based on my own curiosity, and not for medical advice. Trying to oblige to the terms of service: http://www.personalgenomes.org/harvard/sign-up#documents whereby I am relying on my doctors for advice about genetic or other results.
 
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15,786
I am heterzygous for this mutation. (Listed in my results as i5008699) Interesting thanks imdcout.
6 of the 31 ME patients I have full 23andMe data and controls for are heterozygous for it. But so are 4 controls. I'm not quite sure what to make of that, since I can't find any prevalence data for it. I'll check the databases I've downloaded in a bit.

That particular SNP is labeled in OMIM as being associated with Hereditary Motor and Sensory Neuropathy, Type VIA. Type 6 is associated with early onset muscle weakness and optic atrophy. It's autosomal dominant on MFN2, so being heterozygous is sufficient to develop the disease. But that also means that typically one parent will also have the disease.

There's not much data about type 6A (abbreviated HMSN6A), really just at http://www.omim.org/clinicalSynopsis/601152 . But it looks like it might be heavier on the neurological involvement than some of the other types.

I'll try to look into our data for the relevant genes a bit later.
 

nandixon

Senior Member
Messages
1,092
6 of the 31 ME patients I have full 23andMe data and controls for are heterozygous for it.
That seems normal, or at least is consistent with openSNP, which shows 20% of submitters being heterozygous for i5008699 (aka rs119103264):

https://opensnp.org/snps/i5008699

That SNP appears to exhibit incomplete penetrance, so only some smaller percentage of individuals who are heterozygous will actually exhibit clinical symptoms/signs of Charcot-Marie-Tooth disease. (Obviously, or some 20% of the population would have the disease. Although I wonder how many might have some "mild" phenotype of the disease that is actually problematic in some way and simply isn't recognized as being CMT.)
 
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15,786
That seems normal, or at least is consistent with openSNP, which shows 20% of submitters being heterozygous for i5008699 (aka rs119103264):
If it's that high, then the OMIM entry providing support for that SNP being associated with symptoms is probably erroneous. Often there are multiple SNPs in moderate linkage disequilibrium (somewhat inherited together), and there will be ill people with the rarest one, and both all of the ill people and a lot of healthy people will have the more common one too. But it's still the rare one causing the disease, and the common one is just a false positive.
 

nandixon

Senior Member
Messages
1,092
@Valentijn
That's definitely a possibility. Could also be an unlucky combination of this SNP with other SNPs (in other genes), or epigenetics or even dietary influence - given the relationship of MFN2 with insulin.
 
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8
Thanks for this feedback! I had been cautioned about self-diagnosing anything based on 23andme data, and was going to wait until the other more complete genetic tests I had done came back to bring this question up to a doctor (and look at full MFN2 variants). I thought it was worth asking about, as my mothers side of the family does have some of the characteristics of CMT (degenerative disc disease, uncle had MS (could have been CMT though - no MRI or genetic tests back then) and lots of peripheral neuropathy.
 

stetson28

If it aint broke don't fix it...but.
Messages
49
Location
Richmond Virginia
I also share the Hetero SNP for rs119103264 on MFN2. I have a grandmother with Significant health impacts from CMT. Did we ever have anymore information dredge on the topic?
 

Paralee

Senior Member
Messages
571
Location
USA
Don't know, I have no idea what to do with the "I"'s to look them up. I found a list once, can't find it again.
 
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Paralee

Senior Member
Messages
571
Location
USA
If it's that high, then the OMIM entry providing support for that SNP being associated with symptoms is probably erroneous. Often there are multiple SNPs in moderate linkage disequilibrium (somewhat inherited together), and there will be ill people with the rarest one, and both all of the ill people and a lot of healthy people will have the more common one too. But it's still the rare one causing the disease, and the common one is just a false positive.
When I put in the i5008699 I get a different rs #....and my head is foggy today.
 

stetson28

If it aint broke don't fix it...but.
Messages
49
Location
Richmond Virginia
My cynical mind doesn't accept that some of these muscular dystrophy snps are accidentally being removed off the new Chips or proven to serve no purpose. I joined a charcot-marie tooth Forum based in the UK and it seems they have quite a lot of legal difficulties maintaining their medical disability subsidies even with the appropriate medical diagnosis. It's an interesting read to look closer at the mfn2, there is quite a bit more to it than just hammer toes. Mito 2 infusion ATP mitochondrial linkage failures.