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Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

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BACKGROUND: GlcNAc2-epimerase (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. OBJECTIVE: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations. METHODS: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity. RESULTS: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients. CONCLUSIONS: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

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The complement system is a set of over 50 proteins that constitutes an essential part of the innate immune system. Complement system activation involves an organized proteolytic cascade. Overactivation of complement system activation is the main pathogenic mechanism of several diseases and contributes to the manifestations of many other conditions. This review describes the normal complement system and the role for complement dysregulation in critical illnesses, notably sepsis and acute respiratory distress syndrome. Complement activation is involved in the immune system response to pathogens but, when excessive, can contribute to tissue damage, runaway inflammation, and capillary leakage syndrome. Complement overactivation may play a key role in severe forms of coronavirus disease 2019 (COVID-19). Two diseases whose manifestations are mainly caused by complement overactivation, namely, atypical hemolytic and uremic syndrome (aHUS) and myasthenia gravis, are discussed. A diagnostic algorithm for aHUS is provided. Early complement-inhibiting therapy has been proven effective. When renal transplantation is required, complement-inhibiting drugs can be used prophylactically to prevent aHUS recurrence. Similarly, acetylcholine-receptor autoantibody-positive generalized myasthenia gravis involves complement system overactivation and responds to complement inhibition. The two main complement inhibitors used in to date routine are eculizumab and ravulizumab. The main adverse event is Neisseria infection, which is rare and preventable, but can be fatal. The complement system is crucial to health but, when overactivated, can cause or contribute to disease. Effective complement inhibitors are now available, although additional data are required to determine optimal regimens. Further research is also needed to better understand the complement system, develop advanced diagnostic tools, and identify markers that allow the personalization of treatment strategies.

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OBJECTIVE: To evaluate the efficacy and safety of a low-dose, long-term rituximab regimen in the treatment of idiopathic CIDP. METHODS: This study included 15 CIDP patients treated with rituximab. Patients were administered 600 mg of rituximab intravenously every 6 months. Baseline evaluation was conducted before the initiation of rituximab treatment and subsequent evaluations were conducted 6 months after each rituximab infusion at on-site visits. Clinical improvement was objectively determined by improvement of scale score at least decrease ≥1 INCAT or mRS or increase ≥4 MRC or ≥8 cI-RODS after each infusion compared to baseline evaluation. RESULTS: Fifteen CIDP patients were included and 10 of them were typical CIDP and five were distal CIDP. Nine in 15 (60%) patients after first infusion and three in six (50%) patients after second infusion exhibited significant clinical improvement compared to baseline evaluation. Additionally, rituximab facilitated a reduction or cessation of other medications in 73% of patients at last visit. The safety profile was favorable, with no reported adverse events. CONCLUSION: Rituximab presents a promising therapeutic option for idiopathic CIDP, offering both efficacy and safety with a low-dose, long-term regimen.

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Introduction: Efgartigimod is effective and well-tolerated in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (MG). However, the therapeutic potential and the safety profile of efgartigimod in myasthenic crisis (MC) remained largely unknown. Methods: This is an observational, prospective, multicenter, real-world study to follow 2 MC patients who initiated efgartigimod as a first-line rescue therapy and 8 cases who used it as an add-on therapy. Baseline demographic features and immunotherapies were collected, and the MG-activities of daily living (MG-ADL) scale was evaluated every week since efgartigimod treatment for 8 weeks. Additionally, serum IgG and anti-AChR antibody levels and the peripheral CD4+ T lymphocytes were measured before and after one cycle of treatment. Results: Ten patients with MC were enrolled in the study, including 9 anti-AChR antibody positive and 1 anti-muscle-specific kinase (MuSK) positive. All patients were successfully weaned from the ventilation after receiving efgartigimod treatment, with a length of 10.44 ± 4.30 days. After one cycle of infusions, the MG-ADL score reduced from 15.6 ± 4.4 at the baseline to 3.4 ± 2.2, while the corticosteroid dose was tapered from 55.0 ± 20.7 mg to 26.0 ± 14.1 mg. The proportions of regulatory T cells and naïve T cells (% in CD4+ T) significantly decreased post-efgartigimod treatment (5.48 ± 1.23 vs. 6.90 ± 1.80, P=0.0313, and 34.98 ± 6.47 vs. 43.68 ± 6.54, P=0.0313, respectively). Conclusion: These findings validated the rapid action of efgartigimod in facilitating the weaning process with a good safety profile in patients with MC.

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OBJECTIVE: Efgartigimod, a neonatal Fc receptor antagonist, facilitates antibody degradation including pathogenic IgGs. The ADAPT study demonstrated the tolerability and efficacy of efgartigimod in the treatment of generalized myasthenia gravis (gMG). However, very limited evidence is available for the Chinese population, and it remains inconclusive about which kind of patients are selected to preferentially receive efgartigimod in real-world settings. METHODS: This multicenter cohort study included gMG patients treated at 14 neuromuscular reference centers in China. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, immunosuppressants, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected. RESULTS: Of the 1640 gMG admitted between September and December 2023, 61 (3.7%) received efgartigimod for at least one treatment cycle. Among them, 56 cases (92%) were anti-AChR antibody-positive, 4 were anti-MuSK antibody-positive, and 1 was seronegative. Thymoma-associated myasthenia gravis accounted for most cases (44%, 27 out of 61). The principal causes of efgartigimod initiation included MG acute exacerbation (MGAE) (48%, 29 out of 61) and myasthenic crisis (MC) (15%, 9 out of 61). Clinically meaningful improvement was rapidly achieved in 97% (58 out of 61) of patients at 1.3 ± 0.7 weeks. By week 12, the MG-ADL score reduced to 3.8 ± 4.1 (baseline:10.5 ± 5.2) for all participants, while it reduced to 4.0 ± 4.7 for MGAE and 3.8 ± 4.2 for MC, respectively. All but one TMG patient required no additional rescue therapies after efgartigimod initiation. 11.5% (7 out of 61) reported ≥1 TEAEs. INTERPRETATION: This multicenter cohort study demonstrated the efficacy of efgartigimod in rapid control of gMG. Patients with MGAE or MC would benefit from efgartigimod treatment.

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Eculizumab has improved recovery from ventilatory support in myasthenic crisis (MC) cases. However, the safety and efficacy profiles from prospective studies are still lacking. This study aimed to explore eculizumab's safety and efficacy in a prospective case series of patients with refractory MC. We followed a series of anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG) patients who received eculizumab as an add-on therapy for 12 weeks during MC to facilitate the weaning process and reduced disease activity. Serum anti-AChR antibodies and peripheral immune molecules associated with the complement pathway were evaluated before and after eculizumab administration. Compared to the baseline Myasthenia Gravis Foundation of America (MGFA)-quantitative MG test (QMG) scores (22.25 ± 4.92) and MG-activities of daily living (MG-ADL; 18.25 ± 2.5) scores at crisis, improvements were observed from 4 weeks (14.5 ± 10.47 and 7.5 ± 7.59, respectively) through 12 weeks (7.5 ± 5.74 and 2.25 ± 3.86, respectively) post-treatment. Muscle strength consistently improved across ocular, bulbar, respiratory, and limb/gross domain groups. One patient died of cardiac failure at 16 weeks. Three cases remained in remission at 24 weeks, with a mean QMG score of 2.67 ± 2.89 and ADL score of 0.33 ± 0.58. No significant side effects were reported. Serum CH50 and soluble C5b-9 levels significantly declined, while there were no significant changes in serum anti-AChR antibody levels, C1q, C5a levels, or peripheral lymphocyte proportions. Eculizumab was well tolerated and showed efficacy in this case series. Large prospective cohort studies with extended follow-up periods are needed to further explore the safety and efficacy profile in real-world practice.

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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.

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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.

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Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by progressive limb weakness, dysphagia, dysphonia, and respiratory failure due to degeneration of upper and lower motor neurons. The pathogenesis of ALS is still unclear. Neuroinflammation has been found to be involved in its development and progression. Cytokines play a significant role in the inflammatory process. This study aims to identify novel biomarkers that may assist in the diagnosis of ALS. Methods: In Fujian Medical University Union Hospital and Huashan Hospital Fudan University, two independent centers, we prospectively recruited 50 ALS patients, and 41 healthy controls (25 ALS and 26 controls in the first stage and 25 ALS and 15 controls in the validation stage). An 18-plex Luminex kit was used to screen the serum cytokines levels in the first stage. Commercial ELISA kits were used to measure the levels of target cytokines in the validation stage. A single-molecule array HD-X platform was applied to assess the levels of serum neurofilament light chain (NFL). Results: The levels of serum IL-18 were markedly increased in patients with ALS in the first stage (p = 0.016). The ROC curve showed an area under the curve at 0.695 (95% CI 0.50-0.84) in distinguishing ALS patients from healthy controls. The IL-21 was decreased in elderly patients when grouped by 55 years old (the medium age). Furthermore, the IL-5, IL-13, IL-18, and NFL had a positive relationship with the disease progression of ALS. We also found that serum IL-18 was markedly increased in ALS patients in the validation stage (167.67 [148.25-175.59] vs 116.44 [102.43-122.19]pg/ml, p < 0.0015). Conclusion: In this study, we identified systemic cytokine profile changes in the serum of ALS patients, especially the elevated IL-18, as well as the decreased IL-21 in elder patients. These changes in serum cytokine profiles may shed new light on an in-depth understanding of the immunopathogenic characteristics of ALS.

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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.

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Background: Refractory chronic inflammatory demyelinating polyneuropathy (CIDP) is a challenging subset of CIDP. It does not respond well to immune therapy and causes substantial disability. A comprehensive understanding of its clinical profile, electrophysiological characteristics and potential risk factors associated with refractoriness remains to be further elucidated. Methods: Data in this cross-sectional study was collected and reviewed from the Huashan Peripheral Neuropathy Database (HSPN). Included patients were categorized into refractory CIDP and non-refractory CIDP groups based on treatment response. The clinical and electrophysiological characteristics were compared between refractory and non-refractory CIDP groups. Potential risk factors associated with refractory CIDP were explored with a multivariate logistic regression model. Results: Fifty-eight patients with CIDP were included. Four disease course patterns of refractory CIDP are described: a relapsing-remitting form, a stable form, a secondary progressive form and a primary progressive form. Compared to non-refractory CIDP patients, refractory CIDP exhibited a longer disease duration (48.96 ± 33.72 vs. 28.33 ± 13.72 months, p = 0.038) and worse functional impairment (MRC sum score, 46.08 ± 12.69 vs. 52.81 ± 7.34, p = 0.018; mRS, 2.76 ± 0.93 vs. 2.33 ± 0.99, p = 0.082; INCAT, 3.68 ± 1.76 vs. 3.03 ± 2.28, p = 0.056, respectively). Electrophysiological studies further revealed greater axonal impairment (4.15 ± 2.0 vs. 5.94 ± 2.77 mv, p = 0.011, ulnar CMAP) and more severe demyelination (5.56 ± 2.86 vs. 4.18 ± 3.71 ms, p = 0.008, ulnar distal latency, 7.94 ± 5.62 vs. 6.52 ± 6.64 ms, p = 0.035, median distal latency; 30.21 ± 12.59 vs. 37.48 ± 12.44 m/s, p = 0.035, median conduction velocity; 58.66 ± 25.73 vs. 42.30 ± 13.77 ms, p = 0.033, median F-wave latency), compared to non-refractory CIDP. Disease duration was shown to be an independent risk factor for refractory CIDP (p < 0.05, 95%CI [0.007, 0.076]). Conclusion: This study provided a comprehensive description of refractory CIDP, addressing its clinical features, classification of clinical course, electrophysiological characteristics, and prognostic factors, effectively elucidating its various aspects. These findings contribute to a better understanding of this challenging subset of CIDP and might be informative for management and treatment strategies.

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Background: Myasthenic crisis (MC) is a life-threatening condition for myasthenia gravis (MG). Therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) efficaciously treat patients with MC. However, not every MC responds well to rescue therapies, and the determinants for outcome with the evidence from prospective cohorts are still lacking. Objectives: To explore the risk factors for in-hospital outcomes in patients with MC. Methods: Using a national neuromuscular center-based cohort of MG with prospective follow-ups from the crisis to the post-crisis phase, we finally included 90 MC episodes from 76 independent patients who received a standard regimen of rescue therapies. Results: The mean admission age was 52.89 ± 15.72 years. With a female predominance of 63.16% (48/76) and a high proportion of thymoma-associated MG (TMG) of 63.16% (48/76), the overall in-hospital mortality was 2.63% (2/76) and the average duration for mechanical ventilation (MV) use was 17.09 ± 13.36 days (0-53 days). In contrast to the patients with anti-acetylcholine receptor (AChR) antibodies, muscle-specific tyrosine kinase (MuSK)-associated MC exhibited a shorter MV support (5.20 ± 5.07 versus 17.40 ± 13.24 days, p = 0.023), length of intensive care units (ICU) stay (6.00 ± 4.64 versus 19.16 ± 17.54 days, p = 0.046), and hospital stay (16.00 ± 4.12 versus 34.43 ± 20.48 days, p = 0.011). Thymoma [odds ratio (OR): 0.200, 95% confidence interval (CI): 0.058-0.687, p = 0.011], partial pressure of carbon dioxide (PCO2) in blood gas before MV (OR: 1.238, 95% CI: 1.015-1.510, p = 0.035), and pneumonia (OR: 0.204, 95% CI: 0.049-0.841, p = 0.028) were identified as independent risk factors for prolonged MV use. TMG patients with thymoma burden exhibited a notable longer MV use (22.08 ± 17.54 versus 8.88 ± 6.79 days, p = 0.001), a prolonged hospital stay (40.40 ± 26.13 versus 23.67 ± 13.83 days, p = 0.009) compared with non-TMG. Even with complete thymoma resection (R0), TMG exhibited an unfavorable outcome versus non-TMG. Conclusion: With timely rescue therapies and prospective follow-ups, the in-hospital outcome of MCs was substantially improved. Thymoma, PCO2 in blood gas before MV, and pneumonia were identified as independent risk factors for prolonged MV use.

Risk factors for in-hospital outcome of myasthenic crisis Myasthenic crisis (MC) is a life-threatening condition for myasthenia gravis (MG). Therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIg) efficaciously treat patients with MC. However, not every MC responds well to rescue therapies, and the determinants for outcome with the evidence from prospective cohorts are still lacking. Using a national neuromuscular center-based cohort of MG with prospective follow-ups from the crisis to the post-crisis phase, we were able to include 90 MC episodes from 76 independent patients who received a standard regimen of rescue therapies. The mean admission age was 52.89±15.72 years. With a female predominance and a high proportion of thymoma-associated MG. The overall in-hospital mortality was 2.63% (2/76) and the average duration for MV use was 17.09±13.36 days (0-53 days). In contrast to the patients with anti-AChR antibodies, MuSK-associated MC exhibited a shorter MV support, length of ICU stay and hospital stay. Thymoma, PCO2 in blood gas before MV, and pneumonia were identified as independent risk factors for prolonged MV use. TMG patients with thymoma burden exhibited a notable longer MV use, a prolonged hospital stay compared with non-TMG. Even with complete thymoma resection (R0), TMG exhibited an unfavorable outcome versus non-TMG. With timely rescue therapies and prospective follow-ups, the in-hospital outcome of MCs was substantially improved. Thymoma, PCO2 in blood gas before MV, and pneumonia.

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Surveys and retrospective studies have revealed considerable delays in diagnosing late-onset Pompe disease (LOPD) in China, where the contributing factors remain poorly represented. Our study analyzed the diagnostic journey of 34 LOPD patients seen at our neuromuscular clinic from 2005 to 2022. We defined diagnostic delay as the time from the onset of the first relevant symptoms and laboratory findings suggestive of LOPD to the eventual diagnosis, and we constructed a correlation matrix to assess relationships among these variables. The cohort consisted of 34 patients with an equal male-to-female ratio, and the mean age at diagnosis was 27.68 ± 10.03 years. We found the median diagnostic delay to be 5 years, with a range of 0.3 to 20 years, with 97.1% having been misdiagnosed previously, most commonly with "Type II Respiratory insufficiency" (36.7%). Notably, patients at earlier onset (mean age, 18.19 years vs. 31 years; p < 0.005) tended to have higher creatine kinase (CK) levels. Furthermore, 92.6% reported difficulty in sitting up from a supine position since childhood. Our research emphasizes the role of early indicators like dyspnea and difficulty performing sit-ups in adolescents for timely LOPD diagnosis and treatment initiation. The importance of early high-risk screening using dried blood spot testing cannot be overstated.

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AIM: To clarify the role of Eomesodermin (EOMES) to serve as a disease-relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4+T subsets in amyotrophic lateral sclerosis (ALS). METHODS: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T-cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1-year longitudinal follow-ups, the ALSFRS-R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort. RESULTS: In the derivation cohort, the CD4+EOMES+T-cell subsets were significantly increased (p < 0.001). EOMES+ subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4+EOMES+T-cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003). CONCLUSIONS: We demonstrated that increased CD4+EOMES+T-cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.

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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.

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Objectives: This study aimed to assess the feasibility of a machine learning-based radiomics tools to discriminate between Limb-girdle muscular dystrophy R2 (LGMDR2) and immune-mediated necrotizing myopathy (IMNM) using lower-limb muscle magnetic resonance imaging (MRI) examination. Methods: After institutional review board approval, 30 patients with genetically proven LGMDR2 (12 females; age, 34.0 ± 11.3) and 45 patients with IMNM (28 females; age, 49.2 ± 16.6) who underwent lower-limb MRI examination including T1-weighted and interactive decomposition water and fat with echos asymmetric and least-squares estimation (IDEAL) sequences between July 2014 and August 2022 were included. Radiomics features of muscles were obtained, and four machine learning algorithms were conducted to select the optimal radiomics classifier for differential diagnosis. This selected algorithm was performed to construct the T1-weighted (TM), water-only (WM), or the combined model (CM) for calf-only, thigh-only, or the calf and thigh MR images, respectively. And their diagnostic performance was studied using area under the curve (AUC) and compared to the semi-quantitative model constructed by the modified Mercuri scale of calf and thigh muscles scored by two radiologists specialized in musculoskeletal imaging. Results: The logistic regression (LR) model was the optimal radiomics model. The performance of the WM and CM for thigh-only images (AUC 0.893, 0.913) was better than those for calf-only images (AUC 0.846, 0.880) except the TM. For "calf + thigh" images, the TM, WM, and CM models always performed best (AUC 0.953, 0.907, 0.953) with excellent accuracy (92.0, 84.0, 88.0%). The AUCs of the Mercuri model of the calf, thigh, and "calf + thigh" images were 0.847, 0.900, and 0.953 with accuracy (84.0, 84.0, 88.0%). Conclusion: Machine learning-based radiomics models can differentiate LGMDR2 from IMNM, performing better than visual assessment. The model built by combining calf and thigh images presents excellent diagnostic efficiency.

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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.

Assuntos

RESUMO

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.

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