This section is for those nerdy types of individuals who are interested in how to detect mitochondrial depletions.
While the ability to noninvasively diagnose disease or conditions involving the mitochondria has vastly improved, too many doctors are overly utilizing genetic testing just from blood or saliva. Until there are much greater improvements, tissue must still be analyzed and preferably muscle tissue.
Nonetheless, I do recommend that everyone who is getting into this level of detective work get their own genetic sequencing performed. If you can get it through insurance great, but many patients have to resort to paying for their own. In some ways this is better, because you are the master of the data and can have access to your own genome in the future.
The good news is that the prices over the last several years has come down drastically, and it is now possible to get complete genome (nDNA & mtDNA) sequencing for under $400 dollars. Once you have sequencing accomplished you can find several reputable aftermarket companies that will screen your genome for rare mutations.
For the biopsy it is very important that clinically affected tissue, such as skeletal muscle, is the tissue that is biopsied. Myopathy or myopathic changes are a common symptom with mitochondrial involvement, but it is possible to have other organs/tissue involved.
Not all neurologists are well versed in mitochondrial pathology and if they are not they often overlook many issues, basically they will screw it up and not even suspect they are screwing it up. I have firsthand experience with this. Make sure your neurologist knows what your goals are, and that he is up to the task, as it is unfortunately, up to you to determine quarterback the process. Do not hesitate to interrogate the doctor, surgeon, and pathologist, several times if you have to, to make sure they are competent. Reach out to organizations that are familiar with muscle biopsies such as the UMDF to educate yourself. You only get one chance. If the tissue is not handled correctly, it is easy to miss a diagnosis. In my case, I had a deep muscle biopsy of the vastus lateralis, but other tissues may result in better outcomes.
Mayo found abnormalities when looking at the ratio of mitochondrial DNA. More specifically copies of the RNR1 gene in mtDNA compared to nuclear DNA, specifically copies of the RPP30 gene, which is exclusively in the nucleus of the cell. They compare to the nuclear DNA because they want to control for the fact that different samples from different patients might have different total numbers of cells present.
For example, a sample that happened to have only 5 cells present is obviously going to have fewer numbers of mitochondria present than a sample with 500 cells. By dividing the quantity of mtDNA by nuclear DNA, you arrive at the quantity of mtDNA per cell rather than per sample. Effectively taking care of the issue of different numbers of cells potentially being present.
On a side note, mitochondrial depletion is not something that is ‘on the radar’ of most specialists. I was asked “why don’t doctors test for this?” The answer is simple, if you have sequencing completed and no clinical variants show up, they have no reason to pursue specialized testing such as this. Additionally, most neurologist won’t even submit muscle biopsies for mitochondrial depletion testing. It is off their radar, so to speak.