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The present study aimed to investigate whether serum growth differentiation factor 15 concentration is a valuable and reliable diagnostic biomarker of mitochondrial diseases. We examined consecutive patients with mitochondrial diseases, in comparison with patients with non-mitochondrial disease neuromuscular disorders and healthy controls. The serum concentrations of growth differentiation factor 15 were measured by ELISA, and compared with those of FGF21, lactate, and creatine kinase. We also evaluated the correlations between growth differentiation factor 15 concentrations and the Newcastle Mitochondrial Disease Adult Scale, numbers of ragged-red fibers, and COX-negative fibers in the biopsied muscles. The median serum growth differentiation factor 15 concentration was significantly elevated in 42 patients with mitochondrial diseases, compared with 20 patients with non-mitochondrial disease neuromuscular disorders and 50 healthy controls. The area under the curve of growth differentiation factor 15 for the diagnosis of muscle-manifesting mitochondrial diseases was 0.999, in comparison with those area under the curves of the other biomarkers including fibroblast growth factor 21 (0.935, p < 0.01), lactate (0.845 for p < 0.001), and creatine kinase (0.575, p < 0.001). Growth differentiation factor 15 was significantly correlated with mitochondrial disease severity and the proportion of ragged-red fibers identified in the biopsied muscles. Circulating growth differentiation factor 15 measurement is a superior biomarker with high sensitivity and specificity, which can be used as a non-invasive test to screen for primary mitochondrial diseases and dysmetabolic myopathy with associated mitochondrial dysfunction in susceptible individuals.

For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681.

Researchers in the field of mitochondrial biology are increasingly unveiling of the complex mechanisms between mitochondrial dysfunction and noncoding RNAs (ncRNAs). However, roles of ncRNAs underlying mitochondrial myopathy remain unexplored. The aim of this study was to elucidate the regulating networks of dysregulated ncRNAs in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) with mitochondrial DNA (mtDNA) A3243G mutation, which might make contributions to the unveiling of the complex mechanisms underlying mitochondrial myopathy and, possibly, new tools applicable to clinical practice. Through high-throughput technology followed by quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics analyses, for the first time, we found that the dysregulated muscle miRNAs and lncRNAs between 20 MELAS patients with mtDNA A3243G mutation and 20 controls formed complex regulation networks and participated in immune system, signal transduction, translation, muscle contraction and other pathways in discovery and training phase. Then, selected ncRNAs were validated in muscle and serum in independent validation cohorts by qRT-PCR. Finally, ROC curve analysis indicated reduced serum miR-27b-3p had the better diagnosis value than lactate and might serve as a novel, noninvasive biomarker for MELAS. Follow-up investigation is warranted to better understand roles of ncRNAs in mitochondrial myopathy pathogenesis.

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Background:Leigh syndrome (LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity. We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA (mtDNA) mutations.Methods:Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging (MRI) were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid (CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography–mass spectrometry and tandem mass spectrometry. The histopathological traits of skeletal muscles were analyzed under microscope.Results:Among 13 patients, mutations of MT-NDs (n = 8) and MT-ATP6 (n = 4) genes were most common. Strabismus (8/13), muscle weakness (8/13), and ataxia (5/13) were also common, especially for the patients with late-onset age after 2 years old. However, respiratory distress was common in patients with early-onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem (12/13), particularly the dorsal part of midbrain, followed by basal ganglia (6/13), thalamus (6/13), cerebellum (5/13), and supratentorial white matter (2/13). Besides, the elevated lactate levels in CSF (6/6) were more common than those in serum (7/13). However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results (0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late-onset patients but not in the early-onset ones.Conclusions:Noninvasive genetic screening is recommended for mtDNA mutations in MT-NDs and MT-ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations.

These observations, combined with previous reports, indicate that KD should be considered in the adult patients presenting selective pyramidal tract impairment even with sudden onset.