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Objectives: This study was designed to develop and validate a radiomic nomogram for the differential diagnosis of myelin oligodendrocyte glycoprotein antibody-related disease (MOGAD) and aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD)., Methods: We retrospectively analysed data from a primary cohort consisting of 21 MOGAD and 63 AQP4+NMOSD patients and an external validation cohort comprising 10 MOGAD and 34 AQP4+NMOSD patients. Radiomic features were extracted from lesions of the cervical spinal cord and brainstem from sagittal T2-weighted MR images. We constructed a prediction model by integrating radiomic features with clinical data and evaluated its performance using calibration curves and decision curve analysis (DCA)., Results: We developed a comprehensive nomogram that combines clinical and radiomic features to distinguish MOGAD from AQP4+NMOSD. The discriminative ability of the nomogram was quantified by the area under the receiver operating characteristic (ROC) curve (AUC), achieving values of 0.915 (95 % CI, 0.859-0.970) in the primary cohort and 0.837 (95 % CI, 0.715-0.959) in the validation cohort, indicating high diagnostic accuracy. The calibration analyses showed good concordance between the model predicted and actual outcomes., Conclusions: This study successfully validated the radiomic feature model, demonstrating its superior performance in differentiating MOGAD from AQP4+NMOSD. The nomogram, integrating radiomic features with conventional imaging characteristics of brainstem and cervical cord lesions, significantly enhanced differentiation capability. Both models proved valuable in improving diagnostic accuracy, with radiomic features contributing most significantly., Competing Interests: Declaration of competing interest The authors Ningning Wang, Wei Chen, Huijun Wang, Yongjie Yao, Zhuyun Liu, Yuxin Li, Xueling Liu, Haiqing Li, Jingli Shan, and Anning Li declare that they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease, associated with CGG repeat expansions in the 5' untranslated region of LRP12 , GIPC1 , NOTCH2NLC and RILPL1 . However, the genetic cause of a proportion of pathoclinically confirmed cases remains unknown., Methods: A total of 26 OPDM patients with unknown genetic cause(s) from 4 tertiary referral hospitals were included in this study. Clinical data and laboratory findings were collected. Muscle samples were observed by histological and immunofluorescent staining. Long-read sequencing was initially conducted in six patients with OPDM. Repeat-primed PCR was used to screen the CGG repeat expansions in LOC642361/NUTM2B-AS1 in all 26 patients., Results: We identified CGG repeat expansion in the non-coding transcripts of LOC642361/NUTM2B-AS1 in another two unrelated Chinese cases with typical pathoclinical features of OPDM. The repeat expansion was more than 70 times in the patients but less than 40 times in the normal controls. Both patients showed no leucoencephalopathy but one showed mild cognitive impairment detected by Montreal Cognitive Assessment. Rimmed vacuoles and p62-positive intranuclear inclusions (INIs) were identified in muscle pathology, and colocalisation of CGG RNA foci with p62 was also found in the INIs of patient-derived fibroblasts., Conclusions: We identified another two unrelated cases with CGG repeat expansion in the long non-coding RNA of the LOC642361/NUTM2B-AS1 gene, presenting with a phenotype of OPDM. Our cases broadened the recognised phenotypic spectrum and pathogenesis in the disease associated with CGG repeat expansion in LOC642361/NUTM2B-AS1 ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To identify reliable immune-inflammation indicators for distinguishing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from anti-aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSD). To assess these indicators' predictive significance in MOGAD recurrence., Methods: This study included 25 MOGAD patients, 60 AQP4-IgG-positive NMOSD patients, and 60 healthy controls (HCs). Age and gender were matched among these three groups. Participant clinical and imaging findings, expanded disability status scale (EDSS) scores, cerebrospinal fluid (CSF) information, and blood cell counts were documented. Subsequently, immune-inflammation indicators were calculated and compared among the MOGAD, AQP4-IgG-positive NMOSD, and HC groups. Furthermore, we employed ROC curve analysis to assess the predictive performance of each indicator and binary logistic regression analysis to assess potential risk factors., Results: In MOGAD patients, systemic inflammation response index (SIRI), CSF white cell count (WCC), and CSF immunoglobulin A (IgA) levels were significantly higher than in AQP4-IgG-positive NMOSD patients (p = 0.038, p = 0.039, p = 0.021, respectively). The ROC curves showed that SIRI had a sensitivity of 0.68 and a specificity of 0.7 for distinguishing MOGAD from AQP4-IgG-positive NMOSD, with an AUC of 0.692 (95% CI: 0.567-0.818, p = 0.0054). Additionally, compared to HCs, both MOGAD and AQP4-IgG-positive NMOSD patients had higher neutrophils, neutrophil-to-lymphocyte ratio (NLR), SIRI, and systemic immune-inflammation index (SII). Eight (32%) of the 25 MOGAD patients had recurrence within 12 months. We found that the monocyte-to-lymphocyte ratio (MLR, AUC = 0.805, 95% CI = 0.616-0.994, cut-off value = 0.200, sensitivity = 0.750, specificity = 0.882) was an effective predictor of MOGAD recurrence. Binary logistic regression analysis showed that MLR below 0.200 at first admission was the only risk factor for recurrence (p = 0.005, odds ratio =22.5, 95% CI: 2.552-198.376)., Conclusion: Elevated SIRI aids in distinguishing MOGAD from AQP4-IgG-positive NMOSD; lower MLR levels may be linked to the risk of MOGAD recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Xia, Li, Shan and Wang.)

Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare acquired immune-mediated neuropathy. Although microbial infection is potentially a contributing factor, a causative link between CIDP and microbial infection remains unclear. There is also no definitive biomarker for CIDP diagnostics and therapies. The present study aimed to characterize the serum metabolic profile and gut microbiome structure in CIDP., Methods: Targeted metabolomics profiling of serum, using liquid chromatography-mass spectrometry, and metagenomics sequencing of stool samples from a cohort of CIDP and non-CIDP subjects were performed to evaluate serum metabolic profiles and gut microbiome structure in CIDP subjects relative to healthy controls., Results: Metabolome data revealed that the bile acids profile was perturbed in CIDP with bile acids and arachidonic acid enriched significantly in CIDP versus non-CIDP controls. Metagenome data revealed that opportunistic pathogens, such as Klebsiella pneumonia and Megamonas funiformis, and genes involved in bacterial infection were notably more abundant in CIDP subjects, while gut microbes related to biotransformation of secondary bile acids were abnormal in CIDP versus non-CIDP subjects. Correlation analysis revealed that changes in secondary bile acids were associated with altered gut microbes, including Bacteroides ovatus, Bacteroides caccae, and Ruminococcus gnavus., Conclusion: Bile acids and arachidonic acid metabolism were disturbed in CIDP subjects and might be affected by the dysbiosis of gut microbial flora. These findings suggest that the combination of bile acids and arachidonic acid could be used as a CIDP biomarker and that modulation of gut microbiota might impact the clinical course of CIDP., (© 2023. The Author(s).)

Objective: To investigate the clinical features of Han Chinese patients with anti-neurofascin-155 (NF155) antibody-positive neuropathy., Methods: We screened 194 patients with peripheral neuropathy for NF155 antibodies using a cell-based assay (CBA) and teased-fiber immunofluorescence assay. We summarized the clinical findings of seropositive patients., Results: The sera from 17 patients reacted to human embryonic kidney 293 cells transfected with NF155. Eleven of these patients had the immunoglobulin G (IgG) 4 isotype, a younger onset age, tremor, higher levels of cerebrospinal fluid protein, a larger diameter of the lumbosacral nerve root on magnetic resonance imaging, and the distal demyelinating symmetric phenotype. Most patients responded to steroids and rituximab. For the remaining six seropositive patients in CBA, the predominant antibody isotype was IgG3, IgG1, or undetectable, and only one patient with IgG3 showed a positive result in the teased-fiber immunofluorescence assay. These patients did not share the typical features displayed by patients with the IgG4 isotype., Interpretation: In the Han Chinese population, a significant proportion of patients who fulfilled the criteria for chronic inflammatory demyelinating polyradiculoneuropathy diagnosis had anti-NF155 IgG4 antibody-positive neuropathy and displayed specific phenotypes. Ambiguous staining patterns may appear, and the potential for false positivity should be considered. For patients who presented with specific phenotypes, identifying antibodies and subtypes involved a significant laboratory workup., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study, long-read whole-genome sequencing and repeat-primed PCR were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyglycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (RR-MADD) is an inherited fatty acid metabolism disorder mainly caused by genetic defects in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). The variant ETF:QO protein folding deficiency, which can be corrected by therapeutic dosage of riboflavin supplement, has been identified in HEK-293 cells and is believed to be the molecular mechanism of this disease. To verify this hypothesis in vivo, we generated Etfdh (h)A84T knockin (KI) mice., Methods: Tissues from these mice as well as muscle biopsies and fibroblasts from 7 RR-MADD patients were used to examine the flavin adenine dinucleotide (FAD) concentration and ETF:QO protein amount., Results: All of the homozygous KI mice (Etfdh (h)A84T/(h)A84T , KI/KI) were initially normal. After being given a high-fat and vitamin B 2 -deficient (HF-B 2 D) diet for 5 weeks, they developed weight loss, movement ability defects, lipid storage in muscle and liver, and elevated serum acyl-carnitine levels, which are clinically and biochemically similar to RR-MADD patients. Both ETF:QO protein and FAD concentrations were significantly decreased in tissues of HF-B 2 D-KI/KI mice and in cultured fibroblasts from RR-MADD patients. After riboflavin treatment, ETF:QO protein increased in proportion to elevated FAD concentrations, but not related to mRNA levels. These results were further confirmed in cultured fibroblasts from RR-MADD patients., Interpretation: For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681., (© 2018 American Neurological Association.)

Pompe disease is a rare autosomal recessive hereditary disease caused by genetic defects of acid maltase. This disease could be divided into two forms: infantile and late-onset, which mainly affect cardiac, respiratory, and skeletal muscle systems. Late-onset patients mainly show symptoms of skeletal muscle involvement, but recent reports have found that the central nervous system was also affected in some patients. Herein, we report a case of a female, adolescent-onset Pompe patient, who was diagnosed with complicated intracranial aneurysm in adulthood.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterized by ptosis, dysphagia, and proximal muscle weakness. The genetic basis has been identified as an abnormal (GCN) expansion encoding the polyalanine tract in exon 1 of the polyadenylate-binding protein nuclear 1 gene (PABPN1). OPMD is worldwide distributed, but has rarely been reported in East Asians. In this study, we summarized the clinical and genetic characteristics of 34 individuals from 13 unrelated families in Chinese population. In our cohort, the mean age at onset was 47.2 years. Dysphagia, rather than ptosis, was the most common initial symptom. Genetically, we identified seven genotypes in our patients, including one compound heterozygote of (GCN)11/(GCN)12. The genetic heterogeneity implies that there is no single founder effect in Chinese population, and our data also support that the (GCN)11 polymorphism may have a disease-modifying effect. Additionally, the clinical features showed homogeneity within families, which suggests that other genetic factors apart from the already known genotype also play a role in modifying the phenotype.

We report a case of 3-year-old boy who presented with Leigh syndrome but carried a mitochondrial G11778A mutation in the fourth subunit of the NADH dehydrogenase gene (MTND4). Additional to G11778A mutation, a novel C15620A variant was detected, which resulted in the conversion from leucine to isoleucine in the mitochondrial cytochrome b gene. As G11778A mutation is the most common mutation associated with Leber's hereditary optic neuropathy (LHON), given the unusual phenotype, the C15620A mutation was postulated to influence the pathogenicity of the G11778A mutation. This case further expands the clinical spectrum associated with the primary G11778A LHON mutation.

Multiple acyl-coenzyme A dehydrogenation deficiency (MADD) has a wide range of phenotypic variation ranging from a neonatal lethal form to a mild late-onset form. Our previous data showed that in a group of Chinese patients, a mild type of MADD characterized by myopathy with clinically no other systemic involvement was caused by mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene, which encodes electron transfer flavoprotein: ubiquinone oxidoreductase (ETF:QO). Coenzyme Q10 (CoQ10), a downstream electron receptor of ETF:QO was first reported deficient in muscle of MADD patients with ETFDH gene mutations. Nevertheless, this result was not confirmed in a recently published study. Therefore to elucidate muscle CoQ10 level in a large group of MADD patients may provide further insight into the pathomechanism and therapeutic strategies. In this study, we found that 34 riboflavin responsive patients with ETFDH gene mutations had an elevated CoQ10 pool in muscle by high performance liquid chromatography (HPLC). However, when CoQ10 levels were normalized to citrate synthase, a marker of mitochondrial mass, there was no significant difference between patients and normal controls. Meanwhile, the increased mitochondrial DNA copy number in muscle also supported that the elevated CoQ10 pool was mainly due to mitochondrial mass proliferation. The expression of CoQ10 biosynthesis genes showed no significant changes whereas genes involved in lipid metabolism, such as PPARα, were marked up regulated. Our results suggested that CoQ10 seems not to be a primary factor in riboflavin responsive MADD and the apparent increase in CoQ10 may be secondary to mitochondrial proliferation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive disorder characterized by neurodegeneration and iron accumulation in the brain. Classic and atypical PKAN are distinguished on the basis of age at onset and disease progression. PANK2, localized on chromosome20p13, is confirmed as the responsible gene. We report two Chinese siblings with atypical PKAN, who had a 26- and 24-year disease course, respectively. Brain MRI scans of the two siblings showed the specific "eye of the tiger" sign. Genetic analysis identified novel compound heterozygous mutations (IVS1-2 A>T, c.T1130C) in PANK2 gene, which were confirmed to be deleterious. We verify the clinical heterogeneity even in siblings with identical genotype and expand the gene mutation pool for PKAN.