[Retrospective study on clinical manifestation, thigh MRI and electrophysiology characteristics of immune-mediated necrotizing myopathy].

Objective: To summarize the clinical, thigh magnetic resonance (tMRI) and electromyographic (EMG) characteristics in patients with immune-mediated necrotizing myopathy (IMNM). Methods: A total of 32 IMNM patients who were admitted to the Department of Neurology from April 2019 to April 2021 were enrolled at the First Medical Centre of Chinese PLA General Hospital. According to the type of antibody, the patients were divided into anti-SRP antibody positive (SRP+) group, anti-HMGCR antibody positive (HMGCR+) group and seronegative (SN) group. The gender, age, course of disease, myositis antibodies, extramuscular manifestations, EMG were collected and analyzed among three groups. The characteristics of skeletal muscle were assessed by tMRI inflammatory edema and fat infiltration scores. Analysis of variance, Kruskal-Wallis test and Chi-square test were used to compare the differences in different clinical characteristics and tMRI scores among the three groups. When there was a statistical difference among the three groups, the comparison between the two groups was corrected by the Bonferroni method. Result: (1) Of the 32 patients, 20 were females (62.5%).The median age of onset was 47±14 years, 25 (78.1%) patients had an acute or subacute course.There were 17 (53.1%) with SRP+, 8 (25.0%) with HMGCR+, and 7 (21.9%) with MSAs (myositis specific antibodies) negative. Anti-Ro52 antibody was the most common combined antibody (12/32, 37.5%), among which 10 were in SRP+group.(2) The CK of all patients were elevated, median was 5 948 (4 229, 7 664) U/L. There was no statistical difference of MMT scores among three groups. The proximal limb score was lower than distal limb (P<0.01). The axial muscle score was lower than the distal limb score (P<0.05).(3) Extramuscular manifestations of HMGCR+ group were lower than those of the other two groups (12.5% vs. 71.4% and 76.5%, P<0.017). Rash (60.0% vs.14.3%, P<0.05) and interstitial pulmonary diseases (70.0% vs. 14.3%, P<0.05) were more common in patients with anti-SRP coexistence with anti-Ro52 than those with isolated anti-SRP. Connective tissue disease was more common in SN group (57.1% vs. 11.8% and 0, P<0.017).(4) tMRI showed fascial edema of SN group was more obvious than that of the other two groups (P<0.017). There was no statistical difference in the degree of fat infiltration and inflammatory edema among three groups, but SRP+ group had more cases of early fat infiltration.(5) Myotonic potentials (25.0% vs. 0 and 0, P<0.017) and compound repetitive discharges (CRDs) (50.0% vs. 5.9% and 0, P<0.017) were common in HMGCR+ group. Proteomic analysis found significantly different expressed proteins in skeletal muscle of patients with myotonic potentials or CRDs were associated with cytoskeleton, cell junction and extracellular matrix. Conclusion: IMNM with pure anti-SRP antibody positive and anti-HMGCR positive were mainly affected by skeletal muscles. Those who were co-positive for anti-SRP antibody and anti-Ro52 antibody had more extramuscular manifestations, which might be a special subtype of SRP+ group. This study proposed for the first time that myofascial inflammatory edema is an early sign of SN-IMNM injury. EMG of HMGCR+group were more prone to myotonia potential and CRDs.

Muscular pathological features in patients with Lambert-Eaton myasthenic syndrome associated with small cell lung carcinoma.

AIMS: Lambert-Eaton myasthenic syndrome (LEMS) is a kind of autoimmune disease of the neuromuscular junction that is often misdiagnosed as a peripheral nerve disease or myopathy. For some difficult cases, muscle biopsy examination is useful for differential diagnosis. However, studies about the pathological findings of LEMS patients are rare, especially of patients who were diagnosed with small cell lung carcinoma (SCLC). This study aimed to describe several pathological muscle features in patients with LEMS associated with SCLC. MATERIALS AND METHODS: The 5 patients enrolled in this study were diagnosed with LEMS associated with SCLC by clinical manifestation, electromyography, and lung biopsy. Muscle biopsies were performed for the patients, and enzyme histopathology was assessed. RESULTS: The hematoxylin and eosin (H & E) stain showed different sizes of fibers, and the shape of atrophic fibers were angular or polygonal. The adenosine triphosphatase (ATPase) stain demonstrated that the majority of atrophic fibers were type II. Type II fiber predominance was observed in case 1 and case 5. Also, scattered muscle fiber necrosis was shown in case 3. CONCLUSION: Type II fiber atrophy and type II fiber predominance may often be found in patients with LEMS associated with SCLC. Also, scattered fiber necrosis may appear in this disease.

Muscular pathological features in patients with myasthenia gravis.

OBJECTIVE: To analyze muscle histopathology of myasthenia gravis (MG) patients and further explore the underlying mechanism comparing with previous literature. MATERIALS AND METHODS: We analyzed the clinicopathological features of 8 MG patients who had muscle biopsy examinations. RESULTS: Eight patients with a diagnosis of MG were retrospectively recruited from the Chinese PLA General Hospital. One patient had positive anti-MuSK antibodies, 5 patients had positive anti-AChR antibodies (1 of whom had additional positive anti-Titin antibodies), and 2 patients were seronegative. Seronegative-MG presented normal muscle histology, occasionally with lipid deposition. Small angular atrophy (mainly in type II fibers) and necrosis in H & E stain were found in AChR-MG, furthermore, patterns of polymyositis (PM) could be found in AChR-MG with anti-Titin antibodies. Mitochondrial abnormalities were found only in MuSK-MG. CONCLUSION: Muscle histological abnormalities mimicking myopathy may be found in MG patients. Patients with different antibodies present with different muscle histopathology. PM pattern pathology is a special pattern of muscle histology in MG that should not be misdiagnosed. Our study has extended the muscle pathological features of MG in addition to deepening the understanding of MG.

Novel GNE mutations in three Chinese patients with typical GNE myo-pathy.

GNE myopathy is an adult-onset muscle disorder featuring distal muscle atrophy and weakness. Rimmed vacuoles found in the muscle biopsies and gene mutations lead to the diagnosis of GNE myopathy. We collected clinical information, performed muscle biopsies and genetic testing on three patients. These cases developed typical disease presentations with distal muscle weakness at the ages of 26, 23, and 37 years. Their muscle pathologies revealed rimmed vacuoles. Genetic analysis led to the findings which included, c.1543-1544delGA (p.D515QfsX2)/c.38G>C (p.C13S) compound heterozygous mutation, c.733A>G (p.K245E) homozygous mutation and c.527A>T (p.D176V)/c.1634-1G>C (splicing) ; in which c.1543-1544 del GA (p.D515QfsX2), c.733A>G (p.K245E) and c.1634-1G>C (splicing) are three de novo mutations that have never been reported before. In conclusion, this study broadens the mutational spectrum of the GNE gene.

Genetic ablation of P65 subunit of NF-κB in mdx mice to improve muscle physiological function.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a genetic muscle disease characterized by dystrophin deficiency. Beyond gene replacement, the question of whether ablation of the p65 gene of nuclear factor-kappa B (NF-κB) in DMD can improve muscle physiology function is unknown. In this study, we investigated muscle physiological improvement in mdx mice (DMD model) with a genetic reduction of NF-κB. METHODS: Muscle physiological function and histology were studied in 2-month-old mdx/p65+/- , wild-type, mdx, and human minidystrophin gene transgenic mdx (TghΔDys/mdx) mice. RESULTS: Improved muscle physiological function was found in mdx/p65+/- mice when compared with mdx mice; however, it was similar to TghΔDys/mdx mice. The results indicate that genetic reduction of p65 levels diminished chronic inflammation in dystrophic muscle, thus leading to amelioration of muscle pathology and improved muscle physiological function. CONCLUSIONS: The results show that inhibition of NF-κB may be a promising therapy when combined with gene therapy for DMD. Muscle Nerve 56: 759-767, 2017.

Incidence and risk factors of pleural effusions in patients with POEMS syndrome.

Information regarding the characteristics of pleural effusions in patients with POEMS syndrome is limited. The aim of this study was to describe the incidence and risk factors of pleural effusions in patients with POEMS syndrome and characterize the pleural fluid biochemistry in those patients. A retrospective review of 96 patients with POEMS syndrome was conducted. The patients were divided into groups with and without pleural effusions. The clinical data were obtained from medical charts. Risk factors were studied with univariate and multivariate analysis. The median age at the time of diagnosis of POEMS syndrome was 45.1 years, and the median disease duration was 30.4 months. Pleural effusions were detected in 41 (42.7%) of the 96 patients. Increased serum vascular endothelial growth factor (VEGF), complement component 3 (C3), Lambda light chain, tumour necrosis factor (TNF)-α, interleukin (IL)-6 levels and low albumin as well as cardiac disease were found to be significantly correlated with pleural effusions. By multivariate logistic regression, independent risk factors for pleural effusions in POEMS syndrome were VEGF [odds ratio (OR): 2.46, 95% confidence interval (CI): 1.720-3.414, p = 0.01], TNF-α (OR: 3.64, 95% CI: 1.073-4.338, p = 0.04) and C3 (OR: 3.77, 95% CI: 1.225-3.591, p = 0.02) levels. Pleural effusions are the most common thoracic involvement findings in patients with POEMS syndrome, and all the pleural fluids are exudates. Serum VEGF, TNF-α and C3 levels are identified as important risk factors for presence of pleural effusions in POEMS syndrome.

Clinical, pathological, and genetic features of dynamin-2-related centronuclear myopathy in China.

Mutations in the dynamin-2 (DNM2) gene can cause autosomal dominant or sporadic centronuclear myopathy (CNM). We aimed to analyze the clinical, pathological and genetic characteristic of patients with DNM2-related CNM in China. We studied seven patients, all of whom underwent clinical examination, muscle biopsy, electromyography, and genetic tests. DNM2 gene analysis revealed two sporadic patients harboring the p.E368K mutation, two patients from one family carrying p.R369Q, one with p.R369W, one with p.R523G and one with compound heterozygous mutations of p.R522H and p.R718Q. In DNM2-related CNM, ptosis, ophthalmoplegia/paresis, and facial weakness are the frequently observed manifestations. However, among these seven patients, only one had bilateral ptosis; one, external ophthalmoplegia and one, facial weakness. Muscle biopsy showed that the percentage of muscle fibers with centrally located nuclei ranged from 67 to 93 %, all with radial sarcoplasmic strands. To date, five different CNM-related DNM2 mutations have been observed in China. Here, a patient with compound heterozygous DNM2 mutations was reported for the first time. Facial weakness, ptosis and ophthalmoplegia did not appear to be common in Chinese patients. This study on Chinese patients broadens the spectrum of DNM2-related CNM.

Clinicopathologic features of sporadic inclusion body myositis in China.

This study is to investigate the clinical and pathologic features of sporadic inclusion body myositis (sIBM) in China. We retrospectively evaluated the clinical and pathological features of consecutive patients in our department between January 1986 to May 2012. Total 28 cases of sIBM (20 males, 8 females, mean age was 56.93±8.79) were obtained by review of all 4099 muscle biopsy reports. The proportion of sIBM was 0.68% (28/4099) in China. Muscle weakness of quadriceps appeared 100% in 28 cases, while conspicuous atrophy of quadriceps appeared only in five cases (17.86%). Creatase values of 28 patients with sIBM were normal or mildly elevated. Muscle biopsies showed that atrophic fibers resembled more frequent in small angular and irregular shape (82.14%), less common in small round shape (17.86%). Rimmed vacuoles resembled crack (67.86%) and round (32.14%) shape. Mononuclear cell invasion into necrotic muscle fibers (35.71%) was more frequent than non-necrotic muscle fibers (7.14%). sIBM was still a rare disease in China compared to other countries. There were some certain specific pathological characteristics existed in Chinese sIBM patients.

Implementation of a structured guideline-based program for the secondary prevention of ischemic stroke in China.

BACKGROUND AND PURPOSE: High rates of ischemic stroke and poor adherence to secondary prevention measures are observed in the Chinese population. METHODS: We used a national, multicenter, cluster-randomized controlled trial in which 47 hospitals were randomized to either a structured care program group (n=23) or a usual care group (n=24). The structured care program consisted of a specialist-administered, guideline-recommended pharmaceutical treatment and a lifestyle modification algorithm associated with written and Internet-accessed educational material for patients for the secondary prevention of ischemic stroke. The primary efficacy outcome was the proportion of patients who adhered to the recommended measures at 12-month postdischarge. This trial is registered with ClinicalTrial.gov (NCT00664846). RESULTS: At 12 months, 1287 (72.1%) patients in the Standard Medical Management in Secondary Prevention of Ischemic Stroke in China (SMART) group and 1430 (72%) patients in the usual care group had completed the 12-month follow-up (P=0.342). Compared with the usual care group, those in the SMART group showed higher adherence to statins (56% versus 33%; P=0.006) but no difference in adherence to antiplatelet (81% versus 75%; P=0.088), antihypertensive (67% versus 69%; P=0.661), or diabetes mellitus drugs (73% versus 67%; P=0.297). No significant difference in the composite end point (new-onset ischemic stroke, hemorrhagic stroke, acute coronary syndrome, and all-cause death) was observed (3.56% versus 3.59%; P=0.921). CONCLUSIONS: The implementation of a program to improve adherence to secondary ischemic stroke prevention efforts in China is feasible, but these programs had only a limited impact on adherence and no impact on 1-year outcomes. Further development of a structured program to reduce vascular events after stroke is needed. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00664846.

Proteomic study of sporadic inclusion body myositis.

BACKGROUND: Sporadic inclusion body myositis (s-IBM) is the most commonly occurring acquired inflammatory myopathy in elderly people (>45 years); however, pathogenic mechanisms are poorly understood and diagnostic tools are limited. In view of this, new therapeutic and diagnostic molecular markers for s-IBM need to be identified. EXPERIMENTAL DESIGN: In this study, the proteomes from three s-IBM cases were compared with those from three cases of neurogenic muscular atrophy (control). Proteins were separated by 2-dimensional polyacrylamide gel electrophoresis and profiled by mass spectrometric sequencing and subsequently validated by western blot. RESULTS: Differential expression was noted in 29 proteins (16 upregulated and 13 downregulated) in s-IBM compared with the control group. Functions of these proteins include oxidative stress response, regulation of apoptosis, signal transduction, and cytoskeleton. Expression of both amyloid precursor protein (APP) and αB-crystallin was increased in s-IBM cases. CONCLUSIONS: Our study reveals a unique pattern of protein expression in s-IBM, which should be further investigated in a wider cohort of IBM patients to fully realize the potential diagnostic or therapeutic benefits.

Coexistence of peripheral myelin protein 22 and dystrophin mutations in a chinese boy.

INTRODUCTION: We describe a 10-year-old Chinese boy with features of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy (DMD). METHODS: Case report. RESULTS: Weakness and mild sensory loss in the distal extremities, pes cavus, and nerve conduction findings suggested demyelinating neuropathy, while moderate calf pseudohypertrophy, proximal muscle weakness, a myopathic pattern on electromyography, and deficiency of dystrophin immunohistochemical staining on muscle biopsy indicated DMD. Genetic testing revealed a large deletion spanning exon 50 in the gene coding for dystrophin and duplications in the gene coding for peripheral myelin protein 22. CONCLUSIONS: This is an interesting and very rare case of CMT type 1A comorbid with DMD. This results in an unusual phenotype and rapid deterioration of motor function. Usage of both target region capture and next generation sequencing is a powerful tool for predicting precisely the range of the large DNA fragment deletion in DMD.

CSF and serum AFP in patients without gestational or neoplastic AFP-secretion.

BACKGROUND: The measurement of alpha-fetoprotein (AFP) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumors. The current study was performed to establish reference values for AFP in CSF and to explore the relationship of CSF AFP and serum AFP in patients. MATERIAL AND METHODS: CSF samples were obtained from 351 inpatients admitted because of various neurological diseases, excluding those who were pregnant, had active liver disease, or who had trophoblastic or other malignant tumors. In 256 of the 351 patients, paired samples of CSF and serum were obtained. Both CSF AFP and serum AFP were measured. The 97.5th percentile and maximum value of CSF AFP were obtained. The CSF AFP and serum AFP concentrations in each of the 256 paired samples were compared. RESULTS: The 97.5th percentile and maximum value of CSF AFP concentration for overall participants were 1.042 and 1.950 g/L, respectively. The CSF AFP concentration was found to be higher than the simultaneous serum AFP concentration only in 1.6% (4/256) of participants. CONCLUSIONS: The reference value determined in this study for CSF AFP is significantly lower than that usually used in clinical practice. A CSF AFP concentration higher than the simultaneous serum AFP concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal AFP-secretion.

Clinico-pathological features and mutational spectrum of 16 nemaline myopathy patients from a Chinese neuromuscular center.

Nemaline myopathy (NM) is a congenital myopathy of great heterogeneity, characterized by the presence of rods in the cytoplasm of muscle fibers. The samples of 16 nemaline myopathy patients diagnosed by characteristically pathological features went through whole exon sequencing. Clinico-pathological and genetic features of the cases were systematically analyzed. According to the classification of nemaline myopathy by ENMC, 8 cases are typical congenital subtype, 6 cases are childhood/juvenile onset subtype and 2 case are adult onset subtype. In histological findings, characteristic purple-colored rods are discovered under modified gömöri trichrome staining (MGT). Electron microscopy revealed the presence of high electron-dense nemaline bodies around the submucosa and the nucleus nine patients (9/16 56.3%) were detected pathogenic causative mutations, among whom mutations in the NEB gene were the most frequent (6 patients, 66.7%). KBTBD13 gene mutation was discovered in two patients and ACTA1 gene mutation was discovered in 1 patient. Nemaline myopathy is a congenital myopathy with highly clinico-pathological and genetic heterogeneity. NEB gene mutation is the most common mutation, in which splicing change c.21522 +3A > G is hotspot mutation in Chinese NM patients.

Data-independent acquisition-based quantitative proteomic analysis of m.3243A>G MELAS reveals novel potential pathogenesis and therapeutic targets.

The pathogenesis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) syndrome has not been fully elucidated. The m.3243A > G mutation which is responsible for 80% MELAS patients affects proteins with undetermined functions. Therefore, we performed quantitative proteomic analysis on skeletal muscle specimens from MELAS patients. We recruited 10 patients with definitive MELAS and 10 age- and gender- matched controls. Proteomic analysis based on nanospray liquid chromatography-mass spectrometry (LC-MS) was performed using data-independent acquisition (DIA) method and differentially expressed proteins were revealed by bioinformatics analysis. We identified 128 differential proteins between MELAS and controls, including 68 down-regulated proteins and 60 up-regulated proteins. The differential proteins involved in oxidative stress were identified, including heat shock protein beta-1 (HSPB1), alpha-crystallin B chain (CRYAB), heme oxygenase 1 (HMOX1), glucose-6-phosphate dehydrogenase (G6PD) and selenoprotein P. Gene ontology and kyoto encyclopedia of genes and genomes pathway analysis showed significant enrichment in phagosome, ribosome and peroxisome proliferator-activated receptors (PPAR) signaling pathway. The imbalance between oxidative stress and antioxidant defense, the activation of autophagosomes, and the abnormal metabolism of mitochondrial ribosome proteins (MRPs) might play an important role in m.3243A > G MELAS. The combination of proteomic and bioinformatics analysis could contribute potential molecular networks to the pathogenesis of MELAS in a comprehensive manner.

CSF and serum hCG in patients without gestational and neoplastic hCG-secretion.

BACKGROUND: The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumours. The current study was performed to establish reference values for hCG in CSF and to explore the relationship of CSF hCG and serum hCG in patients who are not pregnant or do not have trophoblastic tumours. MATERIAL AND METHODS: CSF samples were obtained from 369 inpatients admitted because of various neurological diseases, excluding pregnancy, trophoblastic tumours and other malignant tumours. In 271 of the 369 patients, paired samples of CSF and serum were obtained. Both CSF hCG and serum hCG were measured. The 97.5th percentile and maximum value of CSF hCG were obtained. The CSF hCG and serum hCG concentrations in each of the 271 paired samples were compared. RESULTS: The 97.5th percentile and maximum value of CSF hCG concentration for overall participants were 1.00 and 5.00 IU/L, respectively. The CSF hCG concentration was found to be higher than the simultaneous serum hCG concentration in 81.9% (222/271) of the participants. CONCLUSIONS: The reference value determined in this study of CSF hCG in men is significantly lower than that usually used in clinical practice. A CSF hCG concentration higher than the simultaneous serum hCG concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal hCG-secretion.

A novel homozygous mutation in ATP13A2 gene causing pure hereditary spastic paraplegia.

SPG78 is a subtype of hereditary spastic paraplegia(HSP) caused by ATP13A2 gene mutations. SPG78 was reported as complicated HSP in several cases, but was never associated with pure HSP. Here we report the first Chinese patient carrying a novel homozygous nonsense mutation in ATP13A2 presenting with pure HSP.

A novel application of tau PET in the diagnosis of sporadic inclusion body myositis: A case report.

RATIONALE: Sporadic inclusion body myositis (sIBM) is a chronic progressive idiopathic inflammatory myopathy, with characteristic rimmed vacuoles and sarcoplasmic abnormal tau protein deposits. THK5317, an F-labelled positron emission tomography (PET) marker, targets tau protein deposits, which are expressed in the brain of patients with Alzheimer's disease (AD). It is assumed that THK5317 PET/MRI may also depict tau protein in the skeletal muscles of patients with sIBM. Here we introduced a novel application of tau PET in diagnosis of sIBM in a rare case. PATIENT CONCERNS: We presented a 46-year-old woman who suffered from progressive lower limb weakness for one and a half year. DIAGNOSES: Needle electromyography showed myogenic damage. Characteristic myopathological changes of sIBM were discovered, and abnormal tau protein deposits were identified by tau immunostaining. Genetic testing ruled out the GNE myopathy, a hereditary distal myopathy with rimmed vacuoles. The patient was finally diagnosed as sIBM. INTERVENTIONS: We performed [F] THK5317 PET/MRI on the patient. OUTCOMES: There were significantly increased tau uptake levels in the quadriceps muscles of sIBM patient. The uptake levels of tau in the quadriceps were significantly higher than that in the posterior group of thigh muscles, which was consistent with the distribution characteristics of involved muscle groups. LESSONS: [F] THK5317 PET can reveal muscular tau deposition in vivo, which provides a new and noninvasive diagnostic method for sIBM and offers the opportunity to monitor the progression of tau pathology along with muscle impairment.

FHL1-related myopathy may not be classified by reducing bodies in muscle biopsy.

FHL1-related myopathies, including reducing body myopathy (RBM), X-linked scapulo-axio-peroneal myopathy, rigid spine syndrome, X-linked myopathy with postural muscle atrophy (XMPMA), X-linked Emery-Dreifuss muscular dystrophy and hypertrophic cardiomyopathy, are clinically and pathologically heterogeneous disorders caused by FHL1 gene mutations. According to previous reports, the first three types are myopathies with reducing bodies observed in biopsies, and the last three are myopathies without reducing bodies. We report four FHL1-related myopathy patients, including an XMPMA patient and a RBM family with three patients. Clinical information, muscle biopsies, electromyograms and genetic testing were obtained. Muscle weakness and atrophy, spinal rigidity, and joint contracture were present in the RBM family. The XMPMA patient showed a pseudoathletic appearance with muscle weakness and atrophy, spinal rigidity and deformity. The index patient of the RBM family underwent two muscle biopsies to find reducing bodies. Interestingly, these muscle biopsies revealed reducing bodies and rimmed vacuoles not only in the RBM family but also in the XMPMA patient. Next-generation sequencing identified a reported single missense mutation c.448 C>T (p. C150R) in the RBM family and a novel mutation c.814T>C (p. S272P) in the XMPMA patient. Therefore, FHL1-related myopathies overlap substantially and may not be simply classified into subtypes depending on reducing bodies. Biopsies of additional affected muscles can aid in finding reducing bodies. We report the first XMPMA patient with a novel FHL1 mutation and reducing bodies in a muscle biopsy in China.