Different mitochondrial DNA (mtDNA) mutations have been identified to cause mitochondrial encephalopathy, lactate acidosis and stroke-like episodes (MELAS). The underlying genetic cause leading to an enormous clinical heterogeneity associated with m.3243A>G-related mitochondrial diseases is still poorly understood. Genotype–phenotype correlation (heteroplasmy levels and clinical symptoms) was analysed in 16 patients (15 literature cases and one unreported case) harbouring the m.3243A>G mutation. mtDNA copy numbers were correlated to heteroplasmy levels in 30 different post-mortem tissue samples, including 14 brain samples of a 46-year-old female. In the central nervous system, higher levels of heteroplasmy correlated significantly with lower mtDNA copy numbers. Skeletal muscle levels of heteroplasmy correlated significantly with kidney and liver. There was no significant difference of heteroplasmy levels between clinically affected and unaffected patients. In the patient presented, we found >75% heteroplasmy levels in all central nervous system samples, without harbouring a MELAS phenotype. This underlines previous suggestions, that really high levels in tissues do not automatically lead to a specific phenotype. Missing significant differences of heteroplasmy levels between clinically affected and unaffected patients underline recent suggestions that there are additional factors such as mtDNA copy number and nuclear factors that may also influence disease severity.

Background and aims: The role of muscle magnetic resonance imaging (MRI) in the diagnostic procedures of myopathies is still controversially discussed. The current study was designed to analyze the status of qualitative muscle MRI, electromyography (EMG), and muscle biopsy in different cases of clinically suspected myopathy. Methods: A total of 191 patients (male: n = 112, female: n = 79) with suspected myopathy who all received muscle MRI, EMG, and muscle biopsy for diagnostic reasons were studied, with the same location of biopsy and muscle MRI (either upper or lower extremities or paravertebral muscles). Muscle MRIs were analyzed using standard rating protocols by two different raters independently. Results: Diagnostic findings according to biopsy results and genetic testing were as follow: non-inflammatory myopathy: n = 65, inflammatory myopathy (myositis): n = 51, neurogenic: n = 18, unspecific: n = 23, and normal: n = 34. The majority of patients showed myopathic changes in the EMG. Edema, atrophy, muscle fatty replacement, and contrast medium enhancement (CM uptake) in MRI were observed across all final diagnostic groups. Only 30% of patients from the myositis group ( n = 15) showed CM uptake. Discussion and conclusion: The study provides guidance in the definition of the impact of muscle MRI in suspected myopathy: despite being an important diagnostic tool, qualitative MRI findings could not distinguish different types of neuromuscular diagnostic groups in comparison with the gold standard histopathologic diagnosis and/or genetic testing. The results suggest that neither muscle edema nor gadolinium enhancement are able to secure a diagnosis of myositis. The current results do not support qualitative MRI as aiding in the diagnostic distinction of various myopathies. Quantitative muscle MRI is, however, useful in the diagnostic procedure of a suspected neuromuscular disease, especially with regard to assessing progression of a chronic myopathy by quantification of the degree of atrophy and fatty replacement and in exploring patterns of muscle group involvements in certain genetic myopathies.

Mitochondrial function is essential for ATP-supply, especially in response to different cellular stressors. Increased mitochondrial biogenesis resulting from caloric restriction (CR) has been reported. Resveratrol (RSV) is believed to mimic the physiological effects of CR mainly via a sirtuin (SIRT) 1-dependent pathway. The effect of RSV on the physiological function of mitochondrial respiratory complexes was evaluated using a Seahorse XF96. Myoblasts of five patients harboring the m.3243A>G mutation and five controls were analyzed. The relative expression of several genes involved in mitochondrial biogenesis was evaluated for a better understanding of the coherent mechanisms. Additionally, media-dependent effects of nutritional compounds and hormonal restrictions (R) on myoblasts from patients and controls in the presence or absence of RSV were investigated. Culturing of myoblasts under these conditions led to an upregulation of almost all the investigated genes compared to normal nutrition. Under normal conditions, there was no positive effect of RSV on mitochondrial respiration in patients and controls. However, under restricted conditions, the respiratory factors measured by Seahorse were improved in the presence of RSV. Further studies are necessary to clarify the involved mechanisms and elucidate the controversial effects of resveratrol on SIRT1 and SIRT3 expression.

Pathogenic variants in the MT-ATP6 are a well-known cause for maternally inherited mitochondrial disorders associated with a wide range of clinical phenotypes. Here, we present a 31- year old female with insulin-dependent diabetes mellitus, recurrent lactic acidosis and ketoacidosis recurrent infections with suspected immunodeficiency with T cell lymphopenia and hypogammaglobulinemia as well as proximal tetraparesis with severe muscle and limb pain and rapid physical exhaustion. Muscle biopsy and respiratory chain activities were normal. Single-exome sequencing revealed a variant in the MT-ATP6 gene: m.9143T>C. Analysis of further specimen of the index and mother (segregation studies) revealed the highest mutation load in muscle (99% level of mtDNA heteroplasmy) of the index patient. Interestingly, acute metabolic and physical decompensation during recurrent illness was documented to be a common clinical feature in patients with MT-ATP6 variants. However, it was not mentioned as a key symptom. Thus, we suggest that the clinical spectrum might be expanded in ATP6-associated diseases.

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