# Tissue-specific mitochondrial DNA, MT-TF, pathogenic variants in mitochondrial myopathies

## TL;DR

This paper highlights the importance of analyzing mitochondrial DNA in muscle tissue rather than blood for diagnosing mitochondrial myopathies due to variable genetic mutations across tissues.

## Contribution

The study demonstrates that mtDNA variants in muscle tissue can be missed when only blood samples are analyzed.

## Key findings

- MT-TF variants were found in muscle tissue with high heteroplasmy levels, even when blood samples showed no mutations.
- Clinical symptoms varied among patients, emphasizing the need for tissue-specific genetic testing.
- Muscle DNA analysis is crucial for accurate diagnosis when blood tests are negative but clinical suspicion remains high.

## Abstract

Mitochondrial myopathies are progressive muscle disorders caused by impaired mitochondrial oxidative phosphorylation, leading to reduced adenosine triphosphate production. Skeletal muscles have a high energy demand and are often the first to be affected. In addition to muscular symptoms (muscle weakness, effort intolerance, fatigue), the disease can affect the central and peripheral nervous systems, as well as the heart, liver, kidneys and endocrine system (diabetes). Molecular genetic diagnostic is currently based on leukocyte DNA obtained from blood samples, considered less invasive than muscle biopsy. We report four patients from three families with mitochondrial myopathy associated with ptosis, sensorineural hearing loss, epilepsy, tubulointerstitial nephropathy and cardiomyopathy. Genetic studies identified MT-TF variants (m.586G > A, m.601G > A, m.616 T > C) with highly variable heteroplasmy levels in the same patient from one tissue to another (5 % to 70 % mutant load in circulating blood leukocytes and in muscle respectively).

We emphasize the importance of performing mtDNA analysis on muscle DNA, even in patients with negative blood leukocytes mtDNA sequencing, if there is strong clinical suspicion of mitochondrial myopathy.