ObjectiveThe concurrence of anti-contactin-1 (CNTN1) antibody-associated autoimmune nodopathies (AN) and nephropathy has been sporadically reported, though the underlying relationship remains unclear. This case series study aimed to investigate the clinical characteristics and renal pathology of anti-CNTN1 antibody-associated AN with nephropathy.MethodsA retrospective case series was conducted including 69 patients diagnosed with AN, among whom 11 patients tested positive for anti-CNTN1 antibodies. Clinical manifestations, electrophysiological data, laboratory results, and renal biopsy findings were collected and analyzed. The presence of nodal/paranodal antibodies was confirmed using serum cell-based assays. Renal biopsies were performed in four patients, with immunohistochemical and immunofluorescence staining, including CNTN1 staining, to characterize renal pathology.ResultsCompared to patients with non-anti-CNTN1 antibody-associated AN, the anti-CNTN1 antibody group had a significantly lower proportion of males (54.5% vs. 84.5%, p = 0.024) but showed higher rates of hypertension (36.4% vs. 8.6%, p = 0.021) and positive autoimmune antibodies (50% vs. 5%, p < 0.001). This group also exhibited a markedly higher prevalence of proteinuria (63.6% vs. 10.3%, p < 0.001) and nephropathy (63.6% vs. 3.4%, p < 0.001). Among anti-CNTN1 antibody-positive patients, females were more prone to concomitant nephropathy. Patients with both conditions exhibited onset ages ranging from 17 to 67 years, with a chronic course, frequent positive Romberg’s sign, and prolonged distal motor and F-wave latencies. Renal biopsy in four patients revealed membranous nephropathy (MN) in three cases and lupus nephritis (LN) in one case. Notably, CNTN1 staining of kidney tissue was positive only in patients with anti-CNTN1 antibody-associated AN with MN.ConclusionAnti-CNTN1 antibody-associated AN patients have a higher prevalence of nephropathy compared to those AN without anti-CNTN1 antibodies. Females demonstrate a particularly higher risk of comorbid AN and nephropathy. Renal pathology in these patients is not limited to MN but can also include LN. These findings highlight a complex immunopathological relationship between anti-CNTN1 antibody-associated AN and nephropathy, warranting further studies to understand the underlying mechanisms.

Background:The UNC13D gene encodes Munc13-4, a critical regulator of cytotoxic granule exocytosis in lymphocytes and the protein responsible for familial hemophagocytic lymphohistiocytosis (FHL). As an essential mediator of perforin release from cytotoxic T and NK cells, Munc13-4 ensures immune surveillance by facilitating granule-plasma membrane fusion. Defects in this pathway, termed "perforinopathy" manifest as impaired cytotoxicity and consequent immune dysregulation. While central nervous system involvement and systemic inflammation are established features of Munc13-4 deficiency, its association with autoimmune neuropathy remains largely unrecognized. Case report:We report two patients with a unique disease trajectory, presenting initially with autoimmune neuropathy before developing progressive FHL several years later. Both patients met the HLH-2004 diagnostic criteria, including fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. Genetic analysis revealed heterozygous UNC13D mutations: in Case 1, a nonsense (c.3193C>T; p.Arg1065*) and a missense (c.1135G>A; p.Glu379Lys) mutation; in Case 2, compound heterozygous mutations comprising a maternal splicing variant (c.2447 + 1G>A) and a paternal missense mutation (c.1241G>T; p.Arg414Leu). Case 1 underwent hematopoietic stem cell transplantation (HSCT), with significant recovery of weakness and numbness, and no recurrence of fever or lymphadenopathy at one year. Case 2 succumbed to disease progression after no timely, suitable allogeneic hematopoietic stem cell donor could be found. Discussion:Our findings identify autoimmune neuropathy as a potential harbinger of FHL in perforinopathy, suggesting these neurological manifestations may be the initial phenotype of an underlying cytotoxic dysfunction. This temporal association mandates heightened clinical vigilance for immunodeficiency in patients with refractory neuropathy, particularly when accompanied by axonal degeneration or systemic inflammation. Recognizing this novel disease continuum has immediate diagnostic and therapeutic implications, as early genetic identification creates a critical window for potentially curative intervention with HSCT before irreversible multi-organ damage occurs. These cases expand the clinical spectrum of perforinopathy and challenge current diagnostic paradigms, emphasizing the need for an integrated neurological and immunological evaluation for unexplained autoimmune neuropathy.

BACKGROUND AND PURPOSE: Hierarchy is a fundamental principle of network organization in the human brain. Functional gradient introduces a new perspective in identifying hierarchy alterations by capturing major axes of functional connectivity in low-dimensional space. However, whether this gradient structure is disrupted in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and how this disruption is modulated by the gene-expression profiles remain unknown. MATERIALS AND METHODS: Thirty-one patients with MELAS at the acute stage (MELAS-acute) and 31 healthy controls underwent resting-state functional MR imaging. On the basis of whole-brain voxelwise functional connectivity patterns, functional gradient values were generated and group-averaged gradient values were further extracted and compared from the global-to-voxel level. In combination with the Allen Human Brain Atlas, we then assessed the spatial correlations between MELAS-related gradient alterations and gene-expression profiles. RESULTS: Relative to the healthy controls, patients with MELAS-acute exhibited global alterations in the principal gradients, including reduced gradient range and gradient variation. In addition, patients showed lower gradient values in the default mode network but higher values in the ventral attention network and the sensorimotor network at the network and voxel levels. Furthermore, we established a link between MELAS-acute-related principal gradient and gene-expression profiles, with 2 gene sets mainly enriched in mitochondrion, neuron, glutamatergic synapse, and ATPase activity. CONCLUSIONS: These results highlight the connectome gradient alterations in patients with MELAS at the acute stage and their linkage with gene-expression profiles, providing insight into the neurobiological basis of functional alterations during the acute stroke-like episodes stage in MELAS.

Background: Efgartigimod, a human immunoglobulin (Ig)G1 antibody Fc fragment, blocks the neonatal Fc receptor, reducing IgGs involved in chronic inflammatory demyelinating polyneuropathy (CIDP), a rare, progressive, immune-mediated disease that can lead to irreversible disability. The multi-stage, double-blinded, placebo-controlled ADHERE (NCT04281472) trial assessed efgartigimod PH20 SC in participants with CIDP. Methods: Participants with active CIDP received open-label, weekly efgartigimod PH20 SC 1000 mg during ≤12-week run-in (stage-A). Responders were randomized (1:1) to weekly efgartigimod or placebo for ≤48 weeks (stage-B). This posthoc analysis evaluated changes from run-in baseline (study enrollment) to stage-B last assessment and items of the Inflammatory Rasch-built Overall Disability Scale (I-RODS). Results: Of 322 participants who entered stage-A, 221 were randomized and treated in stage-B, and 191/221 had data for run-in baseline and post–stage-B timepoints. Mean (SE) I-RODS change at stage-B last assessment vs run-in baseline was 5.7 (1.88) and -4.9 (1.82) in participants randomized to efgartigimod and placebo, respectively. 37/97 (38.1%) and 24/92 (26.1%) participants randomized to efgartigimod and placebo, respectively, experienced ≥4-point improvements in I-RODS score. Efgartigimod-treated participants improved ≥1 point in I-RODS items of clinical interest. Conclusions: Participants who received efgartigimod in stage-B experienced improvements in I-RODS score from study enrollment to stage-B last assessment.

Background and Objectives:Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression. Methods:Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the "Common Data Elements for Muscle Biopsy Reporting." Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes. Result:A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences in biopsy findings among the 4 most common VCP gene variants, except for the absence of degeneration niches in muscle biopsies of 12 patients with c.277C>T (p.Arg93Cys). MRI data from 30 patients showed fat pockets corresponding to these niches and STIR hyperintensity correlated with inflammatory infiltrates in 42.9%. Concordance between clinical phenotype, biopsy, and neurophysiology was observed in only 49.4% of cases, indicating significant heterogeneity. Discussion:VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression. Some lack vacuoles, challenging diagnosis. Discrepancies between clinical, neurophysiology, and biopsy findings should prompt consideration of VCP-MSP to improve detection and management.

Background Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the key enzyme initiating protein O - and N -glycosylation at the postsynaptic membrane. Variants in GFPT1 gene cause congenital myasthenic (GFPT1-CMS). However, the understanding of the phenotype and genetic spectrum of GFPT1-CMS remains limited. Methods A total of 24 patients with GFPT1-CMS from 22 Han Chinese families across four neuromuscular disease centers were included in this study. Clinical assessments involved detailed medical histories, muscle biopsies, and electrophysiological studies. GFPT1 variants were identified using targeted next-generation sequencing or WES. Additionally, published GFPT1-CMS case data from 2011 to 2024 were compiled and combined with this cohort for genotype-phenotype correlation analysis. Results In addition to the limb girdle myasthenia pattern, our cohort presented with extraocular involvement including eyelid ptosis and mild ophthalmoparesis (25.0%), facial weakness (20.8%) and a relatively high prevalence of distal weakness (62.5%). Electrophysiological testing revealed myopathic changes in 95.0% of cases and decremental CMAPs in all cases during RNS. We found that c.331 C > T is a hotspot variant in GFPT1-CMS patients and may have a founder effect in the Chinese population. Patients with homozygous null variants presented a more severe phenotype, including earlier onset and more frequent bulbar involvement. Conclusion We have described the clinical features and variant spectrum in a cohort of 24 Chinese GFPT1-CMS patients. Our findings update the understanding of clinical manifestation, pathological features and mutational spectrum in GFPT1-CMS patients.

BACKGROUND AND AIMS:To investigate the treatment of ofatumumab in autoimmune nodopathy (AN). METHODS:An open-label, prospective, observational study was conducted in patients with AN. The regimen was 20 mg ofatumumab subcutaneously on day 0, 7, 14, 28, and subsequently every 4 weeks in a total of 24 weeks. The primary endpoint of the study was the proportion of patients with confirmed clinical improvement. RESULTS:All of the eight patients (100%) improved at Week 24. The median time to improvement was 8 (IQR: 7-10) weeks. The four patients previously treated with rituximab and two with irregular injections of ofatumumab (OFA) improved. At Week 24, the adjusted INCAT score, MRC sum score, cI-RODS, and grip strength in nondominant hand significantly improved from baseline. In nerve conduction studies, all of the six patients with available data (100%) improved. The median sNfL significantly reduced from baseline at Week 8. Anti-paranodal antibody in seven patients with anti-NF155 antibodies reduced from baseline at Week 20. In seven of the eight patients, CD19+ B cells were significantly reduced at Week 4. No serious adverse events were reported. INTERPRETATION:The regimen was 20 mg ofatumumab subcutaneously on day 0, 7, 14, 28, and every 4 weeks from Week 4, in a total of 24 weeks. The ofatumumab therapy may provide a more convenient and safer treatment for patients with AN, while serving as an effective alternative for those who did not respond to rituximab.

BACKGROUND:Chronic orofacial pain is a prevalent health issue with multifactorial aetiology, including potential contributions from diet-related inflammation. This study aimed to investigate the association between dietary inflammatory potential, assessed using the Dietary Inflammatory Index (DII), and self-reported oral pain among US adults. METHODS:We conducted a cross-sectional analysis using data from 23 802 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2018 who completed dietary recalls and responded to oral health questions. Oral pain was assessed by the frequency of self-reported aching in the mouth over the past year (NHANES variable OHQ620). Logistic regression models were used to assess the association between DII scores and oral pain. Subgroup analyses were conducted to identify populations most affected by a pro-inflammatory diet. RESULTS:Higher DII scores were significantly associated with an increased likelihood of experiencing oral pain. Participants in the highest DII quintile (27.19%) had a 19% higher risk of oral pain compared with those in the lowest quintile (20.69%), even after full adjustment (OR = 1.19, 95% CI: 1.03-1.37, p = 0.016). The association was particularly pronounced in younger individuals, females, non-Hispanic Whites, those with higher socio-economic status, normal BMI, a history of smoking, and relatively low alcohol consumption. CONCLUSION:These findings suggest that pro-inflammatory dietary patterns may exacerbate oral pain, potentially mediated through systemic inflammation or local mucosal irritation. While based on self-reported oral pain, the study highlights diet modification as a preventive strategy and calls for further research on specific pain subtypes.

BACKGROUND AND AIMS:Guillain-Barré syndrome (GBS) is an acute autoimmune polyradiculoneuropathy characterized by progressive flaccid paralysis. The standard treatments include intravenous immunoglobulin (IVIg) and plasma exchange (PE), with limited accessibility to these treatments. Efgartigimod is an FcRn antagonist that reduces IgG levels, similar to PE, serving as a potential alternative. This study aims to compare the efficacy of Efgartigimod with standard IVIg in GBS. METHODS:This was a multicenter observational study in China. Eligible participants were aged ≥ 16 years, meeting the diagnostic criteria for GBS, and presented with a GBS Disability Scale score ≤ 5 at baseline assessment. Participants received efgartigimod (10 mg/kg per week up to 4 doses) or IVIg (2 g/kg once). Outcomes were assessed at baseline, week 1, and week 2 post-treatment, and at the last follow-up. The primary efficacy endpoint was the proportion of participants improving at least 1 point on the GBS-DS. RESULTS:Between January and October 2024, 22 GBS patients were enrolled, including 11 in each group. At week 1, 14 patients improved in GBS-DS, with 7 (63.6%) in the efgartigimod group and 7 (63.6%) in the IVIg group. Median time to improvement was 4 days in the efgartigimod group and 8 days in the IVIg group. At week 2, GBS-DS response rates were 90.9% (10/11) for efgartigimod and 81.8% (9/11) for IVIg. INTERPRETATION:Based on our preliminary findings, intravenous efgartigimod may be potentially tolerated in GBS over the short term. However, this study cannot establish comparative efficacy given the methodological limitations, and large-scale well-controlled head-to-head trials remain imperative.

Background and Objective:Neurological disorders are a group of diseases involving motor, sensory, cognitive, and autonomic functions, among which stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are prevalent. Their management, especially in conditions with chronic courses or long-term sequelae, remains a substantial unmet need. With the growing comprehension of neuroscience, the development of digital technology, and the rising demand for quality of life, wearable devices offer a promising solution for disease management. The review aimed to evaluate the application and prospect of wearable devices in neurological disorders. Methods:We conducted the review by searching papers on the application of wearable devices and wearable technology in neurology and neurological disorders using multiple databases. We summarized the present development status of wearable devices, and outlined the potential value and future direction for further research. Key Content and Findings:Existing wearable devices for neurological diseases can be applied to diagnosis and follow-up, as an electronic biomarker detector capturing subtle and objective changes in motor, sensory, and cognitive function. The devices can also be utilized for treatment and rehabilitation, mainly through exoskeletons and brain-computer interface. The application of wearable devices in neurology currently faces several critical limitations, including technical bottlenecks in the detection of fine motor and sensory functions, a lack of industry standards, and a limited sample size. Conclusions:This review demonstrates the potential of wearable technology in people with neurological disorders, enabling disease management and clinical trials outside clinical settings in the future. Nevertheless, further research is required to develop lighter, more user-friendly devices with various functions. It is believed that with increasing demand and technical support, wearable devices would have a promising range of applications.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by pleiotropic contractions of the D4Z4 repeat array on chromosome 4q35 (FSHD1) or by mutations in repressive chromatin regulators of the D4Z4 loci (FSHD2), both resulting in epigenetic dysregulation at the D4Z4 array. DNA methylation of the D4Z4 repeat array has been proposed for diagnosis and prognosis of FSHD disease severity; however, further validation in larger populations is needed. Two hundred forty-seven clinically suspected FSHD cases were retrospectively analyzed with D4Z4 analysis by optical genome mapping or molecular combing and tested the DNA methylation levels for 75 patients and 49 healthy controls. A D4Z4 repeat length-dependent nonlinear increase was observed in both distal and global D4Z4 methylation levels. Distal D4Z4 methylation levels identified patients with FSHD1 with a sensitivity of 100% and a specificity of 97.96% at a cutoff value of 39.66% compared with controls. Distal FSHD1-like hypomethylation was also observed in one subject carrying a special D4Z4 rearrangement, resulting in a proximal contracted array. Clinically, distal methylation levels demonstrated a strong correlation with the age-corrected clinical severity score and onset age. Mediation analysis revealed that the influence of distal methylation on age-corrected clinical severity score was partially mediated by onset age. This study further confirms the distal 4qA D4Z4 methylation analysis as a valuable complement for differential diagnosis in patients with suspected FSHD, including those with complex structural variants.