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Oculopharyngodistal myopathy is a late-onset degenerative muscle disorder characterized by ptosis and weakness of the facial, pharyngeal, and distal limb muscles. A recent report suggested a non-coding trinucleotide repeat expansion in LRP12 to be associated with the disease. Here we report a genetic study in a Chinese cohort of 41 patients with the clinical diagnosis of oculopharyngodistal myopathy (21 cases from seven families and 20 sporadic cases). In a large family with 12 affected individuals, combined haplotype and linkage analysis revealed a maximum two-point logarithm of the odds (LOD) score of 3.3 in chromosomal region chr19p13.11-p13.2 and narrowed the candidate region to an interval of 4.5 Mb. Using a comprehensive strategy combining whole-exome sequencing, long-read sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal CGG repeat expansion in the 5' UTR of the GIPC1 gene that co-segregated with disease. Overall, the repeat expansion in GIPC1 was identified in 51.9% independent pedigrees (4/7 families and 10/20 sporadic cases), while the repeat expansion in LRP12 was only identified in one sporadic case (3.7%) in our cohort. The number of CGG repeats was <30 in controls but >60 in affected individuals. There was a slight correlation between repeat size and the age at onset. Both repeat expansion and retraction were observed during transmission but somatic instability was not evident. These results further support that non-coding CGG repeat expansion plays an essential role in the pathogenesis of oculopharyngodistal myopathy. [ABSTRACT FROM AUTHOR]

Introduction/Aims: GNE myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. Although over 300 GNE variants have been reported, some patients remain undiagnosed with monoallelic pathogenic variants. This study aims to analyze the entire GNE genomic region to identify novel pathogenic variants. Methods: Patients with clinically compatible GNE myopathy and monoallelic pathogenic variants in the GNE gene were enrolled. The other GNE pathogenic variant was verified using comprehensive methods including exon 2 quantitative polymerase chain reaction and nanopore long‐read single‐molecule sequencing (LRS). Results: A deep intronic GNE variant, c.862+870C>T, was identified in nine patients from eight unrelated families. This variant generates a cryptic splice site, resulting in the activation of a novel pseudoexon between exons 5 and 6. It results in the insertion of an extra 146 nucleotides into the messengerRNA (mRNA), which is predicted to result in a truncated humanGNE1(hGNE1) protein. Peanut agglutinin（PNA） lectin staining of muscle tissues showed reduced sialylation of mucin O‐glycans on sarcolemmal glycoproteins. Notably, a third of patients with the c.862+870C>T variant exhibited thrombocytopenia. A common core haplotype harboring the deep intronic GNE variant was found in all these patients. Discussion: The transcript with pseudoexon activation potentially affects sialic acid biosynthesis via nonsense‐mediated mRNA decay, or resulting in a truncated hGNE1 protein, which interferes with normal enzyme function. LRS is expected to be more frequently incorporated in genetic analysis given its efficacy in detecting hard‐to‐find pathogenic variants. [ABSTRACT FROM AUTHOR]

Background: This study aims to establish and validate a predictive nomogram for the short‐term clinical outcomes of myasthenia gravis (MG) patients treated with low‐dose rituximab. Methods: We retrospectively reviewed 108 patients who received rituximab of 600 mg every 6 months in Huashan Hospital and Tangdu Hospital. Of them, 76 patients from Huashan Hospital were included in the derivation cohort to develop the predictive nomogram, which was externally validated using 32 patients from Tangdu Hospital. The clinical response is defined as a ≥ 3 points decrease in QMG score within 6 months. Both clinical and genetic characteristics were included to screen predictors via multivariate logistic regression. Discrimination and calibration were measured by the area under the receiver operating characteristic curve (AUC‐ROC) and Hosmer–Lemeshow test, respectively. Results: Disease duration (OR = 0.987, p = 0.032), positive anti‐muscle‐specific tyrosine kinase antibodies (OR = 19.8, p = 0.007), and genotypes in FCGR2A rs1801274 (AG: OR = 0.131, p = 0.024;GG:OR = 0.037, p = 0.010) were independently associated with clinical response of post‐rituximab patients. The nomogram identified MG patients with clinical response with an AUC‐ROC (95% CI) of 0.875 (0.798–0.952) in the derivation cohort and 0.741(0.501–0.982) in the validation cohort. Hosmer–Lemeshow test showed a good calibration (derivation: Chi‐square = 3.181, p = 0.923; validation: Chi‐square = 8.098, p = 0.424). Conclusions: The nomogram achieved an optimal prediction of short‐term outcomes in patients treated with low‐dose rituximab. [ABSTRACT FROM AUTHOR]

Background: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. Methods: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. Results: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12–74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92–1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. Conclusion: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study wasto investigate the efficacy of tacrolimus treatment in patients with refractory generalized myasthenia gravis (MG) and explore its impact on lymphocytic phenotypes and related cytokines mRNA expression. Methods: A total of 24 refractory generalized MG patients were enrolled. Before treatment and at 2, 6, and 12 months after tacrolimus treatment, the therapeutic effect was evaluated by the quantitative MG score of the Myasthenia Gravis Foundation of America (QMG), Manual Muscle Test (MMT), MG-specific Activities of Daily Living (MG-ADL), 15-item Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), and changes of prednisone dosage. Also, we used the flow cytometer for the lymphocytic immunophenotyping and real-time PCR for the qualification of cytokine mRNA in peripheral blood mononuclear cells (PBMCs) at different time points during the treatment. Results: Significantly decreased QMG, MMT, MG-ADL, and MG-QOL15 were observed at all time points during the tacrolimus treatment. The dosage of prednisone also reduced at the end of the observation period with only 6 adverse events reported. The immunological impact of tacrolimus was revealed by reduced percentages of Tfh, Breg, CD19+BAFF-R+ B cells, and increased percentages of Treg cells as well as down-regulated expression of IL-2, IL-4, IL-10, and IL-13 mRNA levels in PBMCs during the treatment. Conclusion: Our study indicated the clinical efficacy of tacrolimus in patients with refractory generalized MG. The underlying immunoregulatory mechanism of tacrolimus may involve alterations in the phenotypes of peripheral blood lymphocytes and Th1/Th2-related cytokine expression of PBMCs. [ABSTRACT FROM AUTHOR]

• Report of novel mutations in a Chinese cohort of anoctaminopathy. • Presymptomatic hyperCkemia is the most common phenotype in this Chinese cohort of anoctaminopathy. • Adductor magnus and medial gastrocnemius are preferentially involved in muscle MRI of anoctaminopathy. Recessive mutations in anoctamin-5 (ANO5) are causative for limb-girdle muscular dystrophy (LGMD) 2 L and non-dysferlin Miyoshi-like distal myopathy (MMD3). ANO5 mutations are highly prevalent in European countries; however it is not common in patients of Asian origin, and there is no data regarding the Chinese population. We retrospectively reviewed the clinical manifestations and gene mutations of Chinese patients with anoctaminopathy. A total of five ANO5 mutations including four novel mutations and one reported mutation were found in four patients from three families. No hotspot mutation was found. Three patients presented with presymptomatic hyperCKemia and one patient had limb muscle weakness. Muscle imaging of lower limbs showed preferential adductor magnus and medial gastrocnemius involvement. No hotspot mutation has been identified in Chinese patients to date. [ABSTRACT FROM AUTHOR]

• Duration from onset to the crisis is significantly shorter in TMG patients. • The in-hospital clinical outcome of MC is worse in TMG patients compared with that in non-thymoma-associated MG patients. • MG patients with unresected thymoma had longer hospital stays than that with POMC. Thymoma-associated myasthenia gravis (TMG) had more severe symptoms and worse prognoses in comparison to non-thymoma-associated MG. Thymoma recurrence was frequently associated with transient worsening of MG and even acute respiratory failure, namely myasthenic crisis (MC). However, little is known about the clinical features and outcomes of MC in thymoma-associated MG patients. We performed a retrospective cohort study in MG patients recruited from 9 independent tertiary neuromuscular centers in China from Jan 2015, through Oct 2022. Overall, 156 MC from 149 MG patients with positive anti-acetylcholine receptor (AChR) antibodies were finally analyzed. Next, these patients were divided into two subgroups: the TMG group (n = 60 MCs, 58 patients) and the non-thymoma-associated MG group (n = 96 MCs, 91 patients). Compared with non-thymoma-associated MG, TMG patients had a significantly shorter disease duration from symptom onset to the crisis (17.95±40.9 vs 51.31±60.61 months, P <0.0001), a larger proportion of MGFA IVa as the initial onset clinical classification (6.67% vs 0, P = 0.0205), and a longer hospital stay (39.24±22.09 [6–111] vs. 33.2 ± 23.42 days [7–120]; P = 0.0317) during the crisis. Within the TMG group, the hospital stay was significantly longer in patients with unresected thymoma compared to that in postoperative myasthenic crisis (POMC) (47.68±24.9 [6–111] vs. 34.21±18.87 days [12–82]; P = 0.0257). Early identification of the MG categories may provide some hints in tailoring therapeutic strategies to improve the prognosis. [ABSTRACT FROM AUTHOR]

• We reported a pair of siblings with OPDM2 exhibiting significant intrafamilial phenotypic heterogeneity. • The proband demonstrated rare features of neurogenic impairment, tremor and visual disturbance, which have been rarely reported in OPDM2, while the sister showed typical phenotype of OPDM. • The proband showed neurogenic impairment mimicking the phenotype of motor neuron disease (MND). • Ultra-long repeat expansions exceeding the upper limit could be non-pathogenic in OPDM2. Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease characterized by ocular, facial, bulbar and distal limb muscle weakness. Here, we presented a pair of siblings with OPDM2 displaying marked intrafamilial phenotypic heterogeneity. In addition to muscle weakness, the proband also demonstrated tremor and visual disturbance that have not been reported previously in OPDM2. Electrophysiological and pathological studies further suggested the presence of neurogenic impairment in the proband. Repeat-primed polymerase chain reaction (RP-PCR) and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR) confirmed the molecular diagnosis of OPDM2 in the siblings. Given the rarity of the case, the association between OPDM2 and tremor, visual disturbance, or neurogenic impairment remained to be explored. [ABSTRACT FROM AUTHOR]

Autoimmune nodopathy is a peripheral neuropathy characterized by acquired motor and sensory deficit with autoantibodies against the node of Ranvier or paranodal region in the peripheral nervous system. The clinical and pathological characteristics of the disease are distinct from that of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and the standard treatment for CIDP is partially effective. Rituximab is a chimeric monoclonal antibody which binds and depletes B cells in peripheral blood. This prospective observational study included 19 patients with autoimmune nodopathy. Participants received intravenous rituximab treatment 100 mg the first day and 500 mg the next day and given every 6 months. The Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, Inflammatory Rasch-Built Overall Disability Scale (I-RODS), Medical Research Council (MRC) sum score, and Neuropathy Impairment Score (NIS) were collected at entry and before the rituximab infusion every 6 months. At the last visit, 94.7% (18/19) of the patients showed clinical improvement on either the INCAT, I-RODS, MRC, or NIS scale. After the first infusion, 9 patients (47.7%) showed improvement on the INCAT score, and 11 patients (57.9%) on cI-RODS. In patients who received more than one rituximab infusion, the improvement of INCAT score and cI-RODS at the last assessment was higher than that after the first infusion. We also observed tapered or withdrawn concomitant oral medications in these patients. [ABSTRACT FROM AUTHOR]

Background: Myasthenia gravis (MG) is the most prevalent autoimmune disorder affecting the neuromuscular junction. A rapid deterioration in respiratory muscle can lead to a myasthenic crisis (MC), which represents a life-threatening condition with high mortality in MG. Multiple CD4+ T subsets and hypercytokinemia have been identified in the peripheral pro-inflammatory milieu during the crisis. However, the pathogenesis is complicated due to the many types of cells involved, leaving the underlying mechanism largely unexplored. Methods: We conducted single-cell transcriptomic and immune repertoire sequencing on 33,577 peripheral blood mononuclear cells (PBMCs) from two acetylcholine receptor antibody-positive (AChR +) MG patients during MC and again three months post-MC. We followed the Scanpy workflow for quality control, dimension reduction, and clustering of the single-cell data. Subsequently, we annotated high-resolution cell types utilizing transfer-learning models derived from publicly available single-cell immune datasets. RNA velocity calculations from unspliced and spliced mRNAs were applied to infer cellular state progression. We analyzed cell communication and MG-relevant cytokines and chemokines to identify potential inflammation initiators. Results: We identified a unique subset of monocytes, termed monocytes 3 (FCGR3B+ monocytes), which exhibited significant differential expression of pro-inflammatory signaling pathways during and after the crisis. In line with the activated innate immune state indicated by MC, a high neutrophil–lymphocyte ratio (NLR) was confirmed in an additional 22 AChR + MC patients in subsequent hemogram analysis and was associated with MG-relevant clinical scores. Furthermore, oligoclonal expansions were identified in age-associated B cells exhibiting high autoimmune activity, and in CD4+ and CD8+ T cells demonstrating persistent T exhaustion. Conclusions: In summary, our integrated analysis of single-cell transcriptomics and TCR/BCR sequencing has underscored the role of innate immune activation which is associated with hypercytokinemia in MC. The identification of a specific monocyte cluster that dominates the peripheral immune profile may provide some hints into the etiology and pathology of MC. However, future functional studies are required to explore causality. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of tacrolimus in patients with myasthenia gravis (MG), a systematic review and meta-analysis was performed. We searched PubMed and Embase for randomized controlled trials and clinical controlled trials in English language. Demographic and clinical characteristics of the MG patients were extracted. Differences in the current glucocorticoids (GC) dose in each included study were the primary outcome measure. The adverse events reported in each included study were used as safety evaluation. There were 5 trials included involving 683 patients. In this systematic review, we identified treatment with tacrolimus did not exhibit a statistically significant difference in the GC dose reduction at 6 months and 12 months compared with placebo. The standard mean differences in the GC dose reduction were −1.95 [(−4.20 to 0.30); p = 0.09] at 6 months and −1.72 [(−4.21 to 0.77); p = 0.18] at 12 months. But GC dose reduction from baseline in the tacrolimus group exceeded that in the controlled group. The weighted mean differences were −1.34 [(−2.46 to 0.23); p = 0.02] in the quantitative myasthenia gravis score and −1.10 [(−1.84 to −0.36); p = 0.004] in the myasthenia gravis activities of daily living score at 6 months. Adverse events were recorded in 80 of 347 patients (23%) treated with tacrolimus and most of them were mild. This meta-analysis proves that tacrolimus therapy is beneficial to improve clinical symptoms in MG patients. Tacrolimus may be a worthy therapy to relieve MG symptoms. [ABSTRACT FROM AUTHOR]

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions. Cytokines play important roles in facilitating the immune response and augmenting the pathogenic antibody production. The current study aims to sensitively characterize the serum levels of cytokines with very low concentration in generalized MG (gMG). Methods: Using ultrasensitive single-molecule arrays (SIMOA), we measured serum IL-2, IL-4, IL-5 and IL-12p70 in 228 participants including 152 immunotherapy-naïve anti-acetylcholine receptor (AChR) subtype gMG from Huashan MG registry and 76 age-matched healthy controls. Subgroup analysis was then performed by stratifying patients according to the onset ages, MGFA classification, disease duration at baseline. Results: Serum IL-2, IL-4, IL-5 and IL-12p70 levels were significantly elevated in gMG compared to controls (0.179 pg/mL versus 0.011 pg/mL, P < 0.0001; 0.029 pg/mL versus 0.018 pg/mL, P = 0.0259; 0.215 pg/mL versus 0.143 pg/mL, P = 0.0007; 0.132 pg/mL versus 0.118 pg/mL, P = 0.0401). Subgroup analysis revealed that IL-2 levels were slightly elevated in gMG with MGFA II compared to MGFA III/IV (0.195 pg/mL versus 0.160 pg/mL, P = 0.022), as well as elevated levels of IL-2 (0.220 pg/mL versus 0.159 pg/mL, P = 0.0002) and IL-5 (0.251 pg/mL versus 0.181 pg/mL, P = 0.004) in late-onset gMG compared with the early-onset gMG. gMG patients with a long duration had a significant increased serum IL-12p70 than those with a short duration (0.163 pg/mL versus 0.120 pg/mL, P = 0.011). Conclusion: Serum IL-2, IL-4, IL-5 and IL-12p70 levels were increased in AChR subtype gMG using ultrasensitive measurement. Serum cytokines with very low concentrations may provide as potential biomarkers in stratifying gMG patients in future prospective cohort studies. [ABSTRACT FROM AUTHOR]

Recent studies indicate that CGG repeat expansions in LRP12 , GIPC1 , and NOTCH2NLC are associated with oculopharyngodistal myopathy (OPDM) types 1, 2, and 3, respectively. However, some clinicopathologically confirmed OPDM cases continue to have unknown genetic causes. Here, through a combination of long-read whole-genome sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis PCR (AL-PCR), we found that a CGG repeat expansion in the 5' UTR of RILPL1 is associated with familial and simplex OPDM type 4 (OPDM4). The number of repeats ranged from 139 to 197. Methylation analysis indicates that the methylation levels in RILPL1 were unaltered in OPDM4 individuals. Analyses of muscle biopsies suggested that the expanded CGG repeat might be translated into a toxic poly-glycine protein that co-localizes with p62 in intranuclear inclusions. Moreover, analyses suggest that the toxic RNA gain-of-function effects also contributed to the pathogenesis of this disease. Intriguingly, all four types of OPDM have been found to be associated with the CGG repeat expansions located in 5' UTRs. This finding suggests that a common pathogenic mechanism, driven by the CGG repeat expansion, might underlie all cases of OPDM. [ABSTRACT FROM AUTHOR]

• The study used the WIND classification to categorize patients with myasthenic crisis. • The weaning process is significantly associated with clinical outcome in myasthenic crisis patients. • Predictors for difficult-/prolonged-weaning include pneumonia and SIRS presence. Weaning from invasive mechanical ventilation (MV) represents a pivotal step for myasthenic crisis (MC) patients. The aim was to evaluate the association between the weaning process and clinical outcomes, as well as to determine the independent predictors for difficult-/prolonged-weaning in MC. MC patients requiring invasive MV were recruited from Jan 2014 through Sep 2020. Among 124 consecutive MC patients, we finally included 66 patients (age 48.4 ± 18.7 years, female 45.5%). According to the WIND (Weaning according to a New Definition) classification, these patients were classified into no-weaning (n = 5, 7.6%), short-weaning (n = 13, 19.7%), difficult-weaning (n = 26, 39.4%), and prolonged-weaning group (n = 22, 33.3%). Four-week functional assessment in short-weaning group was more favorable than that in difficult-/prolonged-weaning group (p <0.001). Length of hospital stay (23.0 (15.0–28.0) vs. 37.5 (27.0–54.8), p <0.001), length of ICU stay (17.0 (8.5–22.5) vs. 34.0 (20.3–45.0), p <0.001), duration on ventilation (6.0 (6.0–8.5) vs. 18.0 (13.3–30.0), p <0.001), and time interval from MV to first weaning (6.0 (6.0–8.0) vs. 11.0 (8.0–20.8), p <0.001) in short-weaning group were significantly shorter than those in difficult-/prolonged-weaning group. Short-weaning group had a lower prevalence of pneumonia (23.1% vs. 75.0%) and systemic inflammatory response syndrome (SIRS) (38.5% vs. 85.4%), and a higher value in the lowest hemoglobin level (123.0 ± 12.9 g/L vs. 108.3 ± 18.1 g/L) and the lowest serum albumin level (33.2 ± 3.4 g/L vs. 29.9 ± 4.2 g/L) than difficult-/prolonged-weaning group. Multivariate logistic regression analysis identified pneumonia and the presence of SIRS within one week of MC as independent predictors for difficult-/prolonged-weaning. The weaning process is associated with clinical outcomes in MC patients requiring ventilation. Pneumonia concurrence and the presence of SIRS within one week of MC were identified as independent predictors for difficult-/prolonged-weaning after invasive MV. [ABSTRACT FROM AUTHOR]

The impact of Omicron infections on the clinical outcome and immune responses of myasthenia gravis (MG) remained largely unknown. From a prospective multicenter MG cohort (n = 189) with 197 myasthenic crisis (MC), we finally included 41 independent MG patients to classify into two groups: the Omicron Group (n = 13) and the Control Group (n = 28). In this matched cohort study, all-cause mortality was 7.69% (1/13) in Omicron Group and 14.29% (4/28) in Control Group. A higher proportion of elevated serum IL-6 was identified in the Omicron Group (88.89% vs 52.38%, P = 0.049). In addition, the proportions of CD3+CD8+T in lymphocytes and Tregs in CD3+CD4+ T cells were significantly elevated in the Omicron Group (both P = 0.0101). After treatment, the Omicron Group exhibited a marked improvement in MG-ADL score (P = 0.026) and MG-QoL-15 (P = 0.0357). MCs with Omicron infections were associated with elevated serum IL-6 and CD3+CD8+T response. These patients tended to present a better therapeutic response after fast-acting therapies and anti-IL-6 treatment. [ABSTRACT FROM AUTHOR]

Background: An accurate prediction for prognosis can help in guiding the therapeutic options and optimizing the trial design for generalized myasthenia gravis (gMG). We aimed to develop and validate a predictive nomogram to assess the short-term outcome in patients with the anti-acetylcholine receptor (AChR) subtype gMG.Methods: We retrospectively reviewed 165 patients with AChR subtype gMG who were immunotherapy naïve at the first visit from five tertiary centers in China. The short-term clinical outcome is defined as the achievement of minimal symptom expression (MSE) at 12 months. Of them, 120 gMG patients from Huashan Hospital were enrolled to form a derivation cohort (n = 96) and a temporal validation cohort (n = 24) for the nomogram. Then, this nomogram was externally validated using 45 immunotherapy naïve AChR subtype gMG from the other four hospitals. Multivariate logistic regression was used to screen independent factors and construct the nomogram.Results: MSE was achieved in 70 (72.9%), 20 (83.3%), and 33 (73.3%) patients in the training, temporal validation, and external validation cohort, respectively. The duration ≤ 12 months (p = 0.021), ocular score ≤ 2 (p = 0.006), QMG score > 13 (p = 0.008), and gross motor score ≤ 9 (p = 0.006) were statistically associated with MSE in AChR subtype gMG. The nomogram has good performance in predicting MSE as the concordance indexes are 0.81 (95% CI, 0.72-0.90) in the development cohort, 0.944 (95% CI, 0.83-1.00) in the temporal validation cohort, and 0.773 (95% CI, 0.63-0.92) in the external validation cohort.Conclusion: The nomogram achieved an optimal prediction of MSE in AChR subtype gMG patients using the baseline clinical characters. [ABSTRACT FROM AUTHOR]

Introduction/aims: The study aims to investigate the short-term efficacy of low-dose rituximab and its effect on immunological biomarker levels in myasthenia gravis (MG) patients with antibodies against muscle-specific tyrosine kinase (MuSK-MG).Methods: Twelve MuSK-MG patients were enrolled in this prospective, open-label, self-controlled pilot study. Clinical severity was evaluated at baseline and 6 mo after a single rituximab treatment (600 mg). B lymphocyte subtypes, MuSK antibody titers, together with levels of immunoglobulins, serum B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), soluble CD40L, and four exosomal microRNAs were evaluated. A correlation matrix to reveal pairwise relationships among above variables was also generated.Results: The single rituximab treatment significantly lowered the clinical severity scores and reduced daily dosage of prednisone (P = .032) at 6 mo. MuSK antibody titers decreased (P = .035) without significant changes in immunoglobulin levels. Serum BAFF level increased (P = .010), which negatively correlated with the percentages of B cells in lymphocytes as well as clinical severity. Additionally, serum exosomal miR-151a-3p showed a reduction of 28.1% (P = .031).Discussion: We confirmed the clinical efficacy of low-dose rituximab in MuSK-MG, accompanied by a decrease in MuSK antibody titers and an increase in serum BAFF. Serum BAFF levels negatively correlated with B-cell counts as well as clinical severity. [ABSTRACT FROM AUTHOR]

Objective: Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies against neuromuscular junctions. Myasthenic crisis (MC) represents the most severe state of MG with high in‐hospital mortality. We aimed to identify immune signatures using in‐depth profiling in MC, and to assess the correlations between immune biomarkers with clinical severity longitudinally. Methods: We studied 181 participants including 57 healthy controls, 96 patients with MG who never experienced crisis and 28 MC patients from December 2018 through June 2020. Follow‐up visits occurred prospectively from crisis to 6 months off‐mechanical ventilation. The frequencies of 20 CD4+ T subpopulations and 18 serum cytokines were associated with clinical scores using correlations and principal component analysis. Results: Patients in crisis exhibited a proinflammatory CD4+T response with elevated Th1 (P = 0.026), and Th17 cells (P = 0.032); decreased T follicular helper 2 (Tfh2) cells (P < 0.001), Tnaive in Tfh cells (P < 0.001), ICOS−Tfh cells (P = 0.017), and T central memory in Tfh (P = 0.022) compared with controls, and increased frequencies of Tregs (P = 0.026) and Tfh17 (P = 0.045) compared with non‐crisis MG. Cytokine cascade was identified in crisis including the ones associated with Th1 (IL‐1β/2/12p70/18/27/IFN‐γ/TNF‐α), Th2 (IL‐4/5/13), Th17 (IL‐6/17A/21/22/23/GM‐CSF), Th9 (IL‐9), and Treg (IL‐10). Longitudinally, seven immune biomarkers including Tregs, IL‐2/4/17A/IFN‐γ/TNF‐α/GM‐CSF had significant correlations with MG‐activities of daily living score. Interpretation: Vigorous inflammatory CD4+ T signatures were identified in MC and are associated with clinical severity. Future research is needed to explore its potential candidacy for therapeutic intervention and predicting impending crisis. [ABSTRACT FROM AUTHOR]

Introduction: In this prospective, open-label study we explore the effectiveness of low-dose rituximab every 6 months in treating refractory generalized myasthenia gravis (GMG).Methods: Twelve patients with acetylcholine receptor (AChR)-positive refractory GMG were enrolled for the study. The primary endpoint was the change in quantitative myasthenia gravis (QMG) score from baseline to the study end. Secondary endpoints included changes in manual muscle testing (MMT), MG-Related Activities of Daily Living (MG-ADL), and 15-item Quality-of-Life (MGQOL-15) scores, as well as prednisolone reduction.Results: MG decreased from 18.25 ± 4.03 to 8.42 ± 3.99 (P = .0001), MMT from 27.50 ± 17.78 to 4.58 ± 4.34 (P = .0001), ADL from 8.50 ± 2.84 to 1.17 ± 1.27 (P < .0001), MGQOL-15 from 37.25 ± 13.78 to 17.50 ± 9.73 (P = .0015), and prednisolone dose from 29.38 ± 11.92 mg/day to 8.86 ± 1.88 mg/day (P ≤ .01).Discussion: Low-dose rituximab every 6 months is effective in treating refractory GMG patients. [ABSTRACT FROM AUTHOR]

Introduction: The conversion rate from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) was reported to be much lower in Asian population since most OMG patients are juvenile onset. However, the exact conversion rate for adult-onset OMG to GMG is still unknown. Objective: We aimed to delineate the conversion rate and risk factors for adult patients with ocular onset to GMG. Methods: Adult myasthenia gravis (MG) patients with ocular onset (age > 18 years) were retrospectively reviewed. Patients with confined ocular involvement lasting more than 2 years (pure OMG group) and those who converted into GMG (converted OMG group) were enrolled for subsequent analysis. We then analyzed 5 clinical variables, including onset age, sex, onset symptoms, anti-acetylcholine receptor antibody (AChR Ab), and thymus CT. Survival analysis was applied to all enrolled patients to explore risk factors associated with conversion. Results: In a total number of 249 ocular-onset MG patients initially enrolled, we excluded 122 patients with OMG lasting less than 2 years. The remaining 127 patients were enrolled, including 106 converted OMG and 21 pure OMG patients. Converted OMG patients had an older onset age (threshold: 43 years) and higher anti-AChR Ab titer (threshold: 6.13 nmol/L). The estimated conversion rate was 70.64%. Moreover, 67% of conversion occurred within 2 years after onset. Cox regression of survival analysis revealed that higher anti-AChR Ab titer and bilateral ptosis were associated with a higher conversion rate. Conclusions: The conversion of adult OMG was associated with anti-AChR Ab titer, onset age, and bilateral ptosis. The estimated conversion rate of Chinese adult OMG patients was 70%. [ABSTRACT FROM AUTHOR]

Background: Patients in China with juvenile-onset myasthenia gravis present early, with a high prevalence of purely ocular symptoms, spontaneous remission rates, and low antibody seropositivity. Antibody detection using a cell-based assay has been reported to increase the diagnostic sensitivity in adult-onset myasthenia gravis. However, this method in patients with juvenile-onset myasthenia gravis has not been investigated.Methods: Patients with juvenile-onset myasthenia gravis who had not received prednisone or immunosuppressive therapy were recruited between June 2015 and April 2018 at the Huashan Hospital. Clinical information was collected. Serum anti-acetylcholine receptor antibodies were detected via cell-based assay with HEK293T cells expressing acetylcholine receptor subunits and rapsyn. Additionally, the IgG antibody subclass was identified.Results: Eighty-two patients with juvenile-onset myasthenia gravis were enrolled in the current study. Among them, 48 patients were anti-acetylcholine receptor positive (58.5%) and 34 were seronegative (41.5%), as assessed via enzyme-linked immunosorbent assay. Cell-based assay yielded 63 positive subjects (76.8%) and 19 seronegative subjects (23.2%). All the enzyme-linked immunosorbent assay-positive samples showed robust immunofluorescence in the cell-based assay, whereas 15 of 34 enzyme-linked immunosorbent assay-negative patients (44.1%) were found to have low-affinity acetylcholine receptor antibodies. Among all the cell-based assay-positive patients, 41 were positive for both adult and fetal acetylcholine receptor antibodies (50.0%), 18 were found positive for only adult acetylcholine receptor antibodies (21.9%), and four were found to possess only fetal acetylcholine receptor antibodies (4.9%). Fifteen antibody-positive samples underwent subclassification and were confirmed to be IgG1 subclass predominant (n = 15, including eight adult and fetal acetylcholine receptor antibody positive, five only adult acetylcholine receptor antibody positive, and two only fetal acetylcholine receptor antibody positive). There were no significant differences in clinical features among patients with different antibody profiles.Conclusions: The cell-based assay showed increased sensitivity in acetylcholine receptor antibody detection in Chinese patients with juvenile-onset myasthenia gravis, and most cases of Chinese juvenile-onset myasthenia gravis are still acetylcholine receptor autoantibody mediated. Furthermore, the antibodies detected are predominately of the IgG1 subclass. [ABSTRACT FROM AUTHOR]

We aimed to explore the effects of low-dose rituximab (RTX) on circulating T- and B-cell lymphocytes and the improvement of clinical symptoms in refractory myasthenia gravis (MG) patients. Fifteen patients with refractory MG were treated with a low dose of 600 mg RTX and were evaluated by serial-clinical scales, flow cytometry of peripheral blood T and B cells, and antibody titer before and after six months of RTX treatment. The quantitative MG score (QMGS), manual muscle testing (MMT), MG-related activities of daily living (MG-ADL) and MG-specific quality-of-life (QOL) were significantly improved and the average steroid-dosage reduction was 40% (p =.001) in refractory MG patients at six months after RTX infusion. Compared to eighteen non-refractory MG patients and eighteen Healthy controls, our study showed that the frequencies of circulating regulatory B cells (Bregs) and regulatory T cells (Tregs) were significantly lower and the expression of B-cell activating factor receptors (BAFF-Rs) was greater in refractory MG patients without RTX treatment. Importantly, 600-mg RTX was sufficient to deplete B cells and maintain low B-cell counts for up to six months after infusion. Additionally, a low dose of RTX further increased the frequencies of Tregs. Hence, there is an immune imbalance in circulating T- and B-cell lymphocytes in refractory MG patients compared to non-refractory MG patients. We conclude that remarkable T- and B-cell lymphocyte imbalance exists in refractory MG. Low-dose RTX can improve myasthenic symptom and deplete B cells and increase Tregs%. Unlabelled Image • Imbalance of T- and B-cell population exists in refractory MG. • Low-dose RTX may be effective in refractory MG. • Low-dose RTX can deplete B cells and increase Tregs%. [ABSTRACT FROM AUTHOR]

Introduction: Myasthenic crisis (MC) is a life-threatening condition usually occurred in patients with myasthenia gravis (MG). Objective: On the basis of a retrospective case series review, we try to develop a scoring system to evaluate the probability for in-hospital death in MC patients. Methods: We retrospectively reviewed 78 MC patients who were hospitalized from January 2014 to December 2018. Clinical and laboratory data including 17 variables were analyzed univariately. The main clinical outcome was defined as the in-hospital death. Then eligible variables were evaluated by a stepwise multivariate regression and a scoring system was then generated. Calibration and discrimination methods were used to evaluate and validate the model performance. Results: The overall in-hospital mortality was 11.5% (9/78) in the MC cohort. Five clinical variables including Myasthenia Gravis Foundation of America (MGFA) classification at onset, septic shock, thymoma classification, cardiac arrest, and the lowest serum albumin were found to be associated with in-hospital mortality. Further 3 variables entered the final regression, and internal validation showed that the area under the curve was 0.919 (95% CI 0.788–1.000). A scoring system with a full credit of 7 points was generated to predict the in-hospital mortality (MGFA at onset, 2 points; septic shock, 4 points; and cardiac arrest, 3 points). Conclusions: A 7-point scoring model was established on the basis of a retrospective review of MC patients to predict the in-hospital mortality. [ABSTRACT FROM AUTHOR]

Introduction: Limb-girdle muscular dystrophy type 2A (LGMD2A) is characterized by progressive wasting of muscles for which the disease-monitoring tools are still deficient.Methods: We performed muscle MRI of the lower limbs in 32 LGMD2A patients and 21 controls. The modified Mercuri scale was employed to evaluate the degree of fatty infiltration.Results: Severe fatty infiltration in the long head of biceps femoris (modified Mercuri scale 3.99) and sparing of extensor digitorum longus (modified Mercuri scale 0.17) were observed. The sensitivity and specificity of this pattern in diagnostic testing was 76.00% and 90.48%, respectively. A comprehensive clinical and MRI evaluation revealed that progressive fatty infiltration in the upper leg correlated well with disease progression, but neither calf involvement nor muscle strength deterioration showed a good correlation.Discussion: The selective involvement pattern is potentially useful for LGMD2A diagnosis. Upper leg muscle MRI is a sensitive evaluation method for monitoring disease progression. Muscle Nerve 58: 536-541, 2018. [ABSTRACT FROM AUTHOR]

Background: Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present two cases with novel mutations of AGRN of which we further investigated possible pathogenesis.Results: Patient 1 had general limb weakness with fluctuation and deterioration in the afternoon and in hot weather. Patient 2 had early-onset weakness of lower extremities with suspected fluctuation in the early stages, which then progressed to the upper limbs. Both distal and proximal muscles were involved. Repetitive stimulation on EMG in both patients showed decrement in proximal and distal limbs. Patient 2 showed a marked response to salbutamol while Patient 1 did not. By targeted exome sequencing, two novel homozygous missense variants, p.L1176P and p.R1698C, in the SEA and LG2 domain of agrin were identified respectively. Further functional analysis revealed instability of the protein and impaired clustering of the acetylcholine receptor (AChR) by both mutations.Conclusions: The mutations identified in AGRN in our study may cause congenital myasthenic syndrome by damaging protein stability and interfering with AChR clustering. These results broaden the understandings on the phenotype, genotype and pathogenesis of this rare disorder. [ABSTRACT FROM AUTHOR]

We aim to investigate the effect of a low dose of rituximab (RTX) in improving the clinical symptoms of refractory generalized myasthenia gravis (MG). Eight patients with refractory generalized MG were treated with a low dose of 600 mg RTX. Patients were evaluated by serial clinical scales, flow cytometry of peripheral blood B, T and NK cells, immunoglobulin, complement levels and antibody titer. The quantitative MG score (QMGS), manual muscle testing (MMT), MG-related activities of daily living (MG-ADL) and MG-specific quality-of-life (QOL) were recorded at baseline as well as 1, 3, and 6 months after RTX infusion. The initial improvement was recorded at 1 month after treatment. QMGS, MMT and MG-ADL were significantly improved and the average steroid dosage reduction was 43% ( p = 0.018) at 6 months. 600 mg RTX was sufficient to deplete B cells and maintain low B-cell counts until 6 months after infusion. Treatment with RTX did not result in a significant change in the percentage of CD 4 + , CD 8 + T-cells while an average increase in the percentage of NK cells. Our study found successful B cell depletion was parallel to symptoms remission and change in serum C3 and C4 levels. Serum AChR antibody levels were independent of clinical response and not influenced by RTX. Therefore, low dose of 600 mg RTX may be sufficient in depleting B cells, maintaining low B-cell counts and improving the clinical symptoms of MG in 6 months. [ABSTRACT FROM AUTHOR]

Mutations in the GMPPB gene may underlie both limb girdle muscular dystrophy (LGMD) and congenital myasthenic syndrome (CMS). Forty-one cases have been reported to date and hotspot mutations are emerging in the Caucasian population. Clinical and pathological features of 5 patients with compound heterozygous GMPPB mutations were collected and retrospectively reviewed. In vitro functional analysis was performed to investigate the pathogeneity of GMPPB variants. The patients presented with proximal limb weakness in their first to second decades. Fluctuating muscle weakness, myalgia and calf hypertrophy were the major complaints. Myogenic changes on electromyography and marked attenuation on 3 Hz repetitive nerve stimulation were observed in all patients. Four reported a beneficial response to pyridostigmine. Muscle MRI showed selective involvement in the calf in case 1. Immunolabeling of α-dystroglycan was abnormal for case 1 and case 2. Four novel missense mutations in the C-terminal region of GMPPB were identified, with p.(Arg357His) being present in all the cases. In vitro functional assays demonstrated that these variants did not markedly reduce the amount of GMPPB, but gave rise to an increased propensity for protein aggregation. Increasingly, patients with GMPPB mutations are found to present with an overlapping LGMD/myasthenic syndrome. The mutation spectrum in Chinese patients may differ from that of European populations, with the mutation p.(Arg357His) most frequently found. These mutations may lead to abnormal folding of GMPPB leading to protein aggregates in the cytoplasm rather than an overall loss in protein expression. [ABSTRACT FROM AUTHOR]

The interrelationship between mental health and autoimmunity gains more and more attention in recent years. However, the causality between personality traits and autoimmune diseases remained largely unknown. We first conducted two-sample mendelian randomization (MR) analysis on the relationships between mood instability, which is a common personality trait in the general population, and 10 autoimmune diseases. The results were further validated in secondary analyses of sensitivity where different MR methods, ethnicities, genders, and ascertainment methods were compared. In the primary analyses, three autoimmune diseases showed genetical predisposition to mood instability: asthma (OR [95%CI] = 3.45 [2.48, 4.78], P = 1.33E- 13), hypothyroidism (OR [95%CI] = 1.02 [1.00, 1.03], P = 1.71E-02), and systemic lupus erythematosus (OR [95%CI] = 5.25 [1.21, 22.76], P = 2.67E-02). The results were consistent in subsequent secondary analyses. Three diseases remained significantly correlated with mood instability by different MR methods with asthma remaining significant in Finnish and mixed populations, and in females from the UK biobank, while hypothyroidism remained significant in both genders from the UK biobank. Mood instability is a modifiable risk factor for three autoimmune diseases including asthma, hypothyroidism and systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Myasthenic crisis (MC) is a life-threatening state with respiratory failure in patients with myasthenia gravis (MG). The fast-acting immunomodulatory therapies for treating MC included plasma exchange (PE) and intravenous immunoglobulin (IVIG). However, the efficacy and the impact on antibody changes remained unknown. We prospectively followed 40 anti-acetylcholine receptors (AChR) antibody-positive MC patients who received either PE (n = 12) or IVIG (n = 28) at crisis. PE was associated with a reduced ICU stay length (p = 0.018) and an early response by the average changes in MGFA-QMG (p = 0.003), MMT (p = 0.020), and ADL (p = 0.011) at one-week off-ventilation. However, the clinical efficacy was equally comparable in both groups after 1 month. Post-treatment hemoglobin drop was significant in both groups, while IVIG was associated with a significant reduction in anti-AChR antibody titers (p < 0.001). This analysis provides real-world evidence in supporting the use of PE as a fast-acting therapy for shortening the ICU stay in AChR-associated MC. [ABSTRACT FROM AUTHOR]

We report two patients of Chinese ancestry with hereditary myopathy with early respiratory failure, one sporadic with atypical onset as rigid spine syndrome, the other familial with 10 years' history of hyperCKemia. Muscle biopsy was either nonspecific or typical with cytoplasmic bodies and rimmed vacuoles. Despite the phenotypic variety, both patients showed fatty infiltration of semitendinosus on muscle magnetic resonance imaging. Genetic analysis of case 1 disclosed de novo heterozygous missense mutations in the 119th fibronectin 3 domain of titin [c.90272C>T, p.P30091L]. Haplotype analysis of case 2 revealed a heterozygous missense mutation [c.90211T>C, p.C30071R] on a new disease allele incompatible with the British common haplotype. These findings suggest that hereditary myopathy with early respiratory failure is a worldwide distributed disorder and indicate the mutational vulnerability of TTN exon 343 in which de novo mutations could occur on different haplotype backgrounds. [ABSTRACT FROM AUTHOR]

Myasthenia Gravis (MG) is a T cell-driven, autoantibody-mediated disease. Here we show that oral Berberine (BBR) ameliorated clinical symptoms of experimental autoimmune myasthenia gravis(EAMG) rat model via decreasing the frequencies of Th1, Th17, Th1/17 cell subsets. JAK-STAT pathway was highlighted by transcriptomic analysis with EAMG mononuclear cells (MNCs). Surface plasmon resonance identified ligand binding interaction between BBR and JAK2, and electrostatic interaction was proposed by molecular dynamic simulation. Reduced phosphorylated JAK1/2/3 and STAT1/3 in MNCs from BBR-fed EAMG rats were demonstrated. These results suggest that BBR might improve EAMG by rebalancing T cell subsets through targeting JAK-STAT pathway. [Display omitted] • Berberine could ameliorate clinical symptoms of EAMG rat model. • Berberine treatment rebalances T helper cell subsets and inhibits JAK-STAT pathway. • There is ligand binding interaction between Berberine and JAK2. [ABSTRACT FROM AUTHOR]

We report the case of a patient who developed right hemiparesis with an acute onset 2 weeks before being transferred to our hospital. The brain MRI revealed multiple lesions in deep white matter; some were ovoid and perpendicular to the lateral ventricle, typical of cerebral demyelinating disease such as multiple sclerosis. The patient reported no history of hypertension, diabetes, dyslipidemia or other conventional vascular risk factors. The initial diagnosis was clinically isolated syndrome. However, low fever and petechiae in the extremities developed during hospitalization, which reminded us of cardioembolism. Echocardiography finally revealed a left atrial myxoma. The patient’s symptom alleviated after resection of the tumor. [ABSTRACT FROM PUBLISHER]

Juvenile-onset myasthenia gravis (JOMG) is a unique clinical subtype in China, featured by a higher prevalence of ocular myasthenia gravis (OMG), higher seronegativity of acetylcholine receptor (AChR) antibodies, and better prognosis than that in adult-onset myasthenia gravis (AOMG). We previously identified low-affinity AChR antibodies in Chinese JOMG patients using cell-based assays (CBAs), indicating a predominantly AChR antibody-positive profile. Here, we further screened AChR antibodies in both Chinese AOMG and JOMG patients by CBAs. We recruited patients with MG who had not received prednisone or immunosuppressive therapies between June 2015 and June 2019, and divided them into AOMG and JOMG subgroups according to their ages at the time of recruitment. Clinical information and blood samples were collected. Serum AChR antibodies were detected by CBAs in HEK293T cells expressing clustered adult and fetal AChRs, as well as by enzyme-linked immunosorbent assays (ELISAs). Differences in AChR antibody profiles between AOMG and JOMG subgroups were determined. A total of 239 patients with MG were enrolled in the present study, including 121 AOMG and 118 JOMG patients. Based on ELISAs, 74.4% of AOMG (90/121) and 59.3% of JOMG (70/118) patients were anti-AChR positive (p = 0.02). However, CBAs yielded equal anti-AChR positivities (p = 0.64), as indicated by 80.2% of AOMG patients (97/121) and 77.1% of JOMG patients (91/118). Furthermore, among AOMG patients, 67.8% (82/121) were positive for both adult and fetal AChR antibodies, 5.8% (7/121) were positive for only adult AChR antibodies, and 6.6% (8/121) were positive for only fetal AChR antibodies, while these rates were 50.8% (60/118), 21.2% (25/118), and 5.1% (6/118), respectively, in JOMG cohorts (p < 0.01). Twenty-nine AOMG patients and 10 JOMG patients underwent IgG subclassification of AChR antibodies, which were all confirmed to be predominantly IgG1. The positive rates of AChR antibodies did not differ between Chinese AOMG and JOMG patients, as revealed by CBAs. Furthermore, the screened AChR antibodies were predominantly IgG1 in both AOMG and JOMG patients. Unlabelled Image • CBA efficiently improve the detection sensitivity of AChR antibodies in both Chinese AOMG and JOMG group. • Chinese JOMG and AOMG share a comparable positive rate of anti-AChR antibodies. • AChR antibodies in both Chinese JOMG and AOMG patients were prominently of IgG1 subclass. [ABSTRACT FROM AUTHOR]

Two potentially related microRNAs (miRNAs; miR-150-5p and miR-146a-5p) were examined after low-dose rituximab (RTX) treatment in patients with acetylcholine receptor antibody (AChR)-positive refractory myasthenia gravis (MG). In this prospective, open-label, and self-controlled pilot trial, 12 AChR-positive refractory MG patients were administrated a single, low dose of RTX and followed up at six months. Results showed that RTX decreased the serum exosomal miR-150-5p, scores on three clinical indices (MGFA, MMT, ADL), and patients' prednisolone requirement. Additionally, CD19+ and CD27+ B cells decreased, showing a strong correlation with miR-150-5p. In conclusion, low-dose RTX is effective for AChR-positive refractory MG treatment. Furthermore, our data support the role of miR-150-5p as a potential biomarker for MG. Unlabelled Image [ABSTRACT FROM AUTHOR]

Background: Primary periodic paralysis is characterized by recurrent quadriplegia typically associated with abnormal serum potassium levels. The molecular diagnosis of primary PP previously based on Sanger sequencing of hot spots or exon-by-exon screening of the reported genes.Methods: We developed a gene panel that includes 10 ion channel-related genes and 245 muscular dystrophy- and myopathy-related genes and used this panel to diagnose 60 patients with primary periodic paralysis and identify the disease-causing or risk-associated gene mutations.Results: Mutations of 5 genes were discovered in 39 patients (65.0%). SCN4A, KCNJ2 and CACNA1S variants accounted for 92.5% of the patients with a genetic diagnosis.Conclusions: Targeted next-generation sequencing offers a cost-effective approach to expand the genotypes of primary periodic paralysis. A clearer genetic profile enables the prevention of paralysis attacks, avoidance of triggers and the monitoring of complications. [ABSTRACT FROM AUTHOR]