The study aimed to evaluate the body composition of patients with mitochondrial diseases (MD) and correlate it with disease severity. Overall, 89 patients (age ≥ 18 years) with MD were recruited, includin g 49 with chronic progressive external ophthalmoplegia (CPEO) and 40 with mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS). Body composition, including fat mass index (FMI), fat-free mass index (FFMI), skeletal muscle mass index (SMI), and appendicular skeletal muscle mass index (ASMI), were examined using multifrequency bioelectric impedance analysis. Clinical assessments, including muscle strength, usual gait speed, and disease severity determined by the Newcastle Mitochondrial Disease Adult Scale score (NMDAS), were performed. The comparisons between patients group and age- and gender-matched healthy controls, as well as the correlations between anthropometric measurements, body composition, and disease severity were analyzed. Height, weight, body mass index (BMI), FFMI, SMI, and ASMI were significantly lower in patients with MD than in healthy controls. Notably, low muscle mass was noted in 69.7% (62/89) of MD patients, with 22 patients also presenting with compromised physical performance as indicated by decreased gait speed, resulting in 24.7% satisfied the sarcopenia diagnostic criteria. Disease severity was more negatively correlated with ASMI than it was with height, weight, and BMI. Subgroup analysis showed that in the MELAS subgroup, disease severity was negatively correlated with height, weight, and ASMI; whereas in the CPEO subgroup, it was only negatively correlated with ASMI and SMI. Additionally, ASMI was positively associated with muscle strength. Altogether, compared with BMI, ASMI is a more sensitive biomarker predicting disease severity of MD, both in MELAS and CPEO patients.

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Mutations in the fused in sarcoma (FUS) gene have been reported to be the most common genetic cause of early-onset amyotrophic lateral sclerosis (ALS); cytoplasmic inclusions containing FUS protein are the predominant pathological feature. Recent studies indicated that mutant FUS impaired neuromuscular junctions and induced muscle intrinsic toxicity in cell and animal models. However, the role of FUS in muscle degeneration remains unclear. In this study, we investigated FUS protein distribution in skeletal muscle fibers in ALS-FUS. Our data show that cytoplasmic mislocalized FUS in the unaggregated form represented a remarkable pathological feature in affected muscle fibers in ALS-FUS. Additional studies found that cytoplasmic FUS colocalized with some mitochondria and was associated with mitochondrial swelling and disorganized cristae. RNA sequencing and quantitative real-time polymerase chain reaction analyses indicated downregulation of the key subunits of mitochondrial oxidative phosphorylation complexes in the affected skeletal muscle in ALS-FUS patients. Further immunoblot analysis showed increased levels of FUS, but decreased levels of Cox I (subunit of complex IV) in ALS-FUS patients compared with age-matched controls. This is the first demonstration of the close association of cytoplasmic mislocalized FUS with mitochondrial dysfunction in skeletal muscle, implicating the presence of a cell-autonomous mechanism in muscle degeneration in ALS.

Objective The present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR‐PN) and other similar neuropathies. Methods A total of 41 patients with ATTR‐PN, 58 patients of other common peripheral neuropathies, and 17 age‐and gender‐matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD. Results Except the vasculitic neuropathy group, the total and small MFD of patients in the ATTR‐PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR‐PN group. The disease course of early‐onset and late‐onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late‐onset and most early‐onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR‐PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life‐diabetic neuropathy (Norfolk QOL‐DN) score. Conclusion MF is lost differently in ATTR‐PN and in other common peripheral neuropathies. The late‐onset and early‐onset ATTR‐PN patients have different patterns of loss of large and small MF.

Background: Studies on the relationship between antiepileptic drug (AED) administration and clinical outcomes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) remain scarce. Levetiracetam (LEV) is an AED that is neuroprotective in various neurologic disorders. This study aimed to determine the impact of LEV on the outcome of MELAS. Methods: A retrospective, single-center study was performed based on a large cohort of patients with MELAS with a history of seizures ( n = 102). Decisions on antiepileptic therapies were made empirically. Patients were followed up for 1 to 8 years (median, 4 years) and divided into 2 groups based on whether LEV was administered (LEV or non-LEV). The modified Rankin scale (mRS) scores and mortality risks were analyzed in all patients. Results: LEV, carbamazepine, benzodiazepines, topiramate, oxcarbazepine, valproate, and lamotrigine were administered in 48, 37, 18, 13, 11, 9, and 9 patients, singly or in combination, respectively. The mean mRS score of the LEV group ( n = 48) was lower than that of the non-LEV group ( n = 54; mean ± standard deviation, 2.79 ± 1.47 vs . 3.83 ± 1.93, P = 0.006) up to the end of the study. Nevertheless, there was no difference in the proportion of subjects without disability (mRS ranging 0–1) between the groups ( P = 0.37). The multivariate regressions revealed that LEV treatment was associated with lower mRS scores (odds ratio 0.32, 95% confidence interval [CI] 0.15–0.68, P = 0.003) and mortality rates (hazard ratio 0.24, 95% CI 0.08–0.74, P = 0.013). There was a significant difference in the Kaplan-Meier survival curves between the groups (χ 2 = 4.29, P = 0.04). Conclusions: The LEV administration is associated with lower mortality in patients with MELAS in this retrospective study. Further laboratory research and prospective cohort studies are needed to confirm whether LEV has neuroprotective effects on patients with mitochondrial diseases.