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Neuronal intranuclear inclusion disease (NIID) used to be considered as a neurodegenerative disease. Due to the availability of skin biopsy, the diagnostic efficiency of the disease has been greatly improved. Recently, researchers have successfully identified that the GGC repeat expansion in the 5′-untranslated region of the NOTCH2NLC gene is the causative mutation of NIID. Besides the typical phenotype of brain degeneration, peripheral neuropathy, and autonomic disturbance, the gene mutation is also associated with Alzheimer's disease, frontotemporal dementia, Parkinson’s disease, multiple system atrophy, essential tremor, adult leukoencephalopathy, and oculopharyngodistal myopathy. However, it still needs more studies to elucidate whether those variable NIID phenotypes can categorize into NOTCH2NLC repeat expansion related disorders. We update the discovery milestone, clinical phenotype, laboratory examinations, as well as new insight into the diagnosis and treatment of NIID. NIID is an unusual degenerative disease that can involve multiple systems, especially involves the nervous system. Originally, it is named after the pathological characteristics with extensive intranuclear eosinophilic inclusions in central and peripheral nervous tissues, as well as in multiple other organs (Sone et al., Brain 139:3170–3186, 2016). In 2019, several research teams from China and Japan have simultaneously identified that the GGC repeat expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene is the pathogenic mutation of NIID (Ishiura et al., Nat Genet 51:1222–1232, 2019; Deng et al., J Med Genet 56:758–764, 2019; Sone et al., Nat Genet 51:1215–1221, 2019; Sun et al., Brain 143:222–233, 2020; Tian et al., Am J Hum Genet 105:166–176, 2019). Since then, the number of reported NIID cases is rapidly increasing, and the spectrum of NOTCH2NLC repeat expansion related disorders is significantly broadening (Westenberger and Klein, Brain 143:5–8, 2020). However, the NIID associated with GGC repeat expansion of the NOTCH2NLC gene might be account for a part of patients, probably more frequently in the Asian population, because this expansion has not been identified in an European series with postmortem confirmed NIID cases (Chen et al., Ann Clin Transl Neurol 2020). In order to better understand of the disease, we need to revisit the current state of NIID in combination with the findings based on our experiences in recent years and update the concepts about the clinical and pathogenic progression of NIID.

Background Peripheral neuropathy is caused by numerous etiologies, such as immune, infectious, neoplastic, metabolic, toxic, traumatic, vasculitic, hereditary factors, etc. Each etiological type has no special manifestation, and the misdiagnosis rate is relatively high. Acute intermittent porphyria (AIP) is a rare disease, often complicated by peripheral nerve injury, and can develop sequelae after delayed diagnosis or treatment. Case presentation A 26-year-old female patient presented with recurrent abdominal pain, limb numbness and weakness, and autonomic neuropathy. Symptoms aggravated and respiratory and circulatory failure develop gradually, following the recurrence of the disease. She was initially diagnosed with neurosis, intestinal obstruction, and Guillain-Barré syndrome. She underwent treatment for inflammatory peripheral neuropathy, including intravenous immunoglobulin (IVIG) and plasmapheresis; however, no improvement in symptoms was observed. Clinical assessment revealed brown urine that turned reddish-brown after sunlight exposure. Whole exome sequencing (WES) identified a mutation in the HMBS gene (exon 10, c.651G > C, p.Gln217His), which was confirmed through Sanger sequencing and diagnosed as rare AIP with severe peripheral nerve damage. Numbness and weakness gradually improved after the initiation of hemin therapy and high-carbohydrate therapy. Conclusion The AIP is an easily missed or misdiagnosed disease. In the absence of timely and effective intervention, patients are at risk of developing irreversible and permanent neurological damage. It is essential for clinicians to enhance their awareness of the disease to ensure prompt diagnosis, appropriate treatment, and avoidance of triggering factors.

Population aging is a prominent global problem in today’s society. However, there are currently no good methods to treat or prevent aging, so anti-aging research has crucial implications. In this research, we screened bacteria from centenarians, and finally selected four probiotics (Lactobacillus fermentum SX-0718, L. casei SX-1107, Bifidobacterium longum SX-1326 , and B. animalis SX-0582 ) to form a probiotic combination. By using the senescence accelerated mouse prone 8 (SAMP8) model, the anti-aging effects of the probiotic combination were evaluated by using behavioural testing, neuroinflammation, intestinal inflammation, and intestinal microbiota. The results showed that probiotic combination improved the impaired spatial memory, motor dysfunction, and decreased exploratory behavior in aging mice. The probiotic combination inhibited Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)-induced neuroinflammation and up-regulated the expression of Sirt 1 to protect hippocampal neurons. At the same time, the probiotic combination regulated the intestinal microbiota, reduced the relative abundance of Alistipes and Prevotella in SAMP8 mice, inhibited TLR4/NFκB-induced intestinal inflammation, and increased the expression of intestinal permeability related proteins zonula occludens-1 (ZO-1) and Occuldin. The anti-aging effects of the probiotic combination may be through the regulating intestinal microbiota and inhibiting TLR4/NFκB-induced inflammation. This research provides the basis and technical support for the future production and application of the probiotic combination.

BackgroundGGC repeat expansion in NOTCH2NLC has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID.MethodsMultiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared.ResultsIn two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in NOTCH2NLC of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier.ConclusionOur study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.

Objective Previous studies have suggested a potential association between the platelet-to-lymphocyte ratio and disease activity in myasthenia gravis. However, the immunological mechanisms underlying this association remain insufficiently elucidated. Methods A retrospective cohort of 229 patients with myasthenia gravis and a single-cell RNA sequencing dataset were analyzed to investigate the relationship between platelet-to-lymphocyte ratio and disease severity. Clinical associations were assessed using the Myasthenia Gravis Foundation of America classification and multivariable logistic regression, while single-cell RNA sequencing data were integrated to characterize immune alterations associated with elevated platelet-to-lymphocyte ratio. Results Patients with severe myasthenia gravis had longer disease duration and higher frequencies of bulbar symptoms, thymoma, and repetitive nerve stimulation positivity (all p < 0.001). Although median platelet-to-lymphocyte ratio values did not demonstrate significant groupwise differences (p = 0.108), multivariate analysis confirmed that an elevated platelet-to-lymphocyte ratio was independently associated with greater myasthenia gravis severity (adjusted odds ratio = 1.027, 95% confidence interval: 1.003–1.052, p = 0.034). Single-cell RNA sequencing revealed immune dysregulation in patients with a high platelet-to-lymphocyte ratio, characterized by increased platelets and neutrophils, reduced natural killer cells, and upregulation of platelet activation, cell–cell adhesion, and integrin-mediated signaling pathways, indicating a shift toward innate immune activation and impaired immune coordination. Conclusion Elevated platelet-to-lymphocyte ratio independently predicts myasthenia gravis severity and may reflect immune dysregulation that contributes to disease progression and neuromuscular junction dysfunction.

Patients with myasthenia gravis (MG) are prone to resulting in a significant psychological burden. This study aims to investigate the condition of fear of progression (FoP) and identify factors associated with FoP among MG patients. This cross-sectional study included 83 patients with MG admitted to the First Affiliated Hospital of Nanchang University from January to November 2024. Data were collected through clinical records and questionnaires, including demographic details, disease duration, comorbidities, current drug regimen, and the fear of progression questionnaire-short form (FoP-Q-SF). The simplified fear of progression scale score for 83 MG patients was 31.36 ± 10.22. Among these participants, 38.6% exhibited dysfunction FoP. There was no significant difference concerning age, marital status, course of the disease, crisis of MG, STAI score, and TAI score in the total score of fear of disease progression in MG patients. However, gender, progress of MG and MGFA classification were positively correlated with the fear of progression ( P  < 0.05), which was statistically significant. Furthermore, gender and disease progression were identified as factors influencing FoP in MG patients ( P  < 0.05). FoP among MG patients varies according to their socio-demographic and clinical characteristics. Gender and progress history of MG are associated with Fop.

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 < 0.001). Conclusion: Our findings revealed patterns of treatment responses among AChR-gMG subtypes, with LOMG patients potentially presenting a more sustained response. These findings likely provide preliminary data for precision therapy in MG in the era of biologics. Trial registration: NCT04535843. Plain language summary Patterns and predictors of therapeutic response to efgartigimod in AChR generalized myasthenia gravis Myasthenia Gravis (MG) is an autoimmune disorder that can lead to potentially life-threatening complications. Efgartigimod is an approved biologic for generalized myasthenia gravis (gMG). However, the patterns and predictors of therapeutic response to efgartigimod among the acetylcholine receptor-generalized MG (AChR-gMG) subtypes remain inconclusive. Our findings revealed patterns of treatment responses among AChR-gMG subtypes, with LOMG patients potentially presenting a more sustained response.

Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5’ untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

Introduction Anti-metabotropic glutamate receptors (mGluR) encephalitis is a rare form of autoimmune encephalitis (AE) with a very limited number of documented cases. Objective To report detailed characteristics of a case series of patients with anti-mGluR encephalitis and perform literature review of previously described cases. Methods We described clinical data from a case series of anti-mGluR patients, including clinical presentation, paraclinical findings and response to treatment. Moreover, we performed a literature review according to PRISMA to identify already described cases. Results In our hospital we identified eight patients tested positive for anti-mGluR antibodies (1 for anti-mglur1, 1 for anti-mglur2 and 6 for anti-mglur2) either cerebrospinal fluid or serum. In most cases, brain magnetic resonance imaging (MRI) was unremarkable (at early stage) and most patients showed marked improvement after immunotherapy. Literature review allowed us to further identify 36 cases of anti-mGluR1 AE, 8 cases of anti-mGluR2 AE, 34 cases of anti-mGluR5 AE. Overall, 53(%), 13 (%) and 69(%) of patients with anti-mGluR1, anti-mGluR2 and anti-mGluR5, respectively, were male. The mean age of onset was respectively 51, 37 and 38. Patients with anti-mGLUR1 and anti-mGLur2 mainly manifested ataxia, while those with anti-mGLUR5 antibodies manifested psychiatric symptoms. In patients with anti-mGluR5 AE, associations with Hodgkin’s lymphoma (HL), other antibodies associated with AE and infectious triggers were frequent. Conclusion Anti-mGluR AE may present with heterogenous manifestations, according to the subtype of antibody. Early immunotherapy often improves outcomes, though some cases may relapse or develop cerebellar atrophy. Long-term follow-up is necessary, and underlying tumors—particularly HL in anti-mGluR5 AE—should be monitored.

Background Migraine pathophysiology involves trigeminovascular activation and neuroinflammation, with neuropeptides such as calcitonin gene-related peptide (CGRP) playing a key role. Growing evidence implicates glymphatic system dysfunction, particularly meningeal lymphatic vessel (mLV) mediated cerebrospinal fluid (CSF) and waste clearance, as a potential contributor. However, multi-level imaging assessments glymphatic system in episodic migraine (EM) remain limited. Methods We prospectively enrolled 38 EM patients and 22 age- and sex- comparable healthy controls (HCs). Glymphatic function was systematically evaluated using 3T MRI. Dynamic contrast-enhanced MRI (DCE-MRI) was used to quantify mLV drainage kinetics including Wash-in rate, Time-to-Peak (TTP), Initial Area Under Curve (IAUC) and Ktrans along the superior sagittal sinus (mLV-SSS) and sigmoid sinus (mLV-SS). Diffusion tensor imaging along perivascular spaces (DTI-ALPS) index was used to assess parenchymal interstitial fluid dynamics. Structural MRI was used to rate enlarged perivascular spaces (EPVS) in centrum semiovale (CSO), basal ganglia (BG), and midbrain (MB). Finally, the correlations among clinical characteristics and neuroimaging data were analyzed. Results Compared to HCs, EM patients showed impaired meningeal lymphatic drainage on DCE-MRI, with reduced wash-in rate, prolonged TTP, and lower IAUC and Ktrans in both mLV-SSS and mLV-SS. Within the EM cohort, these kinetic abnormalities were associated with higher headache intensity on the visual analogue scale (VAS). Although overall DTI-ALPS index did not differ between groups. but high-grade EPVS in the centrum semiovale was more prevalent in EM, with no between-group differences in the basal ganglia or midbrain. Conclusion We demonstrate in vivo impairment of meningeal lymphatic drainage in EM, linked to headache intensity. While DTI-ALPS index in parenchymal glymphatic flow was not altered, the increased burden of centrum semiovale EPVS provide complementary evidence for glymphatic system involvement. These findings support glymphatic involvement and highlight mLVs as a potential therapeutic target in early stage of migraine.