• Phoenix Rising needs funds to operate: please consider donating to support PR

Mitochondrial disease confirmed!

nandixon

Senior Member
Messages
1,092
Likes
3,133
Novel missense/nonsense SNPs on MT-ND4 on GeneDX, not 23andme:32624
@Learner1, Because the significance of those 4 possible SNPs appears to be unknown, I looked at several of the neighboring SNPs both upstream and downstream from each of them using NCBI's dbSNP to see what sort of pathogenicity those other SNPs might have to try to get an idea of the importance of their locations.

The only fairly close position on MT-ND4 that dbSNP seemed to have a reference for is 11719, next to your 11720. 11719 is actually a marker for maternal haplogroup HV, and although it's just a synonymous SNP there's a large study with very good stats that replicated showing a possible connection with ulcerative colitis (in males):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048482/

So if that 11720 is a true result for you then that one might be having an impact on Complex 1, and since it's a missense variation could potentially not only affect the transcription of MT-ND4, like 11719 may be, but might also affect the quality of the resulting protein/enzyme.
 
Last edited:

nandixon

Senior Member
Messages
1,092
Likes
3,133
I'm not sure if this provides any clarity. Possibly just confirms what you ( @Learner1 & @nandixon ) are interpreting in your earlier tests. My 23andMe was run about 18 months ago and lists both rs2854122 and rs267606893.

View attachment 32621

When I try to search dbSNP for rs2854122 it indicates that they have been merged.

View attachment 32622

Not sure why they are still listed in 23andMe as having different genomic positions and different genotypes for me.
Well, it took me a while to figure this mess out (I think). The reason why @Learner1 and I have the pathogenic C variant called at position 12706 in our VCF files from GeneDX and Veritas, respectively, is that both of those companies are using a very outdated reference system for the mitochondrial genome known as Yoruba.

Yoruba was previously used for the mitogenome in human reference genome GRCh36 and in hg19 (Veritas uses hg19). Since then, it was replaced with the Cambridge mitogenome system in both GRCh37 and the currently used GRCh38. (So far as I can tell, hg19 is a sort of hybrid of GRCh36 and 37 in some respects.)

23andMe switched from Yoruba to Cambridge in 2012.

Bottomline is that people with VCF files that use the old hg19 (which may include Dante Labs as well?) will need to check their mitochondrial positions and convert them as necessary from Yoruba to Cambridge. Many of the positions have the same numbering but some change by 1 or 2. SNPedia has a conversion chart here:
https://www.snpedia.com/index.php/MtDNA_Position_Conversions

So for @Learner1 and myself, 12706 is actually 12705 and our calls are normal there.

(23andMe correctly reports the positions now.)
 
Messages
557
Likes
1,461
How do you covert 23andme "I" numbers to "RS" numbers?
One way is to use the Kaviar database
http://db.systemsbiology.net/kaviar/cgi-pub/Kaviar.pl

Select Human Reference Version hg19, enter the Chromosome and Coordinate given in the 23andMe raw data file for the "i" number, and press submit query.

Also, make sure you download a recent version of your 23andMe file as they update your data now and again to correct errors and enter rsIDs when they have them.

Have you tried the app in this thread to parse your data?
https://forums.phoenixrising.me/thr...e-rare-variants-drug-response-etc-free.76245/
 

stetson28

If it aint broke don't fix it...but.
Messages
49
Likes
32
Location
Richmond Virginia
Thank you wigglethemouse, I'll give those a go. I currently use Enlis but cant be certain if all the I numbers are imputed. I also find much descrepency in the allele frequency percentages, often stating 0% when 5 of the 7 people I have genetic data for have it whom I am not related to. Many of the mutations also appear to be "novel"
 
Messages
557
Likes
1,461
I'll give those a go. I currently use Enlis but cant be certain if all the I numbers are imputed. I also find much descrepency in the allele frequency percentages, often stating 0% when 5 of the 7 people I have genetic data for have it whom I am not related to. Many of the mutations also appear to be "novel"
23andMe is full of errors. I have a bunch of 0% / "novel" mutations in my 23andMe too. Downloading the latest raw data file cleaned up some and @kday 's tool removed others that are known 23andMe errors. @kday answers questions about his tool on the thread I linked above.
 

stetson28

If it aint broke don't fix it...but.
Messages
49
Likes
32
Location
Richmond Virginia
Agreed.

Ultimately unless you have an absolutely known pattern I think it's nearly impossible to determine mitochondrial dysfunction based on mutations. I've read too many reports about centurions having actually the most diverse hetroplasmic mitochondria of anyone. so to me there's a clear mechanism of adaptability at play. And there is a significant range of variability of energy output based on tissue sample type.
Looks like many of the mitochondrial mutations appear to be catastrophic when combined with a nuclear defect.
 
Messages
11
Likes
12
So even though you get mitochondria only from your mother and your father's mitochondria is killed off intentionally during fertilization does that mean we still get two copies from my mother. I don't see the terms homozygous and heterozygous used for mitochondria, are they autosomal dominant meaning one copy mutated means affected output?
 

nandixon

Senior Member
Messages
1,092
Likes
3,133
Thank you so then in a matter of speaking one mutation is comprable to being homozygous?
Yes, in a manner of speaking. Since only one normal or variant SNP will have been inherited at each mitochondrial position (because each person only inherits mitochondrial DNA from their mother, with rare exception) that one SNP can be thought of as the nuclear DNA equivalent of being either homozygous for the normal SNP or homozygous for the variant.

(There's also the mitochondrial issue of heteroplasmy to contend with as well but that's another matter.)
 

pattismith

Senior Member
Messages
2,510
Likes
4,703
@pattismith, two years later, what are your successes in treating mitochondrial disease? Did you find a cure?
Hello @yurybx ,

as explained later in the thread, I had not any mitochondrial disease. It was an error in the 23andme ship.

Two years later, I finally got the answers on my 30 years old ME/CFS/FIBRO disease: Small Fiber Neuropathy (possibly auto-immune, but not sure) with sensory and autonomic involvement (but not OI nor POTS).

I also have delayed muscle relaxation to muscle percussion, but I'm not sure of the significance. (nothing shows up in the EMG/nerve velocity/blood as usual)

I'm still looking for a neuro able to make a definitive diagnostic, still a long way to go where I live...
 

pattismith

Senior Member
Messages
2,510
Likes
4,703
@pattismith, what tests were used to diagnose small fiber neuropathy? Have you found anything that helps you with fatigue?
I had no test done up to now, I'm waiting for a reference center answer to my request. The standard test used to diagnose a SFN is skin biopsy.

I take now some corticosteroids + Hormonal Therapy for menopause, both help a lot for fatigue and pain.