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Objective： Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes （MELAS） is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. M ELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well. Data Sources： The data used in this review came fi-om published peer review articles from October 1984 to October 2014, which were obtained fiom PubMed. The search term is ＂MELAS＂, Study Selection： lnfornmtion selected from those reported studies is mainly based on the progress on clinical tkatures, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS. Results： MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging （MRI） can provide directional information on this disease. Muscle biopsy has meaningflil value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the lnutation in.3243A〉G of the mitochondrial transfer RNA （Leu （UU R）） gene （MT-TLI）. Conclusions： MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MR1, muscle biopsy, and genetics.

Background Skeletal muscle tissue swelling is a common indicator of muscle damage. The microbiopsy (MB) method is considered a less invasive muscle biopsy procedure and may reduce participant burden. However, the swelling and perception of pain associated with MB could discourage participation, while the swelling and pain resulting from exercise may be more socially accepted and less likely to deter participation. This study aims to compare the pain response and muscle swelling following an eccentric leg press (ELP) protocol and MB to better understand tolerability and physiological responses to each condition.Methods Participants, (n = 13; age: 21.0 ± 2.1 years; height: 168.5 ± 10.7 cm; weight: 73.6 ± 14.3 kg; BMI: 26.0 ± 4.9 kg/m2; Sex: ♂: 3 ♀: 10) completed both experimental conditions (MB and ELP) separated by one week. Ultrasound imaging was used to assess swelling (muscle thickness; MT) of the m. vastus lateralis (VL) at four standardized sites (40, 50, 60, and 75% of femur length). Images were captured at baseline (BL), immediately post (IP), and 24-, 48-, and 72-h post-condition to evaluate changes in MT analyzed with NIH Image J. Pain pressure threshold (PPT) was assessed at each time point using a pressure algometer applied to the skin over the VL locations until volitional discomfort. Visual analog scale (VAS) ratings were also collected to measure subjective pain intensity. A RMANOVA was used to determine the effects of condition, location, and time on PPT, VAS, and MT measures.Results PPT values showed no significant main effects for condition (p > .05, η2 = .279), time (p > .05, η2 = .260), condition×location interaction (p > .05, η2 = .083), location×time interaction (p > .05, η2 = .136), or condition×location×time interaction (p > .05, η2 = .086). A significant main effect was observed for location (p = .026, η2 = .279), with higher PPT values at 75% VL compared to 60% VL (p = .044). VAS data showed no significant main effects. MT showed no significant differences between VL locations. At 40% of the VL, there were no significant main effects for time (p > .05, η2 = .124), condition, or the time × condition interaction. At 50% VL, no significant difference was observed for condition (p > .05, η2 = .247); significant main effects were found for time (p < .001, η2 = .473) and the time × condition interaction (p = .049, η2 = .252). At 60% VL, there was a significant main effect for time (p = .008, η2 = .343) and a significant time × condition interaction (p = .044, η2 = .257), with no significant effect of condition. At 75% VL, no significant differences were found for time (p > .05, η2 = .141), condition, or the time × condition interaction.Conclusions Currently, no differences were found in PPT, VAS, and MT measures of the VL between conditions. PPT-assessed location differences were found (75% vs. 60% of VL), which may be explained by fat mass deposition (i.e. “padding”). There were notable and expected time differences for regional MT measures (50 and 60%); the more proximal and distal ends of the VL were unaffected. Pain perception and muscle swelling results seem to be similar when comparing ELP and MB.

Abstract Competence in muscle biopsy evaluation is a core component of neuropathology practice. The practicing neuropathologist should be able to prepare frozen sections of muscle biopsies with minimal artifacts and identify key histopathologic features of neuromuscular disease in hematoxylin and eosin-stained sections as well as implement and interpret a basic panel of additional histochemical, enzyme histochemical, and immunohistochemical stains. Important to everyday practice is a working knowledge of normal muscle histology at different ages, muscle motor units, pitfalls of myotendinous junctions, nonpathologic variations encountered at traditional and nontraditional muscle sites, the pathophysiology of myonecrosis and regeneration, and approaches to distinguish muscular dystrophies from inflammatory myopathies and other necrotizing myopathies. Here, we provide a brief overview of what every neuropathologist needs to know concerning the muscle biopsy.

Identification of antisynthetase syndrome (ASS) could be challenging due to inaccessibility and technical difficulty of the serology test for the less common non‐Jo‐1 antibodies. This study aimed to describe ASS antibody‐specific myopathology and evaluate the diagnostic utility of myofiber HLA‐DR expression. We reviewed 212 ASS muscle biopsies and compared myopathologic features among subtypes. Additionally, we compared their HLA‐DR staining pattern with 602 non‐ASS myositis and 140 genetically confirmed myopathies known to have an inflammatory component. We used t‐test and Fisher's exact for comparisons and used sensitivity, specificity, positive and negative predictive values to assess the utility of HLA‐DR expression for ASS diagnosis. RNAseq performed from a subset of myositis cases and histologically normal muscle biopsies was used to evaluate interferon (IFN)‐signaling pathway‐related genes. Anti‐OJ ASS showed prominent myopathology with higher scores in muscle fiber (4.6 ± 2.0 vs. 2.8 ± 1.8, p = 0.001) and inflammatory domains (6.8 ± 3.2 vs. 4.5 ± 2.9, p  = 0.006) than non‐OJ ASS. HLA‐DR expression and IFN‐γ‐related genes upregulation were prominent in ASS and inclusion body myositis (IBM). When dermatomyositis and IBM were excluded, HLA‐DR expression was 95.4% specific and 61.2% sensitive for ASS with a positive predictive value of 85.9% and a negative predictive value of 84.2%; perifascicular HLA‐DR pattern is common in anti‐Jo‐1 ASS than non‐Jo‐1 ASS (63.1% vs. 5.1%, p < 0.0001). In the appropriate clinicopathological context, myofiber HLA‐DR expression help support ASS diagnosis. The presence of HLA‐DR expression suggests involvement of IFN‐γ in the pathogenesis of ASS, though the detailed mechanisms have yet to be elucidated. Muscle pathology in anti‐OJ ASS is more prominent than the other ASS subtypes.

Human muscle biopsies are often required to study or diagnose diseases. However, traditional approaches are challenging due to limited sample size, quality, or participant discomfort. Fine-gauge needle biopsies (≥ 14-gauge), present an alternative but may yield insufficient tissue for comprehensive analysis. Ultrasound guidance, coupled with vacuum-assisted, single needle-insertion multiple sampling addresses these challenges. In 19 healthy participants (mean age: 30.1 ± 10 years, 42% male), 2–3 samples were collected from a single needle insertion into the vastus lateralis (VL) and tibialis anterior (TA). Summed VL and TA sample masses averaged 148 ± 38 mg and 166 ± 64 mg, with dimensions of 15.83 ± 8 × 2.9 ± 0.6mm 2 (VL) and 15.07 ± 7 × 3.1 ± 0.9mm 2 (TA). VL had a mean fiber cross-sectional area of 4,347 ± 1,931µm 2 , with 221 ± 86 fibers quantified. Samples were of sufficient size and quality for thorough analyses from a single biopsy procedure, including mitochondrial respirometry, RT-PCR, collagen content, and biomechanical function. Fibers produced typical isometric stress values of 187 kPa with a passive modulus of 239 kPa (peak) and 79 kPa (stress-relaxed). The procedure was well tolerated, with an average immediate pain rating of 1.5 ± 1 (range:0–4, scale: 0–10) and 24-hour follow-up rating of 1.7 ± 1 (range:0–4). This report describes an approach that yields high-quality muscle samples suitable for histological and biochemical analyses while minimizing discomfort.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP‐43 aggregates. Recent evidence has been indicated that phosphorylated TDP‐43 (pTDP‐43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP‐43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP‐43 detectable in routine biopsied muscles? (ii) Can detection of pTDP‐43 aggregation discriminate between ALS and non‐ALS patients? (iii) Can pTDP‐43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non‐ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP‐43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP‐43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non‐ALS controls (16/54; p < 0.001). The pTDP‐43 aggregates were mainly close to the sarcolemma. Using a semi‐quantified pTDP‐43 aggregates score, we applied a cut‐off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP‐43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof‐of‐concept for the detection of pTDP‐43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS. To explore whether testing pTDP‐43 aggregation in muscle tissue would assist in the diagnosis of ALS, we conducted a diagnostic study in 18 ALS patients and 54 randomly matched controls from ALS and muscular disease cohorts. Our results indicated that pTDP‐43 was more prone to accumulation in ALS patients, enabling differentiation between ALS and non‐ALS patients with high sensitivity and specificity. Moreover, we observed that accumulation of pTDP‐43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions.

Recent epidemiological studies on the general population reveal that up to 1.3% have oligo/asymptomatic hyperCKemia. This guideline aims to provide updated, evidence-based recommendations on investigating persons older than 18 years. The guideline followed EAN standard operating procedures and was developed according to the GRADE methodology. Fourteen neuromuscular experts from the EAN neuromuscular group were joined by a methodologist and a patient representative. There are two types of recommendations: evidence-based recommendations, based on published studies, and consensus statements if the quality of evidence is poor. We recommend that: (1) Persistent oligo/asymptomatic hyperCKemia with a CK > 1.5 ULN be investigated (Consensus statement); (2) Neurogenic and non-neuromuscular causes of hyperCKemia be excluded (Expert opinion); (3) A Dried Blood Spot (DBS) be done (Strong recommendation); (4) A NCS/EMG to identify whether there is a myopathy or neuropathy be performed (Weak recommendation); (5) A resting lactate and fasting acyl-carnitine assays, if a metabolic myopathy is suspected, be done (Consensus statement); (6) A skeletal muscle MRI be performed to guide/interpret genetic testing (Strong recommendation); (7) NGS is recommended over sequential gene testing (Consensus statement); (8) NGS is recommended over muscle biopsy (Strong recommendation); (9) A muscle biopsy may be offered, if genetic testing is uninformative and one or more applies: a genetic variant of unknown significance (VUS), suspected metabolic myopathy, suspected inflammatory myopathy, abnormal muscle MRI, a CK ≥ 3 ULN, a family history of muscle disease or age, less than 25 years (Expert opinion). An evidence-based guideline is suggested for when and how to investigate adults with oligo/asymptomatic hyperCKemia.

Objective X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological, and natural history of XMEA. Methods We conducted a retrospective study collecting clinical, genetic, muscle imaging, and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases. Results Eighteen males had genetically confirmed XMEA in France, carrying four different VMA21 variants. Mean age at disease onset was 9.4 ± 9.9 (range 1–40) years. In 14/18 patients (77.8%), onset occurred during childhood (< 15 years); however in four patients, the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9 ± 757.8 U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI ( n  = 10) showed a characteristic pattern of lower limb muscle involvement. In 11 patients, outcome measures were available for an average follow-up period of 10.6 ± 9.8 years and six of them show disease progression. Mean change of functional outcomes was 0.5 ± 1.2 points for Brooke and 2.2 ± 2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound (median age of 40 years old, range 39–48). The variant c.164-7 T > G was associated with a later onset of symptoms. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%). Interpretation XMEA has variable age of onset, but a characteristic clinical, histopathological, and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and relevant genotype–phenotype correlations will help design future clinical trials.

Idiopathic inflammatory myopathies (IIM) are rare, acquired muscle diseases; their diagnosis of is based on clinical, serological, and histological criteria. MHC-I-positive immunostaining, although non-specific, is used as a marker for IIM diagnosis; however, the significance of major histocompatibility complex (MHC)-II immunostaining in IIM remains debated. We investigated patterns of MHC-II immunostaining in myofibers and capillaries in muscle biopsies from 103 patients with dermatomyositis ([DM], n = 31), inclusion body myositis ([IBM], n = 24), anti-synthetase syndrome ([ASyS], n = 10), immune-mediated necrotizing myopathy ([IMNM], n = 18), or overlap myositis ([OM], n = 20). MHC-II immunostaining of myofibers was abnormal in 63/103 of patients (61%) but the patterns differed according to the IIM subgroup. They were diffuse in IBM (96%), negative in IMNM (83%), perifascicular in ASyS (70%), negative (61%) or perifascicular (32%) in DM, and either clustered (40%), perifascicular (30%), or diffuse heterogeneous (15%) in OM. Capillary MHC-II immunostaining also identified quantitative (capillary dropout, n = 47/88, 53%) and qualitative abnormalities, that is, architectural abnormalities, including dilated and leaky capillaries, (n = 79/98, 81%) in all IIM subgroups. Thus, MHC-II myofiber expression patterns allow distinguishing among IIM subgroups. We suggest the addition of MHC-II immunostaining to routine histological panels for IIM diagnosis.