Mitochondrial disease confirmed!

[wigglethemouse]

Strangely my raw datas stop after genomic position "73736167"

Maybe your text viewer can only read an 8MB file. You could try Notepad++?

 

[wigglethemouse]

@pattismith

Another way to search the raw data file contents is to use the windows command line. e.g.

C:\Temp>findstr /i "rs1504401" 23andMe.txt

---------- 23ANDME.TXT
rs1504401 9 73916953 CT
rs150440189 15 100805075 AA

 

[pattismith]

@pattismith

Another way to search the raw data file contents is to use the windows command line. e.g.

C:\Temp>findstr /i "rs1504401" 23andMe.txt

---------- 23ANDME.TXT
rs1504401 9 73916953 CT
rs150440189 15 100805075 AA

that's great! thank you for sharing!

 

[BeautifulDay]

I have trouble following LiveWello's information because the allele frequency is missing. I then spend unnecessary time inputting the allele frequencies into my spreadsheets. The frequencies are very important and should always be looked at for any questionable variation. It would also be helpful if LiveWello would site why they believe a variant might be deleterious with links to the studies.

In this study, there were specific variations on the TRPM3 gene that were significantly associated with CFS.

"Results
Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P≤ 0.016, rs655207; P ≤ 0.018).

Conclusion
The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS."
http://journals.sagepub.com/doi/abs/10.4137/III.S25147

 

[tornerose]

Hi!

I have read this thread with interest as I recently found I have the same four mutations as @pattismith and @wigglethemouse:

MT-ND1: 3377 A>G, 3734 A>G, 3947 A>G
MT-CYB: 15198 C>T

(In addition to these, I have a known mutation; MT-ND4 11253 T>C)

I got tested with the 23andMe version 5 chip, just before this summer.

Have any of you (@pattismith @wigglethemouse ) had the mutations confirmed (or not) through further testing, or found other evidence of the mutations being real/false?

I emailed 23andMe three times asking if these mutations appear often in data from the v5 chip (considering they are unknown). Didn’t get a meaningful answer, just that I should see a doctor if I’m concerned, bla bla bla... I did also send my data to a geneticist who concluded that the mutations (in ND1) could be pathogenic and advised me to have a new test to see if the mutations can be confirmed.

 

[wigglethemouse]

MT-ND1: 3377 A>G, 3734 A>G, 3947 A>G
MT-CYB: 15198 C>T

I think these are bogus. I posted this earlier in this thread

I found the Personal Genome Project website that has v5 data files
https://my.pgp-hms.org/public_genetic_data?data_type=23andMe

I browsed the first 3 files and they are all the same as us
MT-ND1 : 3,377 = G, 3,734 = G, 3,947 = G
MT-CYB : 15,198 = T

Sorry to disappoint but it looks like those locations are perfectly normal for v5 23andme data .

Seems like the v5 chip appeared last summer.

You should focus on the MT-ND4 11253 T>C one (in your file it shows as allele frequency of 0.63% which is much more believable than 0.00%.) which seems to be recognised as a Leber's optic atrophy.
https://www.ncbi.nlm.nih.gov/pubmed/12271374

MT-ND4 causes mitochondrial complex I deficiency
https://ghr.nlm.nih.gov/gene/MT-ND4#conditions

More Info
https://www.omim.org/entry/516003

I have a mutation at MT-ND5. I really need to confirm with WES to see if it is real but when I asked around I was told that
(1) Many companies have errors in the WES raw data
(2) Many companies interpret their raw data wrong
(3) Interpretation of WES data is extremely complex
(4) The best companies charge around >$2,000 for WES

 

[tornerose]

I think these are bogus. I posted this earlier in this thread


You should focus on the MT-ND4 11253 T>C one (in your file it shows as allele frequency of 0.63% which is much more believable than 0.00%.) which seems to be recognised as a Leber's optic atrophy.
https://www.ncbi.nlm.nih.gov/pubmed/12271374

MT-ND4 causes mitochondrial complex I deficiency
https://ghr.nlm.nih.gov/gene/MT-ND4#conditions

More Info
https://www.omim.org/entry/516003

I have a mutation at MT-ND5. I really need to confirm with WES to see if it is real but when I asked around I was told that
(1) Many companies have errors in the WES raw data
(2) Many companies interpret their raw data wrong
(3) Interpretation of WES data is extremely complex
(4) The best companies charge around >$2,000 for WES

Thanks, @wigglethemouse

Really helpful to know that the reported mutations we have in common are false. Do you think that is due to faults with the genotyping, or that these variants are in fact common in the population (despite appearing to be unknown)?

Ive looked up my ND4 mutation and glanced through articles. Even though it is listed as pathogenic, there doesn’t seem to be evidence in the literature to support that conclusion at this point.

Anyway, it looks like it will be challenging getting mt mutations discovered/confirmed, if WES is so pricey and also uncertain. I read that tissue biopsies are recommended for mtDNA analysis, because many variants can’t be detected in blood/saliva. It complicates things even more. Do you happen to know what variants that could apply to?

PS: My knowledge on genes is very limited, so sorry if I’m asking dumb questions and not using the terminology correctly

 

[Learner1]

Fran Kendall suggested the GeneDX trst for both Exome and mtDNA. I had a Seattle doctor draw it. It looks like insurance may pay for it. The extensive forms asked for all.my weird diagnoses to make a case for approval.

 

[wigglethemouse]

Really helpful to know that the reported mutations we have in common are false. Do you think that is due to faults with the genotyping, or that these variants are in fact common in the population (despite appearing to be unknown)?

I'm sorry, I have no idea why.

Ive looked up my ND4 mutation and glanced through articles. Even though it is listed as pathogenic, there doesn’t seem to be evidence in the literature to support that conclusion at this point.

There are a couple of papers that highlight that the 11253 mutation as linked to LHON so there is evidence it may be pathogenic. I linked to one such paper above.

Anyway, it looks like it will be challenging getting mt mutations discovered/confirmed, if WES is so pricey and also uncertain.

You can get cheaper WES and WGS. A few folks on here are trying Dante Labs and it seems they will offer a small customized report if you request when ordering. But they can use any number of different labs and equipment.......

There are several WES/WGS threads here on PR such as this one and there are folks on here that are way more knowledgeable than I am but at the end of the day I'm not sure what we do with the findings unless you can find a geneticist to work with and they seem pretty rare. Just because you have a mutation it doesn't necessarily mean the protein it relates to is impaired and that it is causing your illness. Proving that is much more difficult that a genetic test.

However a genetic test is a starting point, for example MT-ND4 => causes mitochondrial complex I deficiency => affects COQ10 levels => which in this case may suggest supplementing with Ubiquinol/COQ10 may be worth a try (implied from https://en.wikipedia.org/wiki/MT-ND4).

 

[frozenborderline]

I have trouble following LiveWello's information because the allele frequency is missing. I then spend unnecessary time inputting the allele frequencies into my spreadsheets. The frequencies are very important and should always be looked at for any questionable variation. It would also be helpful if LiveWello would site why they believe a variant might be deleterious with links to the studies.

In this study, there were specific variations on the TRPM3 gene that were significantly associated with CFS.

"Results
Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P≤ 0.016, rs655207; P ≤ 0.018).

Conclusion
The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS."
http://journals.sagepub.com/doi/abs/10.4137/III.S25147

Interesting. This makes me wonder if the association btwn these ion channels has to do with why some people with cfs symptoms respond well to gabapentinoids.

also makes me wonder if this ion channel issue could be related to the theory @Iritu1021 and @pattismith talk about re: intracellular calcium

 

[Jenny TipsforME]

I have my WGS and 23andme data (I realised what I wanted to know wasn’t included in 23andme). It seems really d’oh but I hadn’t thought to add my 23andme data into Enlis before this thread. I’m waiting for the analysis now. It will be interesting to see if there are any differences between both versions of ‘me’!

I also have (supposedly) unique mitochondrial variants which are relevant to my symptoms. This has got me referred to a national specialist, so probably worth it even they turn out to be more of an admin error than a genetic error.

So the position is moved over here by one.

I do feel like there’s something up with the reporting of my variants. I gave up looking for a few months because I was confused by these potential errors. Is there any list of mitochondrial variants which have the position moved one over? Eg yesterday I was looking at the list from the Billing-Ross 2016 paper and noticed I had 3 one over from ones mentioned in that. In a sec I’ll find the table and diagram.

Does anyone have MT-ATP6 or ATP8 variants? They can lead to Atypical Periodic Paralysis (episodes of weakness). Though having read up on this specific cause, I think any cause of reduced ATP could lead to same issue.

If it’s called right, I have 3 novel variants on MT-CYB. That gene can be associated with sporadic mitochondrial myopathy which is a good fit for my symptoms (exercise intolerance changeable weakness)

 

[Jenny TipsforME]

This is from the Billing-Ross paper https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0771-6



So more people (within people who have ME) have variants at the positions further from the centre.

ND1, CYB, CO1, ATP6 and ND4 stand out

This table is Association analysis of mtDNA SNPs within ME/CFS status.
https://static-content.springer.com/esm/art:10.1186/s12967-016-0771-6/MediaObjects/12967_2016_771_MOESM5_ESM.docx

 

[Jenny TipsforME]

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

I don’t think it does mean this. If they were 0% it would mean no one else with this version had been found yet. It could be genuinely rare. I don’t think it indicates anything about severity.

Though generally if a variant is called in 23andme it means it isn’t super rare. They tend to include the more common ones (SNPs).

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

I’m not sure about this conclusion either. The heteroplasmy probably isn’t really low but I don’t think you can know heteroplasmy info from 23andme

I think it can also be different in different types of tissue (so if everyone tested saliva it wouldn’t show up differences in muscles).

I’m not a genetic expert though, I’ve just done a couple of online courses.

 

[Jenny TipsforME]

Oh I realise why I didn’t add my 23andme data to Enlis as well - you pay $40 per upload

I’ll have a think about that!

 

[stetson28]

Does the inheritance pattern on mitochondria only require one copy (hetrozygous) to be symptomatic specifically in the example of mitochondrial inheritance from mother to son?

For the lebers optic atrophy it is stated as modes for inheritance to be heterogeneous and mitochondrial.

Also for the aid of others it is worth looking at your data for mutations on the mfn2 gene. My neighbor is 3rd Generation CFS that has been linked down to charcot-marie-tooth. Now before you go and hit Wikipedia and Rule it out because of its definitions of muscle wasting and hammer toes, you should consider to read further into it and understand that some types of cmt are mitochondria in nature specifically called mito 2 infusion deficiencies that disallow the mitochondria to connect to one another.
Snp rs119103264

 

[wastwater]

I see the UK 100,000 genomes project has been completed but they said they are planning to do many more does anyone have details on this

 

[nandixon]

(In addition to these, I have a known mutation; MT-ND4 11253 T>C)

Did you have any follow-up testing done for that one?

I'm showing up in the whole genome sequencing (WGS) results I recently received as having the variant in the neighboring SNP:

MT-ND4 11252 A>G rs879229170
(note that position 11253 is rs200145866)

Both these SNPs are pathogenic missense variants. Yours has the supporting reference that @wigglethemouse cited as well as this second reference which mine also has:
https://iovs.arvojournals.org/article.aspx?articleid=2417293

The symptoms and severity these SNPs might cause is going to depend on their degree of heteroplasmy and which tissues are affected, and what other problems might be present. Because mitochondrial mutations can have such a variable presentation it's probably better to think in terms of these mutations causing a general complex I deficiency rather than their particular cited association with Leber's hereditary optic neuropathy (LHON).

The question is whether these are false positives. (Interestingly, with respect to low frequency mitochondrial DNA variants there is actually a greater risk of false negatives than false positives.)

I have a mutation at MT-ND5

What position is your ND5 mutation at?

I also showed up as having:
MT-ND5 12706 T>C rs267606893

(This is also a missense mutation with supporting evidence for pathogenicity.)

And again the question is whether these ND5 results are false positives.

 

[frozenborderline]

Have a couple questions. Has knowing this helped you with a treatment plan yet? Are there Mito specialists or geneticists that may test for mito mitations as a differential diagnosis with cfs and have it Be covered by insurance?

I had thought that 23qnsme had a high rate of false positives at least w their most commonly looked at snps like the ones involving breast cancer but this post has made me rethink the possible value. Still not sure if I want to drop the $$ on it. If there is mild late onset mito disease does jt rrslly affect treatment much? I’m guessing that if it’s mild it means theres jot an inborn total blockage in a key metabolic pathway, so things that could work in standar me/cfs interventions should not Be different here.

 

[Learner1]

Have a couple questions. Has knowing this helped you with a treatment plan yet?

There are no drugs for primary mitochondrial diseases. A couple are in the works but they are for very specific problems.

Are there Mito specialists or geneticists that may test for mito mitations as a differential diagnosis with cfs and have it Be covered by insurance?

I had a telemedicine appointment with Fran Kendall, she had a letter I sent my insurance who approved my seeing her in-network vs out of network (I have a huge put of network deductible). I sent her a bunch of my labs and a detailed health history.

She sent back a report that contained suggestions for future testimg and asked that I get a GeneDX WES and mtDNA test done. She also gave a generic nutrient protocol for mito patients, however, I am already on everything at higher doses!! (Not sure if it's because she usually deals with children, or that we've customized my protocol to the needs my lans have shown...)

My insurance covered all the testing. I had to appeal the GeneDX who's list price is $17.000.
Their report said nothing, however, running the results through Enlis showed I have several mutations that Alan Light found in patients with the Cell Trend antibodies, most of them in 0% of the population, AMPD1 SNPs which a few people around here serm to have and which could explain why my legs go dead at times, and a few other interesting things.

As Kendall was out of state, she wouldn't order the tests herself, but a local neurologist did, who used to work with mito specialist Russ Saneto here in Seattle. She did a muscle biopsy, and SFN biopsy, and ran Kendall's tests, and has given a few suggestions on tweaking my protocol.

She also told me this week that Richard Boles, who I had a one on one with at the mito conference I went to 3 years ago, and who'd given me Kendall's name as he only did children now has a new gig, CNNH, for around $1,000 he'll go through your genetics and hone in on what you could do about it, which must be ordered through your doctor:

http://molecularmitomd.com/

She wasnt sure it would get me much further, though, given all the work I've done and the comprehensive protocol I'm on Th st has dramatically helped my function.

I had thought that 23qnsme had a high rate of false positives at least w their most commonly looked at snps like the ones involving breast cancer but this post has made me rethink the possible value. Still not sure if I want to drop the $$ on it.

Your genes will be mapped to behave in certain ways. Some have a strong impact that you can't get around, but many others are triggeted or suppressed by environmental factors, or work with or against other genes (ex: I have one that makes me prone to clots, but another that makes me prone to bleeding, which seem to Japan e each other out).

I've heard the current 23andme chip is more brain dead than the one I did a fee years ago. I will say that when I ran both my 23andme and GeneDX raw data through Enlis, they matched up pretty well

GeneDX definitely had a more robust set of data, but there were a few cases where 23andme had more data, and they pretty much agreed with one another.

If I hadn't had the GeneDX done and my insurance wouldn't pay, is look into Dante Labs. I think it runs $3-400, csn be ordered by consumers , but can take up to 8 months for results.

If there is mild late onset mito disease does jt rrslly affect treatment much? I’m guessing that if it’s mild it means theres jot an inborn total blockage in a key metabolic pathway, so things that could work in standar me/cfs interventions should not Be different here.

In March, I went to the FDA meeting with adults with mitochondrial myopathies, where they asked us all what our symptoms were, how they affected our lives, and what we were doing for treatments. it was interesting. While I my symptoms fit with what was reported by others, especially the milder patients, there were definitely patients far worse and it as clear tgat their genetic causes were very permanent and would likely become fatal at some point - many had lost family members.

The question I've been trying to answer is whether i have primary mirochindrial disease or secondary mito dysfunction. At this point, given all the testing I've done, I think I'm thankful I don't have a horrible mito SNP giving me a well known difficult mito disease. Kendall's testing came out pretty clean, so i dont think I'm missing some important enzyme...

But, I found I do have a smattering of mtDNA mutations on genes that are known in mito diseases and tge ones Alan Light identified. My doctors and I surmise that these made me a little more susceptible when I was put on a fluoroquinolone for 4 months and then mitochondrial damaging chemo drugs, which weakened my immune system, and allowed all the infections I had to take over.

Doing the MitoSwab mito function test and a nitric oxide and nitrotyrosine test correlated well with what my Genova Diagnostics NutrEval was saying, and correlated with some of the SNPs my gene testing showed and has allowed us to put together a protocol that has tremendously helped me.

We've focused on repairing damage to mitomembranrs from the oxidative and nitrosative stress, on reducing these damaging stresses by fine tuning my antioxidant intake and methylation, and watching markers like carnitine, succinic acid, manganese, nitrotyrosine, vitamin C, glutathione, asparagine, isoleucine, and leucine.

The patients I talked to at the FDA meeting were in agreement that treatment needs to be personalized for each one of us. There is no magic bullet, and even the same mito gene can be expressed to diffetent degrees yielding completely different mito diseases.

 

[wigglethemouse]

What position is your ND5 mutation at?

@nandixon I had the following MT-ND5 mutations in my 23andMe data which seemed to be real.
12,501 G>A
13,780 A>G
https://forums.phoenixrising.me/threads/mitochondrial-disease-confirmed.57697/post-959044

This is what @BeautifulDay had to say about 12,501

Hi @wigglethemouse


It looks like you pop up for a mutation that @pattismith doesn't. The 12501 mutation on the MT-ND5 gene is associated with post-traumatic stress disorder (PTSD). My understanding from the mitochondrial conferences is that those of us with low mito energy issues have an increased risk of things like PTSD and anxiety because the brain sections that deal with emotions and post-traumatic stress need a lot of energy, and when it's low the brain is not getting the energy it needs to deal with anxiety and PTSD.


The MT-ND5 gene is very important in the production of mitochondrial energy. If there is an issue in the gene that's impacting energy in the brain, then it's going to be having an energy issue elsewhere in the body too. The MT-ND5 is important for the mitochondria in every cell in the body. It's just that this study was studying PTSD (not the whole body).

I'm not sure what the full study says or the position it takes, but here it is for your leisurely reading.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354348/

So, the 12,501 mutation does seem to be related to possible energy reduction in some folks. I haven't done a follow up WES/WGS + mtDNA