Mitochondrial disease confirmed!

pattismith

Senior Member
Messages
2,122
Likes
3,848
Here I am! I got the 23andme data from my mother, and guess what:

She carries exactely the same four missense mutations on her mitochondrial DNA as me, which means that:

-my mutations are hereditary acquiered
-they are probably existing in each of my cells

These mutations are not known, which means that they probably don't ever cause early/severe clinical outcome,

but each of them are stucked to 4 well known pathogenic mutations, so there is a strong probability that they cause the health problems in my mother line.

It was a precious day yesterday when I received this result, because it's so important to us to understand why we do struggle so much, and when finally you get the answer, it is a real weight you lift from your chest.

I wish many other PR members will find some answers here like I found mine.

I especially thank @BeautifulDay and @Learner1 who put me on the right tracks, you probably saved my life.

Thank you to PR and to all the members.

If someone needs help to find his mito DNA mutations in his 23andme datas, I can help and give back a bit of what I was offered here.:hug:


upload_2018-2-12_13-37-10.png
 

Attachments

Last edited:

pattismith

Senior Member
Messages
2,122
Likes
3,848
Hi @pattismith,

Congrats, I hope the results prove to be helpful for better understanding & treatment in the future.

I have 23andme results and would be interested in learning more if you are able to give an overview of where to look?

Thanks,
Ryan
I have to go now, but I'll help you later.

The 23andme current plateform gives a lot of informations on mito DNA, it is just a matter of finding it.

The thing is that they told me they changed the plateform some years ago (4-5 years I think), and I don't know if the previous one gives as much. It is worth give a try:thumbsup:
 

tyson oberle

Senior Member
Messages
134
Likes
104
Location
tampa, florida
It was a precious day yesterday when I received this result, because it's so important to us to understand why we do struggle so much, and when finally you get the answer, it is a real weight you lift from your chest.

I wish many other PR members will find some answers here like I found mine.
Like everyone else here on PR, I too would like to know the "answers" for a treatment. But how do you know if any of these results will help any? I hope the mito DNA panel would help for all our sakes.
 

andyguitar

Senior Member
Messages
1,160
Likes
2,770
Location
South east England
Well done @pattismith for finding out something that will move the debate forward a bit. What makes a person susceptible to ME or CFS is, to my mind, one of the key questions. Sure we can all speculate as to what might be the cause of being ill. But as most people dont get it finding the difference between the ill and healthy is what may well lead to a cure and a way of preventing people getting it. At the moment I am looking into the possibility that a prexisting auto immune disorder allows the illness to get a hold. Using books for this and its going to take a while.
 

wdb

Senior Member
Messages
1,390
Likes
2,970
Location
London
Hi, just curious, how strongly linked are those four DNA locations to mitochondrial disease, what is the mutation prevalence compared to healthy populations, are you able to link to any supporting research where I can learn more?
 
Last edited:

pattismith

Senior Member
Messages
2,122
Likes
3,848
Hi, just curious, how strongly linked are those four DNA locations to mitochondrial disease, what is the mutation prevalence compared to healthy populations, are you able to link to any supporting research where I can learn more?
as you can see in the picture I put in my head post, the allele frequency of my four missense mutations is 0
So it means that they have not be observed before.

So we can't say if other people, healthy or not, carry it.

What you must keep in mind is that

-mito DNA mutations that cause adult onset and mild disease are largely overlooked. Only the ones with early onset and severe diseases have been studyed well.

The reasons are easy to understand, because mito specialists are few and research in this area is not as developped as it could be, so the focus is done on youngsters, because they are the ones that need more medical help.

-in families with adult-onset-mito-diseases and mild clinical outcome, symptoms can vary from one member of the family to another, even when they carry the same mutation, because the expression of the mutation can be modulated by other genes. Some can have fibromyalgia, CFS or Autism, or just intolerance to exercise or migraine for example, or cramps.

It would be long to explain why these missence mutations I have are likely pathogenic, but valentijn has already well explained it here, if you want to go deeper:

http://forums.phoenixrising.me/inde...hondria-related-genes-lost.54061/#post-899502

@andyguitar ,

I guess Mito mutations are just one subgroup in the ME/CFS syndrome (maybe 5% of ME/CFS patients, I found the same 5% mito disease subgroup in autism and in fibromyalgia).
I'm sure the immune group is the main one whereas auto-immunity would be another small subgroup, and thyroid hormons dysfunction could be another one, (and maybe primary channelopathies?)...
 

Wishful

Senior Member
Messages
1,688
Likes
2,710
One thing to keep in mind: cerebral mitochondria are genetically different from the mitochondria in the rest of the body. If ME is due to problems with cerebral mitochondria, defects measured in tissue mito DNA might not be involved. They could, but it's not a sure thing.
 

pattismith

Senior Member
Messages
2,122
Likes
3,848
One thing to keep in mind: cerebral mitochondria are genetically different from the mitochondria in the rest of the body. If ME is due to problems with cerebral mitochondria, defects measured in tissue mito DNA might not be involved. They could, but it's not a sure thing.
would you give me a source for this statement?

In fact mito DNA can differ from a tissu to another only in case of heteroplasmy,

Heteroplasmy vs. Homoplasmy
  • A cell can have some mitochondria that have a mutation in the mtDNA and some that do not. This is termed heteroplasmy. The proportion of mutant mtDNA molecules determines both the penetrance and severity of expression of some diseases.

  • Homoplasmy refers to a cell that has a uniform collection of mtDNA: either completely normal mtDNA or completely mutant mtDNA.

  • A unique feature of mtDNA is that, at cell division, the mtDNA replicates and sorts randomly among mitochondria. In turn, the mitochondria sort randomly among daughter cells. Therefore, in cells where heteroplasmy is present, each daughter cell may receive different proportions of mitochondria carrying normal and mutant mtDNA.
In my case, the fact that both my mother and I have exactely the same mito DNA in saliva means that they are probably homoplasmic mutations. The chance to find the same four in both saliva would have been very small in case of tissue heteroplasmy
 
Last edited by a moderator:

pattismith

Senior Member
Messages
2,122
Likes
3,848
@ryan31337
@Thinktank



The only easy way I know is to buy your personnal genome file on the ENLIS site (40 dollars),
and Enlis software will find the relevant rare mutations when you will run your datas on your computer.
You have to download the ENLIS software at the same time.

When you have these mutations, you note the name of the gene (in my case three of my mutations are in the MT-ND1 gene) and the position (my three mutations are in positions 3377, 3734, 3947), then you go in your 23andme acount and browse your datas: you put the name of this gene in the window, and you will see a blue rs number in the list, just in front of each position number.
You will look for the given position and click on the corresponding rs.

When you click on this rs number, a window will open in the NCBI site,
where you will be able to see one or the other possibilities:

-If the rs is known, you will see on the report if it is a pathogenic one (it will be written in red)
-If the rs is not known, it can open the page of a close known pathogenic rs, so you have to control if the rs number on the page is the same as the one you clicked on.

I will be able to guide you through the procedure

https://www.enlis.com/personal_edition.html

;
 
Last edited:

ryan31337

Senior Member
Messages
568
Likes
1,311
Location
South East, England
Thanks for that @pattismith. I'm seeing a neurologist that heads a muscle disease clinic next week, I'll ask her what she thinks too.

I imagine this is one of the things Nancy Climas' big data study is aiming to uncover - might be worth shooting her an email to see if she has any knowledge of your mutations?

Ryan
 

pattismith

Senior Member
Messages
2,122
Likes
3,848
Thanks for that @pattismith. I'm seeing a neurologist that heads a muscle disease clinic next week, I'll ask her what she thinks too.

I imagine this is one of the things Nancy Climas' big data study is aiming to uncover - might be worth shooting her an email to see if she has any knowledge of your mutations?

Ryan
Once you have identifyed likely pathogen mutations in your mito DNA that could match with clinical outcome in your mother line, I would think visiting a top Mito Disease able to identify new pathogenic mutations would be the best way to go.
A muscle clinic disease is probably one of the best place, I am sure they will do the apropriate tests and that they have top mito D concelling.

I will wait for Nancy Klimas study for sure! I am glad that she is looking into mito DNA susceptibilities.:thumbsup:
 

BeautifulDay

Senior Member
Messages
362
Likes
1,072
@pattismith . I looked up your mutations on the MSeqDR database. None of them were there - - but that doesn't mean much as new rare mutations are added all the time. What I did find was that all three mutations are in areas that are hotspots for other pathogenic mutations. That increases the likelihood (that if 23andme called it correctly), that this one might be pathogenic.

For example, your M:3377 mutation is right next to the pathogenic mutation M:3376G>A.
https://mseqdr.org/mb.php?url=index.php
The NIH Cluster Report on that next door mutation is interesting. If you go halfway down the page, you'll see 4 pathogenic mutations near each other in purple. If you hover over the top of the purple, it will tell you what rs# and if pathogenic.
https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs397515612

Your M:3947 is next to pathogenic mutation M:3946G>A.
https://mseqdr.org/mb.php?url=index.php
The NIH Cluster Report is again very interesting. Again, this is a hot spot for pathogenic mutations near your mutation.
https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs199476123

It's always good to use a note of caution when relying on any raw data. Errors do occur. Following up with a Mitochondrial Specialist is a great way of verifying the accuracy.
 

pattismith

Senior Member
Messages
2,122
Likes
3,848
Yes, and the two other mutations are next to known pathogenic mutations as well :thumbsup:

but none of my mutations have any rs number for now, they are totally unknown.
Is Enlis worth paying $39.95 for?
if you suspect health problems that could match to mitochondrial disease in your mother line, I think it's worth the price.
CFS, fibromyalgia, autism, exercice intolerance, cramps, migraine are among the possible clinical outcome of some mito disease, and mito mutations are rarely investigated by doctors in these problems, so there is little chance that any doc will look for new mutations coding for these diseases.

Promethease is cheaper but will not show you these new mutations, Enlis will do it.

@pattismith . I looked up your mutations on the MSeqDR database. None of them were there - - but that doesn't mean much as new rare mutations are added all the time. What I did find was that all three mutations are in areas that are hotspots for other pathogenic mutations. That increases the likelihood (that if 23andme called it correctly), that this one might be pathogenic.

For example, your M:3377 mutation is right next to the pathogenic mutation M:3376G>A.
https://mseqdr.org/mb.php?url=index.php
The NIH Cluster Report on that next door mutation is interesting. If you go halfway down the page, you'll see 4 pathogenic mutations near each other in purple. If you hover over the top of the purple, it will tell you what rs# and if pathogenic.
https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs397515612

Your M:3947 is next to pathogenic mutation M:3946G>A.
https://mseqdr.org/mb.php?url=index.php
The NIH Cluster Report is again very interesting. Again, this is a hot spot for pathogenic mutations near your mutation.
https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs199476123

It's always good to use a note of caution when relying on any raw data. Errors do occur. Following up with a Mitochondrial Specialist is a great way of verifying the accuracy.
yes, I wish I could see a mito specialist :thumbsup:
 

BeautifulDay

Senior Member
Messages
362
Likes
1,072
While it may not yet have an rs#, it is being discussed. For example, here is A3377G from my Mitomaster SNV query. It confirms that it's rare (less than 0.00% frequency) and it is also a highly conserved position among animals (97.78%). Often when there is high conservation among animals, this can mean (but not always) that a mutation in this position is so devastating that the animal does not survive or is not in a condition to pass it on.
https://www.mitomap.org/mitomaster/view_details.cgi?refp=snvs&query_id=1195050&run_id=1123641

A3947G is also less than 0.00% frequency and even more highly conserved among animals (100%).
https://www.mitomap.org/mitomaster/view_details.cgi?refp=snvs&query_id=1195051&run_id=1123642

The fact that mito specialists are looking at and studying these mutations is a positive.
 

pattismith

Senior Member
Messages
2,122
Likes
3,848
That's amazing, I wonder if I am a zebra :lol:

The other think I wonder is if these three rare mutations on ND1 gene could compensate for one another in a way?:thumbdown:

Would you explain to me how to browse my mito mutation in the mitomap query, I was not able to do it myself :)

While it may not yet have an rs#, it is being discussed. For example, here is A3377G from my Mitomaster SNV query. It confirms that it's rare (less than 0.00% frequency) and it is also a highly conserved position among animals (97.78%). Often when there is high conservation among animals, this can mean (but not always) that a mutation in this position is so devastating that the animal does not survive or is not in a condition to pass it on.
https://www.mitomap.org/mitomaster/view_details.cgi?refp=snvs&query_id=1195050&run_id=1123641

A3947G is also less than 0.00% frequency and even more highly conserved among animals (100%).
https://www.mitomap.org/mitomaster/view_details.cgi?refp=snvs&query_id=1195051&run_id=1123642

The fact that mito specialists are looking at and studying these mutations is a positive.