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Abstract In the present study, we investigated the associations of cachexia (loss of muscle, weight and fat) and frailty (loss of weight and muscle) status with the risk of developing amyotrophic lateral sclerosis, because these specific terms are rarely used in this research area. In this prospective study, we extracted cachexia and frailty status from the UK Biobank cohort to study the associations of these conditions (as determined via international classification of disease-10 codes) with amyotrophic lateral sclerosis. There was a greater risk of developing amyotrophic lateral sclerosis among individuals with cachexia and frailty status after adjusting for age, sex, income (pounds), body mass index, UK Biobank centers and smoking status. Among individuals with frailty status: a grip strength of

Background: Efgartigimod is an approved biologic for generalized myasthenia gravis (gMG), which is an autoimmune disease and can potentially be life-threatening. However, the therapeutic response to efgartigimod among the acetylcholine receptor gMG (AChR-gMG) subtypes remains inconclusive. Objective: To explore the patterns and predictors for the therapeutic response to efgartigimod among AChR-gMG subtypes. Design: This prospective, observational study included AChR-gMG patients treated with efgartigimod at 15 centers in China with a follow-up for at least 20 weeks. Methods: The primary outcome was the proportion of minimal symptom expression (MSE) responders, denoted by a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 0 or 1 within 4 weeks and maintained for ⩾4 weeks. AChR antibody-positive MG (AChR-MG) subtypes were classified into early onset myasthenia gravis (EOMG), late-onset myasthenia gravis (LOMG), and thymoma-associated myasthenia gravis (TAMG). The predictive factors for MSE responders were identified by univariate and multivariate logistic regression analysis. Results: One hundred sixteen patients were included with a median follow-up duration of 238 days (172.5–306.3). There were 50 (43.1%) patients with EOMG, 28 (24.1%) with LOMG and 38 (32.8%) with TAMG. After efgartigimod initiation, 35 (30.2%) patients were MSE responders, and the proportion of MSE responders was highest in the LOMG group (42.9%). The MG-ADL score reduction in the LOMG group was more significant than in the EOMG group by weeks 16 and 20 (both p = 0.022). Response patterns to efgartigimod among the AChR-MG subtypes differed as measured by the proportion of improved patients and MSE. LOMG presented sustained symptom control, while EOMG and TAMG showed more fluctuations. Eight TAMG patients (21.1%) switched to another biologic ( p = 0.005). Baseline MG-ADL was an independent predictor for therapeutic response to efgartigimod ( p

Abstract 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.

Background: Thymoma-associated myasthenia gravis (TAMG) is a subtype of myasthenia gravis (MG) that is associated with more severe symptoms and a relatively poor prognosis. Eculizumab, an inhibitor to target human C5 component of the complement cascade, is considered a treatment option for refractory generalized MG (gMG). Objectives: To explore the safety and efficacy of eculizumab in patients with TAMG. Design: This is an observational multicenter real-world cohort study to assess TAMG who were treated with eculizumab from June 2023 to June 2024. Data sources and methods: Clinical features associated with thymoma-associated multi-organ autoimmunity (TAMA), Myasthenia Gravis Activities of Daily Living (MG-ADL) score, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected. Results: Overall, 42 patients with gMG were treated with eculizumab at 5 research centers, of whom 22 patients with TAMG were finally included. This cohort had a mean age of 51.5 ± 12.1 years and an average disease duration of 4.0 ± 4.3 years. Regarding thymomas, the World Health Organization (WHO) histological classification was primarily B2 and B3 (63.7%), and Masaoka staging was predominantly IV (45.5%). Nine participants (40.9%) switched from efgartigimod to eculizumab aiming at a better clinical improvement and reducing steroid use. By week 12, the MG-ADL score decreased to 4.8 ± 4.7 (baseline: 11.7 ± 6.0), and the corticosteroid dose reduced to 23.2 ± 26.5 mg (baseline: 41.8 ± 63.9 mg). Two patients with TAMA showed significant improvement in skin lesions and thrombocytopenia. Two TEAEs were recorded including COVID-19 and herpes labialis infection. Four patients (18.2%) died of respiratory or circulatory failure owing to thymoma metastasis. Conclusion: This real-world study demonstrates the efficacy of eculizumab in achieving symptom control and corticosteroid reduction for TAMG. It may also be a therapeutic option for refractory TAMG and TAMA. Trial registration: NCT04535843.

BackgroundAs a rare genetic disease, adrenomyeloneuropathy (AMN) is the most common adult phenotype of X-linked adrenoleukodystrophy (X-ALD). Mutations in the ABCD1 gene have been identified to cause AMN.MethodsWe applied clinical evaluation, laboratory tests, and neuroimaging on three patients with progressive spastic paraparesis. In genetic analysis, we investigated ABCD1 gene mutations by whole-exome sequencing and Sanger sequencing. Bioinformatics tools were used to predict the effects of identified ABCD1 mutations on the protein.ResultsAll three patients were men with adult-onset disease, mainly characterized by progressive spastic paraparesis. Among them, two patients had peripheral neuropathy and one patient had signs of adrenal insufficiency. All three patients showed cerebral involvement on brain MRI, while two patients were found with diffuse cord atrophy on spinal MRI. High-VLCFA levels in plasma, as well as C24:0/C22:0 and C26:0/C22:0 ratios, were found in all three patients. In addition, three different ABCD1 mutations were identified in three unrelated Chinese families, including one known mutation (c.1415_1416delAG) and two novel mutations (c.217C>T and c.160_170delACGCAGGAGGC). Based on the clinical assessment, radiographic, biochemical, and genetic testing, the final diagnosis was AMN in these patients with spastic paraparesis.ConclusionThis study reported three patients with AMN and identified two novel mutations in the ABCD1 in the Chinese population. Our finding emphasized that X-ALD is an important cause of adult-onset spastic paraplegia. Thus, neuroimaging, VLCFA testing, and especially the detection of the ABCD1 gene have important implications for the etiological diagnosis of adult patients with spastic paraplegia.

Abstract 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

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the degeneration and death of motor neurons. Systemic neuroinflammation contributes to the pathogenesis of ALS. The proinflammatory milieu depends on the continuous crosstalk between the peripheral immune system (PIS) and central immune system (CIS). Central nervous system (CNS) resident immune cells interact with the peripheral immune cells via immune substances. Dysfunctional CNS barriers, including the blood–brain barrier, and blood–spinal cord barrier, accelerate the inflammatory process, leading to a systemic self-destructive cycle. This review focuses on the crosstalk between PIS and CIS in ALS. Firstly, we briefly introduce the cellular compartments of CIS and PIS, respectively, and update some new understanding of changes specifically occurring in ALS. Then, we will review previous studies on the alterations of the CNS barriers, and discuss their crucial role in the crosstalk in ALS. Finally, we will review the moveable compartments of the crosstalk, including cytokines, chemokines, and peripheral immune cells which were found to infiltrate the CNS, highlighting the interaction between PIS and CIS. This review aims to provide new insights into pathogenic mechanisms and innovative therapeutic approaches for ALS.

Introduction Amyotrophic lateral sclerosis (ALS) is a representative rare disease characterised by progressive, fatal motor neuron degeneration. Due to the unknown aetiology and variability of the phenotypes, there are no accurate reports concerning the epidemiology or clinical characteristics of the disease. The low prevalence, as previously reported, makes it difficult to carry out studies with large samples. The aim of this study was to explore the natural history and clinical features of ALS in mainland China through a multicentre, prospective cohort study. The findings will both offer a better understanding of ALS and also support the development of a model to study other rare diseases.Methods and analysis Patients from 88 representative hospitals in different parts of mainland China will be recruited through a specially designed online data system (http://www.chalsr.net/). We aim to recruit 4752 ALS patients over a 3-year period. Baseline data will be recorded, and follow-up data will be collected every 3 months. The primary outcome is effective survival. Overall survival and indices of disease progression will be measured as the secondary outcomes.Ethics and dissemination Ethical approval has been obtained from the ethics committee of Peking University Third Hospital (M2019388). Informed written consent will be obtained from each participant. Dissemination of the study protocol and data will take place primarily through a specially designed online data system (http://www.chalsr.net/). The collective results of the study will be published in peer-reviewed journals and shared in scientific presentations.Trial registration number NCT04328675

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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and the most common form of dementia in the elderly. It is a complex disorder with environmental and genetic components. There are two major types of AD, early onset and themore common late onset. The genetics of early-onset AD are largely understood withmutations in three different genes leading to the disease. In contrast, while susceptibility loci and alleles associated with late-onset AD have been identified using genetic association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset AD, the clinical features of EOAD according to genotypes, and the clinical implications of the genetics of AD. [ABSTRACT FROM AUTHOR]