144 results on '"Jianwen Deng"'
Search Results
2. A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
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Zhihao Xie, Chang Liu, Chengyue Sun, Yanyu Lu, Shiyi Wu, Yilin Liu, Qi Wang, Yalan Wan, Yikang Wang, Meng Yu, Lingchao Meng, Jianwen Deng, Wei Zhang, Zhaoxia Wang, Chunxia Yang, Yun Yuan, and Zhiying Xie
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Becker muscular dystrophy ,Duchenne muscular dystrophy ,Fibrofatty replacement ,Transcriptome ,Diseases of the musculoskeletal system ,RC925-935 ,Human anatomy ,QM1-695 - Abstract
Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P
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- 2024
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3. A novel deep intronic variant introduce dystrophin pseudoexon in Becker muscular dystrophy: A case report
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Chang Liu, Yanyu Lu, Haiyan Yu, Zhihao Xie, Chengyue Sun, Xinchao Cheng, Fangfang Niu, Yawen Zhao, Jianwen Deng, Lingchao Meng, Zhaoxia Wang, Yun Yuan, and Zhiying Xie
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Becker muscular dystrophy ,DMD ,Aberrant splicing ,Deep intronic variant ,Case report ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Most pathogenic DMD variants are detectable and interpretable by standard genetic testing for dystrophinopthies. However, approximately 1∼3% of dystrophinopthies patients still do not have a detectable DMD variant after standard genetic testing, most likely due to structural chromosome rearrangements and/or deep intronic pseudoexon-activating variants. Here, we report on a boy with a suspected diagnosis of Becker muscular dystrophy (BMD) who remained without a detectable DMD variant after exonic DNA-based standard genetic testing. Dystrophin mRNA studies and genomic Sanger sequencing were performed in the boy, followed by in silico splicing analyses. We successfully detected a novel deep intronic disease-causing variant in the DMD gene (c.2380 + 3317A > T), which consequently resulting in a new dystrophin pseudoexon activation through the enhancement of a cryptic donor splice site. The patient was therefore genetically diagnosed with BMD. Our case report further emphasizes the significant role of disease-causing splicing variants within deep intronic regions in genetically undiagnosed dystrophinopathies.
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- 2024
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4. Pathologic changes in neuronal intranuclear inclusion disease are linked to aberrant FUS interaction under hyperosmotic stress
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Hui Wang, Yilei Zheng, Jiaxi Yu, Lingchao Meng, Wei Zhang, Daojun Hong, Zhaoxia Wang, Yun Yuan, and Jianwen Deng
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NOTCH2NLC ,CGG repeat expansion ,polyG ,Intranuclear inclusions ,Stress granules ,FUS ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
CGG repeat expansion in NOTCH2NLC is the genetic cause of neuronal intranuclear inclusion disease (NIID). Previous studies indicated that the CGG repeats can be translated into polyglycine protein (N2CpolyG) which was toxic to neurons by forming intranuclear inclusions (IIs). However, little is known about the factors governing polyG IIs formation as well as its molecular pathogenesis. Considering that neurogenetic disorders usually involve interactions between genetic and environmental stresses, we investigated the effect of stress on the formation of IIs. Our results revealed that under hyperosmotic stress, N2CpolyG translocated from the cytoplasm to the nucleus and formed IIs in SH-SY5Y cells, recapitulating the pathological hallmark of NIID patients. Furthermore, N2CpolyG interacted/ co-localized with an RNA-binding protein FUS in the IIs of cellular model and NIID patient tissues, thereby disrupting stress granule formation in cytoplasm under hyperosmotic stress. Consequently, dysregulated expression of microRNAs was found both in NIID patients and cellular model, which could be restored by FUS overexpression in cultured cells. Overall, our findings indicate a mechanism of stress-induced pathological changes as well as neuronal damage, and a potential strategy for the treatment of NIID.
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- 2024
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5. Complex I deficiency in m.3243A>G fibroblasts is alleviated by reducing NADH accumulation
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Tongling Liufu, Haiyan Yu, Jiaxi Yu, Meng Yu, Yue Tian, Yichun Ou, Jianwen Deng, Guogang Xing, and Zhaoxia Wang
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complex I ,G%22">m.3243 A>G ,mitochondrial disease ,mitoLbNOX ,NADH ,nr ,Physiology ,QP1-981 - Abstract
Introduction: Mitochondrial disease is a spectrum of debilitating disorders caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA that compromises the respiratory chain. Mitochondrial 3243A>G (m.3243 A>G) is the most common mutation showing great heterogeneity in phenotype. Previous studies have indicated that NADH: ubiquinone oxidoreductase (complex I) deficiency accompanied by a decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio may play a pivotal role in the pathogenesis of m.3243A>G mutation.Methods: To evaluate the potential effects of strategies targeting the imbalanced NAD+/NADH ratio in m.3243A>G mutation, we treated fibroblasts derived from patients with the m.3243 A>G mutation using nicotinamide riboside (NR) or mitochondria-targeted H2O-forming NADH oxidase (mitoLbNOX).Results: M.3243 A>G fibroblasts showed a significant reduction in complex I core subunit 6, complex I enzymatic activity, complex I-dependent oxygen consumption rate (OCR), and adenosine triphosphate (ATP) production compared to the controls. The NAD+/NADH ratio was also significantly reduced in m.3243 A>G fibroblasts, and, using fluorescence lifetime imaging microscopy, we also found that the NADH level was elevated in m.3243 A>G fibroblasts. After NR treatment, the NAD+/NADH ratio, complex I-dependent OCR, and ATP levels increased, whereas NADH levels remained unchanged. More excitingly, after treatment with mitoLbNOX, the NAD+/NADH ratio, complex I-independent OCR, and ATP levels increased more pronouncedly compared with the NR treatment group, accompanied by significantly reduced NADH levels.Discussion: The present study suggests that compared with repletion of NAD+ alone, the combination of this therapeutic modality with alleviation of NADH overload may amplify the treatment effect of restoring NAD+/NADH balance in m.3243A>G fibroblasts.
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- 2023
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6. Novel variants, muscle imaging, and myopathological changes in Chinese patients with VCP‐related multisystem proteinopathy
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Yalan Wan, Qi Wang, Yiming Zheng, Meng Yu, Zhiying Xie, Chen Ling, Lingchao Meng, Jiaxi Yu, Yilei Zheng, Yikang Wang, Wenhao Zhang, Chang Liu, Yawen Zhao, Yun Yuan, Jianwen Deng, Qiang Gang, and Zhaoxia Wang
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IBMPFD ,multisystem proteinopathy ,muscle magnetic resonance imaging ,myopathy ,VCP ,Genetics ,QH426-470 - Abstract
Abstract Objective The objective of this research was to study the clinical features, genetic characteristics, muscle imaging, and muscle pathological changes of a cohort of Chinese patients with mutations in the valosin‐containing protein (VCP) gene. Methods Nine patients from seven Chinese pedigrees were recruited. Variants were detected by next‐generation sequencing and confirmed by Sanger sequencing. Thigh muscle MRIs were performed in five patients. All the patients received muscle biopsies. Results Seven variants in VCP were identified, and two were novel. All the patients presented with adult‐onset muscle weakness. The appearance of “isolated island sign” or “contra‐isolated island sign” was observed in four of the five the patients on muscle MRIs. Muscle biopsies demonstrated the combination of neuropathic and myopathic changes in seven patients and muscle dystrophic changes in two patients. Notably, rimmed vacuoles and cytoplasmic VCP and p62‐positive protein aggregates were observed in all the patients. Conclusion Our finding of novel variants expanded the mutational spectrum of the VCP gene. This cohort of Chinese patients with VCP mutations mainly present with inclusion body myopathy with predominant limb–girdle distribution. The characteristic pattern of fatty infiltration, especially the “isolated island” and “contra‐isolated island” on muscle MRI, along with rimmed vacuoles in muscle biopsy, provides valuable clues for guiding genetic diagnostic workup.
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- 2023
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7. A Myb enhancer-guided analysis of basophil and mast cell differentiation
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Takayoshi Matsumura, Haruhito Totani, Yoshitaka Gunji, Masahiro Fukuda, Rui Yokomori, Jianwen Deng, Malini Rethnam, Chong Yang, Tze King Tan, Tadayoshi Karasawa, Kazuomi Kario, Masafumi Takahashi, Motomi Osato, Takaomi Sanda, and Toshio Suda
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Science - Abstract
The transcription factor MYB has been shown to regulate haematopoietic stem cells but there could be lineage specific enhancers. Here, using lineage tracing and single cell sequencing the authors characterise a Myb −68 enhancer that regulates the differentiation of mast cells and basophils.
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- 2022
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8. Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4‐myopathy
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Qi Wang, Meng Yu, Wei Zhang, Qiang Gang, Zhiying Xie, Jin Xu, Chao Zhou, Depeng Wang, Lingchao Meng, He Lv, Zhirong Jia, Jianwen Deng, Yun Yuan, and Zhaoxia Wang
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract PLIN4‐myopathy is a recently identified autosomal dominant muscular disorder caused by the coding 99 bp repeat expansion in PLIN4, presenting with distal or proximal weakness. Here, we report one family and one sporadic case of adult‐onset PLIN4‐associated limb‐girdle weakness, whose diagnoses were achieved by a comprehensive genetic analysis workup. We provided additional evidence that the combination of subsarcolemmal/cytoplasmic ubiquitin/p62 positive deposits and rimmed vacuoles could serve as a strong indicator of PLIN4‐myopathy. Moreover, we found novel myopathological features that were ultrastructural subsarcolemmal filamentous materials and membrane‐bound granulofilamentous inclusions formed by the co‐deposition of disrupted lipid droplets and p62 protein aggregates.
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- 2022
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9. Patterns of myelinated nerve fibers loss in transthyretin amyloid polyneuropathy and mimics
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Kang Du, Xujun Chu, Yuwei Tang, Xutong Zhao, Meng Yu, Yiming Zheng, Jianwen Deng, He Lv, Wei Zhang, Zhaoxia Wang, Yun Yuan, and Lingchao Meng
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective The present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR‐PN) and other similar neuropathies. Methods A total of 41 patients with ATTR‐PN, 58 patients of other common peripheral neuropathies, and 17 age‐and gender‐matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD. Results Except the vasculitic neuropathy group, the total and small MFD of patients in the ATTR‐PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR‐PN group. The disease course of early‐onset and late‐onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late‐onset and most early‐onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR‐PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life‐diabetic neuropathy (Norfolk QOL‐DN) score. Conclusion MF is lost differently in ATTR‐PN and in other common peripheral neuropathies. The late‐onset and early‐onset ATTR‐PN patients have different patterns of loss of large and small MF.
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- 2022
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10. The polyG diseases: a new disease entity
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Tongling Liufu, Yilei Zheng, Jiaxi Yu, Yun Yuan, Zhaoxia Wang, Jianwen Deng, and Daojun Hong
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PolyG diseases ,Fragile X-associated tremor/ataxia syndrome ,Neuronal intranuclear inclusion disease ,Oculopharyngeal myopathy with leukoencephalopathy ,Oculopharyngodistal myopathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract 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.
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- 2022
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11. Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy
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Chengsi Wu, Haijie Xiang, Ran Chen, Yilei Zheng, Min Zhu, Shuyun Chen, Yanyan Yu, Yun Peng, Yaqing Yu, Jianwen Deng, Meihong Zhou, and Daojun Hong
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of diseases characterized by exclusive degeneration of peripheral motor nerves, while only 20.0–47.8% of dHMN patients are genetically identified. Recently, GGC expansion in the 5’UTR of NOTCH2NLC has been associated with dHMN. Accordingly, short tandem repeat (STR) should be further explored in genetically unsolved patients with dHMN. Methods A total of 128 patients from 90 unrelated families were clinically diagnosed as dHMN, and underwent a comprehensively genetic screening. Skin biopsies were conducted with routine protocols. Results Most patients showed chronic distal weakness of lower limbs (121/128), while 20 patients initially had asymmetrical involvements, 14 had subclinical sensory abnormalities, 11 had pyramidal impairments, five had cerebellar disturbance, and four had hyperCKmia. The rate of genetic detection was achieved in 36.7% (33/90), and the rate increased to 46.7% (42/90) if patients with variants uncertain significance were included. The most common causative genes included chaperone‐related genes (8/33, 24.2%), tRNA synthetase genes (4/33, 12.1%), and cytoskeleton‐related genes (4/33, 12.1%). Additionally, two dominant inherited families were attributed to abnormal expansion of GGC repeats in the 5‘UTR of NOTCH2NLC; and a patient with dHMN and cerebellar symptoms had CAG repeat expansion in the ATXN2 gene. Skin biopsy from patients with GGC expansion in NOTCH2NLC revealed typical intranuclear inclusions on histological and ultrastructural examinations. Interpretations This study further extends the genetic heterogeneity of dHMN. Given some dHMN patients may be associated with nucleotides repeat expansion, STR screening is necessary to perform in genetically unsolved patients.
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- 2022
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12. Sporadic adult-onset neuronal intranuclear inclusion disease without high-intensity signal on DWI and T2WI: a case report
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Hongfen Wang, Feng Feng, Jiajin Liu, Jianwen Deng, Jiongming Bai, Wei Zhang, Luning Wang, Baixuan Xu, and Xusheng Huang
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Neuronal intranuclear inclusion disease ,Diffusion-weighted imaging ,NOTCH2NLC gene ,Skin biopsy ,Case report ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in cells in the central and peripheral nervous system. High-intensity signal in the corticomedullary junction on diffusion-weighted imaging (DWI) is supportive to the diagnosis of NIID. We describe a patient with sporadic adult-onset NIID but without any high-intensity signal on DWI and T2-weighted imaging (T2WI). Case presentation A 58-year-old woman without special family history developed mild persistent tremor in the right hand and deteriorated 2 years later. At 60 years of age, the patient began to conceive the bank, police and internet being deceptive, further presented apathy and confusion after two and a half years, as well as fabrication of non-existent things. Despite the treatment of antipsychotic drugs due to a diagnosis of mental disorder, the patient appeared weakness in the right limbs. Neurological examination revealed mutism, resting tremor, cogwheel-like rigidity in upper limbs, and weakness in all limbs. Brain magnetic resonance imaging displayed no cerebral atrophy initially but atrophy of frontal, temporal and parietal lobes 5 years later. No any high-intensity signal on DWI and T2WI was revealed. However, hypometabolism in the cortexes with atrophy and the right putamen nucleus were showed on 18F-fluoro-deoxy-glucose positron emission tomography/magnetic resonance. On the basis of 107 GGC repeats (normal number
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- 2022
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13. Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report
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Rui Wu, Sai Shao, Ling Yin, Jianwen Deng, Shougang Guo, and Lin Lu
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frameshift mutation ,SQSTM1 ,myopathy ,rimmed vacuoles ,multisystem proteinopathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
p62/Sequestosome-1 (SQSTM1) is a stress-inducible scaffold protein involved in multiple cellular processes, including apoptosis, inflammation, cell survival, and selective autophagy. SQSTM1 mutations are associated with a spectrum of multisystem proteinopathy, including Paget disease of the bone, amyotrophic lateral sclerosis, frontotemporal dementia, and distal myopathy with rimmed vacuoles (MRV). Herein, we report a new phenotype of SQSTM1-associated proteinopathy, a novel frameshift mutation in SQSTM1 causing proximal MRV. A 44-year-old Chinese patient presented with progressive limb–girdle weakness. She had asymmetric proximal limb weakness and myopathic features on electromyography. The magnetic resonance images showed fatty infiltration into muscles, predominantly in the thighs and medial gastrocnemius, sparing the tibialis anterior. Muscle histopathology revealed abnormal protein deposition, p62/SQSTM1-positive inclusions, and rimmed vacuoles. Next-generation sequencing showed a novel pathogenic SQSTM1 frameshift mutation, c.542_549delACAGCCGC (p. H181Lfs*66). We expanded the pathogenic genotype of SQSTM1 to include a new, related phenotype: proximal MRV. We suggest that SQSTM1 variations should be screened in cases of proximal MRV.
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- 2023
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14. Effect of Dl-3-n-butylphthalide on mitochondrial Cox7c in models of cerebral ischemia/reperfusion injury
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Jingjing Jia, Jianwen Deng, Haiqiang Jin, Jie Yang, Ding Nan, Zemou Yu, Weiwei Yu, Zhiyuan Shen, Yuxuan Lu, Ran Liu, Zhaoxia Wang, Xiaozhong Qu, Dong Qiu, Zhenzhong Yang, and Yining Huang
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cerebral ischemia/reperfusion ,Dl-3-n-butylphthalide ,cytochrome c oxidase ,mitochondrial dysfunction ,ROS ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Several studies have demonstrated the protective effect of dl-3-n-Butylphthalide (NBP) against cerebral ischemia, which may be related to the attenuation of mitochondrial dysfunction. However, the specific mechanism and targets of NBP in cerebral ischemia/reperfusion remains unclear. In this study, we used a chemical proteomics approach to search for targets of NBP and identified cytochrome C oxidase 7c (Cox7c) as a key interacting target of NBP. Our findings indicated that NBP inhibits mitochondrial apoptosis and reactive oxygen species (ROS) release and increases ATP production through upregulation of Cox7c. Subsequently, mitochondrial respiratory capacity was improved and the HIF-1α/VEGF pathway was upregulated, which contributed to the maintenance of mitochondrial membrane potential and blood brain barrier integrity and promoting angiogenesis. Therefore, our findings provided a novel insight into the mechanisms underlying the neuroprotective effects of NBP, and also proposed for the first time that Cox7c exerts a critical role by protecting mitochondrial function.
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- 2023
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15. Unraveling rare form of adult-onset NIID by characteristic brain MRI features: A single-center retrospective review
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Fan Li, Qi Wang, Ying Zhu, Jiangxi Xiao, Muliang Gu, Jiaxi Yu, Jianwen Deng, Wei Sun, and Zhaoxia Wang
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neuronal intranuclear inclusion disease (NIID) ,MRI ,ribbon sign ,leukoencephalopathy ,myopathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Adult-onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with high clinical heterogeneity. Previous studies indicated that the high-intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI) on brain MRI, known as the “ribbon sign,” could serve as a strong diagnostic clue. Here we used the explorative approach to study the undiagnosed rate of adult-onset NIID in a single center in China via searching for the ribbon sign in picture archive and communication system (PACS) and report the clinical and radiological features of initially undiagnosed NIID patients.Consecutive brain MRI of 21,563 adult individuals (≥18 years) in the PACS database in 2019 from a tertiary hospital were reviewed. Of them, 4,130 were screened out using the keywords “leukoencephalopathy” and “white matter demyelination.” Next, all 4,130 images were read by four neurologists. The images with the suspected ribbon sign were reanalyzed by two neuroradiologists. Those with the ribbon sign but without previously diagnosed NIID were invited for skin biopsy and/or genetic testing for diagnostic confirmation. The clinical features of all NIID patients were retrospectively reviewed.Five patients with high-intensity in the corticomedullary junction on DWI were enrolled. Three patients were previously diagnosed with NIID confirmed by genetic or pathological findings and presented with episodic encephalopathy or cognitive impairment. The other two patients were initially diagnosed with limb-girdle muscular dystrophy (LGMD) with rimmed vacuoles (RVs) and normal pressure hydrocephalus (NPH) in one each. Genetic analysis demonstrated GGC repeat expansion in the NOTCH2NLC gene of both, and skin biopsy of the first patient showed the presence of intranuclear hyaline inclusion bodies. Thus, five of the 21,563 adult patients (≥18 years) were diagnosed with NIID. The distinctive subcortical high-intensity signal on DWI was distributed extensively throughout the lobes, corpus callosum, basal ganglia, and brainstem. In addition, T2-weighted imaging revealed white matter hyperintensity of Fazekas grade 2 or 3, atrophy, and ventricular dilation. Distinctive DWI hyperintensity in the junction between the gray and white matter can help identify atypical NIID cases. Our findings highly suggest that neurologists and radiologists should recognize the characteristic neuroimaging pattern of NIID.
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- 2022
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16. The role of Nrf2 in periodontal disease by regulating lipid peroxidation, inflammation and apoptosis
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Fengyu Ma, Shangdie Luo, Chunting Lu, Xinrong Jiang, Kexiao Chen, Jianwen Deng, Shuyuan Ma, and Zejian Li
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Nrf2 ,periodontal disease ,lipid peroxidation ,apoptosis ,bone homeostasis ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Nuclear factor E2-related factor 2(Nrf2) is a transcription factor that mainly regulates oxidative stress in the body. It initiates the expression of several downstream antioxidants, anti-inflammatory proteins and detoxification enzymes through the Kelch-like ECH-associating protein 1 (Keap1) -nuclear factor E2-related factor 2(Nrf2) -antioxidant response element (ARE) signaling pathway. Its anti-apoptosis, anti-oxidative stress and anti-inflammatory effects have gradually become the focus of periodontal disease research in recent years. In this paper, the structure and function of Nrf2 pathway and its mechanism of action in the treatment of periodontitis in recent years were analyzed and summarized, so as to further clarify the relationship between Nrf2 pathway and oxidative stress in the occurrence and development of periodontitis, and to provide ideas for the development of new treatment drugs targeting Nrf2 pathway.
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- 2022
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17. Clinical and biochemical characterization of hereditary transthyretin amyloidosis caused by E61K mutation
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Xujun Chu, Mengdie Wang, Ran Tang, Yanan Huang, Jiaxi Yu, Yunfeng Cao, Yilei Zheng, Zhiying Xie, Jianwen Deng, Zhi Wang, Wei Ma, Wenjing Song, Yuan Wu, He Lv, Wei Zhang, Zhaoxia Wang, Yun Yuan, Yu Liu, and Lingchao Meng
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E61K mutation ,kinetic stability ,thermodynamic stability ,TTR tetramer ,kinetic stabilizers ,ATTRv amyloidosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein.Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation.Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration.Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs.
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- 2022
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18. Neuronal intranuclear inclusion disease presented with recurrent vestibular migraine-like attack: a case presentation
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Danhua Zhao, Sha Zhu, Qinlan Xu, Jianwen Deng, Zhaoxia Wang, and Xianzeng Liu
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Neuronal intranuclear inclusion disease ,Vestibular migraine ,Episodic encephalopathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder characterized by dementia, tremor, episodic encephalopathy and autonomic nervous dysfunction. To date, vestibular migraine (VM)-like attack has never been reported in cases with NIID. Here, we describe an 86-year-old patient with NIID who presented with recurrent vertigo associated with headache for more than 30 years. Case presentation An 86-year-old Chinese woman with vertigo, headache, weakness of limbs, fever, and disturbance of consciousness was admitted to our hospital. She had suffered from recurrent vertigo associated with headache since her 50 s,followed by essential tremor and dementia. On this admission, brain magnetic resonance imaging revealed high intensity signals along the corticomedullary junction on diffusion weighted imaging (DWI). Peripheral neuropathy of the extremities was detected through electrophysiological studies. We diagnosed NIID after detecting eosinophilic intranuclear inclusions in the ductal epithelial cells of sweat glands and identifying an abnormal expansion of 81 GGC repeats in the 5’UTR of NOTCH2NLC gene. Conclusions VM-like attack may be associated with NIID.
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- 2021
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19. Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease
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Yiyi Zhou, Pengcheng Huang, Zhaojun Huang, Yun Peng, Yilei Zheng, Yaqing Yu, Min Zhu, Jianwen Deng, Zhaoxia Wang, and Daojun Hong
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neuronal intranuclear inclusion disease ,skin biopsy ,urine cytology ,NOTCH2NLC gene ,pathological diagnosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
ObjectiveThe diagnosis of neuronal intranuclear inclusion disease (NIID) is currently based on CGG repeat expansion in the 5′UTR of the NOTCH2NLC gene, or p62-positive intranuclear inclusions in skin biopsy. The purpose of this study is to explore the value of non-invasive pathological findings in urine sediment cells from NIID patients.Materials and methodsTen patients with clinically suspected NIID were enrolled for skin biopsy and gene screening. Morning urine (500 ml) was collected from each patient, and cell sediment was obtained by centrifugation. Urine cytology, including Giemsa staining, p62 immunostaining, and electron microscopic examination, were conducted on cell sediment.ResultsThe main clinical symptoms of 10 patients included episodic disturbance of consciousness, cognitive impairment, tremor, limb weakness, and so on. Cerebral MRI showed that 9 patients had linear DWI high signal in the corticomedullary junction. Genetic testing found that the number of CGG repeat ranged from 96 to 158 in the NOTCH2NLC gene. Skin biopsy revealed that all patients showed p62-positive intranuclear inclusions in 18.5 ± 6.3% of the duct epithelial cells of sweat gland. In contrast, urine sediment smears revealed that only 3 patients had p62 positive intranuclear inclusions in 3.5 ± 1.2% of the sedimentary cells. Ultrastructural examinations showed that intranuclear inclusions were also identified in the cell sediment of the 3 patients.ConclusionUrine cytology may be a new and non-invasive pathological diagnosis technique for some NIID patients, although the positive rate is not as high as that of skin biopsy, which is a sensitive and reliable pathological method for NIID.
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- 2022
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20. Salivary Microbiome Profile of Diabetes and Periodontitis in a Chinese Population
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Chunting Lu, Qingtong Zhao, Jianwen Deng, Kexiao Chen, Xinrong Jiang, Fengyu Ma, Shuyuan Ma, and Zejian Li
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diabetes ,periodontitis ,saliva ,16S rDNA ,microbiota ,Microbiology ,QR1-502 - Abstract
AimThere is a bidirectional association between diabetes and periodontitis. However, the effect of diabetes on the periodontitis salivary microbiota has not been elucidated. The aim of this study was to determine the effect of the presence of diabetes on the microbiota among Chinese patients with periodontitis.Materials and MethodsUnstimulated whole saliva samples were collected from the periodontitis with diabetes group (TC), chronic periodontitis group (CP), and periodontally healthy and systemically healthy group (H) by spitting method. Bacterial genomic DNA was PCR-amplified at the V4 variable region of 16S rRNA gene. The library was constructed according to the obtained sequence results, and biological analysis and statistical analysis were carried out. Functional prediction of three groups of microbial communities was performed by the PICRUSt algorithm.ResultsThere was no significant difference in bacterial diversity between the TC and CP groups. Compared with the H group, the TC group and CP group presented a higher diversity of salivary flora. Firmicutes, Streptococcus, Haemophilus, Veillonella, and Haemophilus parainfluenzae dominated the H group. Corynebacterium, Leptotrichia, Dialister, Comamonas, Capnocytophaga, Catonella, Filifactor, Campylobacter, Treponema, Campylobacter concisus, Prevotella oralis, and Porphyromonas gingivalis were significantly enriched in the TC and CP groups. Among them, Treponema and P. oralis were the most abundant in the TC group. The PICRUSt results showed that many pathways related to cell motility and functional metabolism of the salivary microbial flora changed in the TC group and the CP group.ConclusionsDiabetes was not the main factor causing the altered diversity of salivary microbiota in patients with periodontitis; however, the presence of diabetes altered the abundance of some microbiota in saliva.
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- 2022
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21. Juvenile-onset PSAT1-related neuropathy: A milder phenotype of serine deficiency disorder
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Yu Shen, Yun Peng, Pengcheng Huang, Yilei Zheng, Shumeng Li, Kaiyan Jiang, Meihong Zhou, Jianwen Deng, Min Zhu, and Daojun Hong
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serine deficiency disorder ,PSAT1 gene ,ichthyosis ,peripheral neuropathy ,juvenile-onset ,Genetics ,QH426-470 - Abstract
Background: Primary serine deficiency disorders have a broad range of the phenotypic spectrum. As an inborn error of metabolism, individuals with severe phenotype may be easily recognized with Neu-Laxova syndrome. However, late-onset mild phenotypes may be underdiagnosed and will lead to disastrous consequences due to treatment delays.Materials and Methods: Clinical features of patients with serine deficiency disorders were summarized in two unrelated patients. Skin and sural nerve biopsies were conducted on the patients. Whole exome sequencing (WES) was performed in the index patients. Sanger sequencing was used to analyze family cosegregation.Results: Patient 1 was a 19-year-old male presenting with infancy-onset ichthyosis and juvenile-onset neuropathy. Patient 2 was a 17-year-old male manifesting childhood-onset ichthyosis and juvenile-onset neuropathy. Except for nystagmus, no other developmental or neurodegenerative disorders were found in the patients. Electrophysiological studies indicated a severe sensorimotor axonal neuropathy with a possible demyelinating component. High-dose oral L-serine and glycine completely alleviated skin lesions and only slightly improved neuropathy symptoms. Skin biopsies showed typical features consistent with ichthyosis and severe loss of unmyelinated axons. Sural biopsies revealed a severe loss of axons and a few thinly myelinated fibers. WES found the same homozygous variant c.43G > C (p.A15P) in the PSAT1 gene, which was cosegregated in the two families.Conclusions: The skin and nervous system may be the main affected targets in serine deficiency disorders. Our patients show a more simple and mild phenotype of PSAT1-related serine deficiency disorder. The pathological changes and regenerative ability of skin and peripheral nerves determine their response to serine supplements.
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- 2022
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22. Research Note: Comparison of the texture, structure, and composition of eggs from local Chinese chickens and a highly selected line of egg-type chickens and analysis of the effects of lipids on texture
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Ruiqi Zhang, Jianwen Deng, Xingze Li, Wenxi Shang, and Zhonghua Ning
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egg yolk ,texture ,microstructure ,lipidomics ,Animal culture ,SF1-1100 - Abstract
ABSTRACT: Egg yolk texture affects consumer egg preference. The sensory characteristics of eggs are affected by not only the cooking method but also the maternal breed. In this study, we investigated the texture, structure, and nutritional differences between the cooked yolks of eggs obtained from Hetian Dahei (HTDH) and Rhode Island Red (RIR) chickens. The springiness, cohesiveness, gumminess, chewiness, and resilience of HTDH egg yolks were lower, and the hardness was higher than those of RIR egg yolks. Moreover, scanning electron microscopy revealed that HTDH egg yolk particles were smaller and that HTDH egg yolks had a denser protein network than those of RIR egg yolks. Lipid and protein levels were higher, whereas water contents were lower in uncooked HTDH egg yolks than in uncooked RIR egg yolks. Liquid chromatography tandem mass spectrometry further revealed that lower cohesiveness was associated with higher levels and greater variety of lipids in egg yolks. Moreover, increased phospholipid levels reduced egg yolk cohesiveness. Thus, the eggs of local Chinese chicken breeds were superior to those of a highly selected broiler chicken breed in terms of texture, structure, and nutritional composition, which may influence egg variety selection.
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- 2022
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23. Exonization of a deep intronic long interspersed nuclear element in Becker muscular dystrophy
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Zhiying Xie, Chang Liu, Yanyu Lu, Chengyue Sun, Yilin Liu, Meng Yu, Junlong Shu, Lingchao Meng, Jianwen Deng, Wei Zhang, Zhaoxia Wang, He Lv, and Yun Yuan
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DMD ,LINE-1 ,aberrant splicing ,deep-intronic structural variant ,long-read sequencing ,Genetics ,QH426-470 - Abstract
The precise identification of pathogenic DMD variants is sometimes rather difficult, mainly due to complex structural variants (SVs) and deep intronic splice-altering variants. We performed genomic long-read whole DMD gene sequencing in a boy with asymptomatic hyper-creatine kinase-emia who remained genetically undiagnosed after standard genetic testing, dystrophin protein and DMD mRNA studies, and genomic short-read whole DMD gene sequencing. We successfully identified a novel pathogenic SV in DMD intron 1 via long-read sequencing. The deep intronic SV consists of a long interspersed nuclear element-1 (LINE-1) insertion/non-tandem duplication rearrangement causing partial exonization of the LINE-1, establishing a genetic diagnosis of Becker muscular dystrophy. Our study expands the genetic spectrum of dystrophinopathies and highlights the significant role of disease-causing LINE-1 insertions in monogenic diseases.
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- 2022
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24. GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy
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Jiaxi Yu, Xing‐hua Luan, Meng Yu, Wei Zhang, He Lv, Li Cao, Lingchao Meng, Min Zhu, Binbin Zhou, Xiao‐rong Wu, Pidong Li, Qiang Gang, Jing Liu, Xin Shi, Wei Liang, Zhirong Jia, Sheng Yao, Yun Yuan, Jianwen Deng, Daojun Hong, and Zhaoxia Wang
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. Methods Whole‐exome sequencing (WES) and long‐read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. Results We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. Interpretation These phenotypes enrich the class of features associated with NOTCH2NLC‐related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.
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- 2021
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25. First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy
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Zhiying Xie, Chengyue Sun, Chang Liu, Xujun Chu, Qiang Gang, Meng Yu, Yiming Zheng, Lingchao Meng, Fan Li, Dongliang Xia, Li Wang, Ying Li, Jianwen Deng, He Lv, Zhaoxia Wang, Wei Zhang, and Yun Yuan
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SGCB ,aberrant splicing ,intron ,splice-altering variants ,diagnosis ,Pediatrics ,RJ1-570 - Abstract
BackgroundThe precise genetic diagnosis of a sarcoglycanopathy or dystrophinopathy is sometimes extremely challenging, as pathogenic non-coding variants and/or complex structural variants do exist in DMD or sarcoglycan genes. This study aimed to determine the genetic diagnosis of three patients from two unrelated families with a suspected sarcoglycanopathy or dystrophinopathy based on their clinical, radiological, and pathological features, for whom routine genomic detection approaches failed to yield a definite genetic diagnosis.MethodsMuscle-derived reverse transcription-polymerase chain reaction analysis and/or TA cloning of DMD, SGCA, SGCB, SGCD, and SGCG mRNA were performed to identify aberrant transcripts. Genomic Sanger sequencing around the aberrant transcripts was performed to detect possible splice-altering variants. Bioinformatic and segregation studies of the detected genomic variants were performed in both families.ResultsIn patients F1-II1 and F1-II2, we identified two novel pathogenic compound heterozygous variants in SGCB. One is a deep intronic splice-altering variant (DISV), c.243 + 1558C > T in intron 2 causing the activation of an 87-base pair (bp) pseudoexon, and the other one is a non-canonical splicing site variant, c.243 + 6T > A leading to the partial intron inclusion of 10-bp sequence. A novel DISV, c.243 + 1576C > G causing a 106-bp pseudoexon activation, and a nonsense variant in SGCB were identified in compound heterozygous state in patient F2-II1. Unexpectedly, the predicted nonsense variant, c.334C > T in exon 3, created a new donor splice site in exon 3 that was stronger than the natural one, resulting in a 97-bp deletion of exon 3 (r.333_429del).ConclusionThis is the first identification of rare exonic and DISVs in the SGCB gene.
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- 2022
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26. Skeletal Muscle Involvement Pattern of Hereditary Transthyretin Amyloidosis: A Study Based on Muscle MRI
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Xujun Chu, Kang Du, Yuwei Tang, Xutong Zhao, Meng Yu, Yiming Zheng, Jianwen Deng, He Lv, Wei Zhang, Zhaoxia Wang, Yun Yuan, and Lingchao Meng
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amyloidosis ,transthyretin ,MRI ,fatty infiltration ,polyneuropathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
ObjectsThis study was intended to explore the characteristics of muscle magnetic resonance imaging (MRI) of patients with hereditary transthyretin amyloidosis (ATTRv amyloidosis) prospectively.MethodsThe clinical data of 20 patients with ATTRv amyloidosis at our hospital between July 2020 and August 2021 were analyzed. MRI of lower limbs including calf muscles was performed in all these 20 patients and MRI of thigh muscles was performed in 16 of them.ResultsThe mean age of the 20 patients with ATTRv amyloidosis was 44.2 years (ranging from 26 to 60) whose mean duration of weakness was 23.3 ± 23.0 (ranging from 0 to 84) months. All the patients presented with polyneuropathy, and 18 of them with weakness in their lower limbs. Muscle involvement was selective in these patients with ATTRv amyloidosis. The posterior group of muscles was heavily fatty, and the soleus muscle was the most heavily involved. The proportion of fatty infiltration scores at the calf level was higher than at the thigh level with paired comparison for most patients. Three of these patients had more severely fatty infiltration of muscles at the thigh level. The fatty infiltration of posterior compartments at the calf level was highly consistent with neuropathy impairment scores of lower limbs (weakness), the strength of ankle plantar flexion muscles, and the amplitude of the compound muscle action potential of the tibial nerve.ConclusionsIt was found that the pattern of muscle fatty infiltration was consistent with a distal-to-proximal gradient on the whole and that proximal involvements in MRI of lower limbs in some patients could also be observed. Selective fatty infiltration of muscles of posterior compartments and fatty infiltration of the soleus muscle might be typical of ATTRv amyloidosis.
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- 2022
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27. Mitochondrial morphology and MAVS‐IFN1 signaling pathway in muscles of anti‐MDA5 dermatomyositis
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Yanyan Jiang, Yilin Liu, Yawen Zhao, Yiming Zheng, Meng Yu, Jianwen Deng, Hongjun Hao, Wei Zhang, Zhaoxia Wang, and Yun Yuan
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Objective This study aimed to investigate mitochondrial changes and the mitochondrial antiviral‐signaling protein (MAVS)‐type I interferon (IFN1) signaling pathway in the muscles of anti‐melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients. Methods Eleven anti‐MDA5 DM and ten antibody‐negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN‐stimulated gene 15, which are components of the MAVS‐IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed. Results Anti‐MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P
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- 2021
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28. Chicken Hypothalamic and Ovarian DNA Methylome Alteration in Response to Forced Molting
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Tongyu Zhang, Chengfeng Li, Jianwen Deng, Yaxiong Jia, Lujiang Qu, and Zhonghua Ning
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forced molting ,DNA methylation ,functional regions ,reproductive function ,chicken ,Veterinary medicine ,SF600-1100 ,Zoology ,QL1-991 - Abstract
Epigenetic modifications play an important role in regulating animal adaptation to external stress. To explore how DNA methylation regulates the expression levels of related genes during forced molting (FM) of laying hens, the hypothalamus and ovary tissues were analyzed at five periods using Whole-Genome Bisulfite Sequencing. The results show that methylation levels fluctuated differently in the exon, intron, 5′UTR, 3′UTR, promoter, and intergenic regions of the genome during FM. In addition, 16 differentially methylated genes (DMGs) regulating cell aging, immunity, and development were identified in the two reversible processes of starvation and redevelopment during FM. Comparing DMGs with differentially expressed genes (DEGs) obtained in the same periods, five hypermethylated DMGs (DSTYK, NKTR, SMOC1, SCAMP3, and ATOH8) that inhibited the expression of DEGs were found. Therefore, DMGs epigenetically modify the DEGs during the FM process of chickens, leading to the rapid closure and restart of their reproductive function and a re-increase in the egg-laying rate. Therefore, this study further confirmed that epigenetic modifications could regulate gene expression during FM and provides theoretical support for the subsequent optimization of FM technology.
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- 2023
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29. A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia
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Weiwei Yu, Haiqiang Jin, Jianwen Deng, Ding Nan, and Yining Huang
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Hereditary spastic paraplegia ,Gait disorder ,Whole exome sequencing ,SPAST gene ,In-frame deletion ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function. Results Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein. Conclusion In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.
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- 2020
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30. Profiling of Differentially Expressed MicroRNAs in Saliva of Parkinson's Disease Patients
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Yanyan Jiang, Jing Chen, Yunchuang Sun, Fan Li, Luhua Wei, Wei Sun, Jianwen Deng, Yun Yuan, and Zhaoxia Wang
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Parkinson's disease ,diagnosis ,saliva ,biomarker ,microRNA ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Objective: This study aims to identify differentially expressed salivary miRNAs and validate the diagnostic potential for idiopathic Parkinson's disease (PD). Also, the disease specificity of candidate miRNAs was evaluated between PD, multiple system atrophy (MSA), and essential tremor (ET).Methods: We collected salivary samples from 50 PD, 20 ET, and 20 MSA patients, as well as 30 healthy controls (HCs). In the discovery phase, salivary miRNA microarray analysis was performed. In-silico analysis was used to investigate the target genes of differentially expressed miRNAs and clustered pathways. In validation phase, RT-qPCR was performed with samples from 30 PD patients and 30 HCs. Subsequently, we investigated candidate miRNAs in all recruited subjects. Receiver operating characteristic curve and Spearman correlation analysis was performed to determine diagnostic usefulness.Results: We identified 43 miRNAs that were differentially expressed between 5 PD patients and 5 HCs by miRNA microarray analysis. Computational analysis revealed the target genes were clustered in the pathways associated with ubiquitin protein ligase activity. The result of RT-qPCR showed that the miR-29a-3p and miR-29c-3p were found to be significantly downregulated (p = 0.004, p = 0.027), whereas the miR-6756-5p was significantly upregulated in 30 PD patients compared with 30 HCs (p = 0.032). The miR-29a-3p expression level in PD patients was significantly lower than ET patients (p = 0.035), but higher than MSA patients (p < 0.0001). The diagnostic efficacy reached a little higher when the combination of miR-29a-3p and miR-29c-3p.Conclusion: The miRNA combination of salivary miR-29a-3p and miR-29c-3p has potential to be a diagnostic biomarker for idiopathic PD.
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- 2021
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31. Ferroptosis: A New Development Trend in Periodontitis
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Kexiao Chen, Shuyuan Ma, Jianwen Deng, Xinrong Jiang, Fengyu Ma, and Zejian Li
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ferroptosis ,periodontitis ,iron overload ,lipid peroxidation ,oxidative stress ,periodontal pathogen ,Cytology ,QH573-671 - Abstract
Periodontitis is a chronic inflammatory disease associated with bacterial biofilm. It is characterized by loss of periodontal support tissue and has long been considered as a “silent disease”. Because it is difficult to prevent and has a health impact that can not be ignored, researchers have been focusing on a mechanism-based treatment model. Ferroptosis is an iron-dependent regulatory form of cell death, that directly or indirectly affects glutathione peroxidase through different signaling pathways, resulting in a decrease in cell antioxidant capacity, accumulation of reactive oxygen species and lipid peroxidation, which cause oxidative cell death and tissue damage. Recently, some studies have proven that iron overload, oxidative stress, and lipid peroxidation exist in the process of periodontitis. Based on this, this article reviews the relationship between periodontitis and ferroptosis, in order to provide a theoretical reference for future research on the prevention and treatment of periodontal disease.
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- 2022
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32. GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor–Sensory and Autonomic Neuropathy
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Hui Wang, Jiaxi Yu, Meng Yu, Jianwen Deng, Wei Zhang, He Lv, Jing Liu, Xin Shi, Wei Liang, Zhirong Jia, Daojun Hong, Lingchao Meng, Zhaoxia Wang, and Yun Yuan
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inherited peripheral neuropathy ,motor–sensory and autonomic neuropathy ,NOTCH2NLC ,GGC repeat expansions ,NOTCH2NLC-related repeat expansion spectrum ,Genetics ,QH426-470 - Abstract
There is still a considerable proportion of patients with inherited peripheral neuropathy (IPN) whose pathogenic genes are unknown. This study was intended to investigate whether the GGC repeat expansion in the NOTCH2NLC is presented in some patients with IPN. A total of 142 unrelated mainland Chinese patients with highly suspected diagnosis of IPN without any known causative gene were recruited. Repeat-primed polymerase chain reaction (RP-PCR) was performed to screen GGC repeat expansion in NOTCH2NLC, followed by fluorescence amplicon length analysis-PCR (AL-PCR) to determine the GGC repeat size. Detailed clinical data as well as nerve, muscle, and skin biopsy were reviewed and analyzed in the NOTCH2NLC-related IPN patients. In total, five of the 142 patients (3.52%) were found to have pathogenic GGC expansion in NOTCH2NLC, with repeat size ranging from 126 to 206 repeats. All the NOTCH2NLC-related IPN patients presented with adult-onset motor–sensory and autonomic neuropathy that predominantly affected the motor component of peripheral nerves. While tremor and irritating dry cough were noted in four-fifths of the patients, no other signs of the central nervous system were presented. Electrophysiological studies revealed both demyelinating and axonal changes of polyneuropathy that were more severe in lower limbs and asymmetrically in upper limbs. Sural nerve pathology was characterized by multiple fibers with thin myelination, indicating a predominant demyelinating process. Muscle pathology was consistent with neuropathic changes. P62-positive intranuclear inclusions were observed in nerve, skin, and muscle tissues. Our study has demonstrated that GGC expansion in NOTCH2NLC is associated with IPN presenting as predominant motor–sensory and autonomic neuropathy, which expands the phenotype of the NOTCH2NLC-related repeat expansion spectrum. Screening of GGC repeat expansions in the NOTCH2NLC should be considered in patients presenting with peripheral neuropathy with tremor and irritating dry cough.
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- 2021
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33. Novel and Recurrent Mutations in a Cohort of Chinese Patients With Young-Onset Amyotrophic Lateral Sclerosis
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Jianwen Deng, Wei Wu, Zhiying Xie, Qiang Gang, Meng Yu, Jing Liu, Qingqing Wang, He Lv, Wei Zhang, Yining Huang, Tao Wang, Yun Yuan, Daojun Hong, and Zhaoxia Wang
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amyotrophic lateral sclerosis ,young-onset ,fused in sarcoma ,novel mutation ,+C+%28p%2E+K510Q%29%22">c.1528A > C (p. K510Q) ,Drosophila model ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. More than 25 ALS-related genes have been identified, accounting for approximately 10% of sporadic ALS (SALS) and two-thirds of familial ALS (FALS) cases. Several recent studies showed that genetic factors might have a larger contribution to young-onset ALS than to ALS cases overall. However, the genetic profile of young-onset ALS patients is not yet fully understood. Here, we investigated a cohort of 27 young-onset ALS patients (onset age < 45 years) through whole-exome sequencing (WES). Genetic analysis identified pathogenic variants of FUS (25.9%), SOD1 (22.2%), TARDBP (3.7%), and VCP (3.7%) in 27 young-onset ALS patients. Of 12 identified types of mutations, c.1528A > C in FUS and c.266G > A in VCP were novel. All of the cases in this study reflect a monogenic origin with an autosomal dominant mode of inheritance. Notably, a novel de novo missense mutation, c.1528A > C (p.K510Q), in FUS was identified in a 29-year-old ALS patient. Expression of the K510Q mutant FUS resulted in cytoplasmic mislocalization of FUS in cultured cells and induced neural toxicity in a fly model. This study provides further evidence of the genetic profile of young-onset ALS patients from China and expands the mutational spectrum of the FUS gene, with one new K510Q mutation identified.
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- 2019
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34. TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response.
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Peng Wang, Jianwen Deng, Jie Dong, Jianghong Liu, Eileen H Bigio, Marsel Mesulam, Tao Wang, Lei Sun, Li Wang, Alan Yueh-Luen Lee, Warren A McGee, Xiaoping Chen, Kazuo Fushimi, Li Zhu, and Jane Y Wu
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Genetics ,QH426-470 - Abstract
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.
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- 2019
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35. FUS Interacts with HSP60 to Promote Mitochondrial Damage.
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Jianwen Deng, Mengxue Yang, Yanbo Chen, Xiaoping Chen, Jianghong Liu, Shufeng Sun, Haipeng Cheng, Yang Li, Eileen H Bigio, Marsel Mesulam, Qi Xu, Sidan Du, Kazuo Fushimi, Li Zhu, and Jane Y Wu
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Genetics ,QH426-470 - Abstract
FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
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- 2015
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36. Novel TUBA4A variant causes congenital myopathy with focal myofibrillar disorganisation.
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Yalan Wan, Chao Zhou, Xingzhi Chang, Liwen Wu, Yilei Zheng, Jiaxi Yu, Li Bai, Mingyue Luan, Meng Yu, Qi Wang, Wei Zhang, Yun Yuan, Jianwen Deng, and Zhaoxia Wang
- Abstract
Background Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy. Methods A comprehensive strategy combining laser capture microdissection, proteomics and wholeexome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant. Results We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model. Conclusion Our findings expanded the phenotypic and genetic manifestations of TUBA4A as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Non-coding CGG repeat expansion in LOC642361/NUTM2B-AS1 is associated with a phenotype of oculopharyngodistal myopathy.
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Xinyu Gu, Jiaxi Yu, Kexin Jiao, Jianwen Deng, Xingyu Xia, Kai Qiao, Dongyue Yue, Mingshi Gao, Chongbo Zhao, Jihong Dong, Gongchun Huang, Jingli Shan, Chuanzhu Yan, Li Di, Yuwei Da, Wenhua Zhu, Jianying Xi, and Zhaoxia Wang
- Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2024
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38. The role of AFAP1-AS1 in mitotic catastrophe and metastasis of triple-negative breast cancer cells by activating the PLK1 signaling pathway
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SHUIZHONG CEN, XIAOJIE PENG, JIANWEN DENG, HAIYUN JIN, ZHINAN DENG, XIAOHUA LIN, DI ZHU, MING JIN, YANWEN ZHU, PUSHENG ZHANG, YUNFENG LUO, and HONGYAN HUANG
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Cancer Research ,Oncology ,General Medicine - Published
- 2023
39. Clinical, muscle imaging, and genetic characteristics of dystrophinopathies with deep-intronic DMD variants
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Zhiying Xie, Chengyue Sun, Chang Liu, Zhihao Xie, Luhua Wei, Jiaxi Yu, Chen Ling, Xuejun Guo, Yilin Liu, Meng Yu, Yinglin Leng, Lingchao Meng, Yunchuang Sun, Jianwen Deng, Suzanne M. Leal, Isabelle Schrauwen, Zhaoxia Wang, and Yun Yuan
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Neurology ,Neurology (clinical) - Abstract
Phenotypic heterogeneity within or between families with a same deep-intronic splice-altering variant in the DMD gene has never been systematically analyzed. This study aimed to determine the phenotypic and genetic characteristics of patients with deep-intronic DMD variants.Of 1338 male patients with a suspected dystrophinopathy, 38 were confirmed to have atypical pathogenic DMD variants via our comprehensive genetic testing approach. Of the 38 patients, 30 patients from 22 unrelated families with deep-intronic DMD variants underwent a detailed clinical and imaging assessment.Nineteen different deep-intronic DMD variants were identified in the 30 patients, including 15 with Duchenne muscular dystrophy (DMD), 14 with Becker muscular dystrophy (BMD), and one with X-linked dilated cardiomyopathy. Of the 19 variants, 15 were single-nucleotide variants, 2 were structural variants (SVs), and 2 were pure-intronic large-scale SVs causing aberrant inclusion of other protein-coding genes sequences into the mature DMD transcripts. The trefoil with single fruit sign was observed in 18 patients and the concentric fatty infiltration pattern was observed in 2 patients. Remarkable phenotypic heterogeneity was observed not only in skeletal but also cardiac muscle involvement in 2 families harboring a same deep-intronic variant. Different skeletal muscle involvement between families with a same variant was observed in 4 families. High inter-individual phenotypic heterogeneity was observed within two BMD families and one DMD family.Our study first highlights the variable phenotypic expressivity of deep-intronic DMD variants and demonstrates a new class of deep-intronic DMD variants, i.e., pure-intronic SVs involving other protein-coding genes.
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- 2022
40. FUS Mutation Causes Disordered Lipid Metabolism in Skeletal Muscle Associated with ALS
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Binbin Zhou, Yilei Zheng, Xiaobing Li, Huifang Dong, Jiaxi Yu, Yang Zou, Min Zhu, Yanyan Yu, Xin Fang, Meihong Zhou, Wei Zhang, Yun Yuan, Zhaoxia Wang, Jianwen Deng, and Daojun Hong
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Cellular and Molecular Neuroscience ,Neurology ,Amyotrophic Lateral Sclerosis ,Mutation ,Neuroscience (miscellaneous) ,Animals ,RNA-Binding Protein FUS ,Neurodegenerative Diseases ,Lipid Metabolism ,Muscle, Skeletal - Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by dysfunction of the upper and lower motor neurons resulting in muscle weakness and wasting. Recently, several studies on ALS patients and ALS animal models indicated that intramuscular toxicity played a role in ALS disease progression; however, the mechanisms driving this are unknown. In this study, we explored the possible dysfunction of lipid metabolism in myocytes associated with ALS. Initially, skeletal muscle from 41 ALS patients, as well as 53 non-ALS control subjects, was investigated, and we identified that lipid droplet accumulation in the muscle fibers of ALS patients was significantly increased, especially in patients with FUS mutations. A myoblast (C2C12) cell line expressing mutant FUS (FUS-K510Q) was able to induce lipid droplet accumulation and mitochondrial dysfunction. Consistently, transgenic flies expressing FUS-K510Q under a muscle-specific driver showed elevated triglyceride levels in the flight muscles, as well as locomotor defects. Biochemical analysis of C2C12 cells and fly muscle tissues showed upregulation of PLIN2, and downregulation of ATGL and CPT1A, indicating inhibition of lipolysis and fatty acid β-oxidation in muscle cells with FUS mutations. Our study provided a potential explanation for the pathogenesis associated with lipid droplets accumulating in skeletal muscle in ALS. Our data also suggested that disordered lipid metabolism and mitochondrial dysfunction play a crucial role in intramuscular toxicity in ALS.
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- 2022
41. A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3
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Yuwei Tang, Meng Yu, Wei Zhang, He Lv, Jianwen Deng, Jing Liu, Xin Shi, Wei Liang, Zhirong Jia, Yun Yuan, Zhaoxia Wang, and Lingchao Meng
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Neurology ,Neurology (clinical) ,General Medicine ,Pathology and Forensic Medicine - Published
- 2022
42. Oculopharyngodistal myopathy
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Jiaxi, Yu, Jianwen, Deng, and Zhaoxia, Wang
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Muscle Weakness ,Phenotype ,Neurology ,Humans ,Neurology (clinical) ,Muscular Dystrophies - Abstract
Oculopharyngodistal myopathy (OPDM) is a rare adolescent or adult-onset neuromuscular disease that is characterized by progressive ocular, facial, pharyngeal and distal limb muscle weakness. The rimmed vacuoles and intranuclear inclusions in myofibers constitute the pathological hallmark of OPDM. In this review, the latest findings related to the genetic, molecular and clinical features of OPDM, as well as the diagnosis and management are summarized.Four gene mutations, CGG repeats in the 5'-untranslated region of LRP12 , GIPC1 , NOTCH2NLC and RILPL1 have been reported to be disease-causing genes in OPDM, namely OPDM1, OPDM2, OPDM3 and OPDM4, accordingly. So far, limited studies have suggested that CGG repeat expansion within the pathogenic range may play a key role in the pathogenesis of OPDM with the gain-of-function mechanism at the RNA and/or protein level, while repeat expansion over a threshold limit may cause hypermethylation, leading to the transcriptional silencing of the CGG repeats in the expanded allele, which results in the existence of mild phenotype or asymptomatic carriers.Novel gene mutations, possible molecular mechanisms and the clinical features related to different causative genes are discussed in this review. More studies on the exact pathogenic mechanism are needed.
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- 2022
43. Les myopathies oculo-pharyngo-distales : des nouvelles maladies à expansions de répétitions CGG
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Manon Boivin, Jianwen Deng, Zhaoxia Wang, and Nicolas Charlet-Berguerand
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La myopathie oculo-pharyngo-distale (OPDM) est une maladie génétique rare de l’adulte affectant les muscles squelettiques du visage, du pharynx et des extrémités des membres. Récemment, des variants dans quatre gènes distincts ont été identifiés comme responsables de cette pathologie. Bien que localisées dans différents gènes, le mécanisme mutationnel est identique, à savoir une expansion de 50 à 200-300 répétitions de triplets de nucléotides CGG. Dans cet article, nous décrivons les aspects cliniques, histopathologiques et génétiques de l’OPDM, ainsi que les mécanismes moléculaires pouvant expliquer la toxicité de ces expansions de répétitions trinucléotidiques.
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- 2022
44. Aquaporin 4 Mediates the Effect of Iron Overload on Hydrocephalus After Intraventricular Hemorrhage
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Ying Li, Ding Nan, Ran Liu, Jieyu Li, Zhuangzhuang Zhang, Jianwen Deng, Yang Zhang, Ziguang Yan, Chao Hou, Ensheng Yao, Weiping Sun, Zhaoxia Wang, and Yining Huang
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Neurology (clinical) ,Critical Care and Intensive Care Medicine - Abstract
Background Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH. Methods There were three parts to this study. First, Sprague–Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin–stained brain sections were obtained to assess the ventricular wall damage on day 28. Results Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage. Conclusions AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.
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- 2023
45. <scp>CAG</scp> Repeat Expansion in <scp> THAP11 </scp> Is Associated with a Novel Spinocerebellar Ataxia
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Dandan Tan, Cuijie Wei, Zhao Chen, Yu Huang, Jianwen Deng, Jingjing Li, Yidan Liu, Xinhua Bao, Jin Xu, Zhengmao Hu, Suxia Wang, Yanbin Fan, Yizheng Jiang, Ye Wu, Yuan Wu, Shuang Wang, Panyan Liu, Yuehua Zhang, Zhixian Yang, Yuwu Jiang, Hong Zhang, Daojun Hong, Nanbert Zhong, Hong Jiang, and Hui Xiong
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Neurology ,Neurology (clinical) - Published
- 2023
46. CGG repeat expansion in
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Jiaxi, Yu, Tongling, Liufu, Yilei, Zheng, Jin, Xu, Lingchao, Meng, Wei, Zhang, Yun, Yuan, Daojun, Hong, Nicolas, Charlet-Berguerand, Zhaoxia, Wang, and Jianwen, Deng
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Animals, Genetically Modified ,Leucine ,Intranuclear Inclusion Bodies ,Animals ,RNA-Binding Proteins ,Drosophila ,Neurodegenerative Diseases ,5' Untranslated Regions ,Trinucleotide Repeat Expansion ,Mitochondria - Abstract
Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5' untranslated region (UTR) of the
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- 2023
47. Novel variants, muscle imaging, and myopathological changes in Chinese patients with <scp>VCP</scp> ‐related multisystem proteinopathy
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Yalan Wan, Qi Wang, Yiming Zheng, Meng Yu, Zhiying Xie, Chen Ling, Lingchao Meng, Jiaxi Yu, Yilei Zheng, Yikang Wang, Wenhao Zhang, Chang Liu, Yawen Zhao, Yun Yuan, Jianwen Deng, Qiang Gang, and Zhaoxia Wang
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Genetics ,Molecular Biology ,Genetics (clinical) - Published
- 2023
48. The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4
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Jiaxi Yu, Jingli Shan, Meng Yu, Li Di, Zhiying Xie, Wei Zhang, He Lv, Lingchao Meng, Yiming Zheng, Yawen Zhao, Qiang Gang, Xueyu Guo, Yang Wang, Jianying Xi, Wenhua Zhu, Yuwei Da, Daojun Hong, Yun Yuan, Chuanzhu Yan, Zhaoxia Wang, and Jianwen Deng
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Report ,Genetics ,Genetics (clinical) - Abstract
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.
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- 2022
49. Widespread Mislocalization of FUS Is Associated With Mitochondrial Abnormalities in Skeletal Muscle in Amyotrophic Lateral Sclerosis With FUS Mutations
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Meng, Yu, Xutong, Zhao, Wei, Wu, Qingqing, Wang, Jing, Liu, Wei, Zhang, Yun, Yuan, Daojun, Hong, Zhaoxia, Wang, and Jianwen, Deng
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Inclusion Bodies ,Cellular and Molecular Neuroscience ,Neurology ,Amyotrophic Lateral Sclerosis ,Muscle Fibers, Skeletal ,Mutation ,Animals ,Humans ,RNA-Binding Protein FUS ,Neurology (clinical) ,General Medicine ,Pathology and Forensic Medicine - Abstract
Mutations in the fused in sarcoma (FUS) gene have been reported to be the most common genetic cause of early-onset amyotrophic lateral sclerosis (ALS); cytoplasmic inclusions containing FUS protein are the predominant pathological feature. Recent studies indicated that mutant FUS impaired neuromuscular junctions and induced muscle intrinsic toxicity in cell and animal models. However, the role of FUS in muscle degeneration remains unclear. In this study, we investigated FUS protein distribution in skeletal muscle fibers in ALS-FUS. Our data show that cytoplasmic mislocalized FUS in the unaggregated form represented a remarkable pathological feature in affected muscle fibers in ALS-FUS. Additional studies found that cytoplasmic FUS colocalized with some mitochondria and was associated with mitochondrial swelling and disorganized cristae. RNA sequencing and quantitative real-time polymerase chain reaction analyses indicated downregulation of the key subunits of mitochondrial oxidative phosphorylation complexes in the affected skeletal muscle in ALS-FUS patients. Further immunoblot analysis showed increased levels of FUS, but decreased levels of Cox I (subunit of complex IV) in ALS-FUS patients compared with age-matched controls. This is the first demonstration of the close association of cytoplasmic mislocalized FUS with mitochondrial dysfunction in skeletal muscle, implicating the presence of a cell-autonomous mechanism in muscle degeneration in ALS.
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- 2022
50. Subclinical peripheral neuropathy is common in neuronal intranuclear inclusion disease with dominant encephalopathy
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Daojun Hong, Hui Wang, Min Zhu, Yun Peng, Pengcheng Huang, Yilei Zheng, Meng Yu, Lingchao Meng, Fan Li, Jiaxi Yu, Meihong Zhou, Jianwen Deng, Zhaoxia Wang, and Yun Yuan
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Neurology ,Neurology (clinical) - Abstract
Neuronal intranuclear inclusion disease (NIID) is associated with CGG repeat expansion in the NOTCH2NLC gene. Although pure or dominant peripheral neuropathy has been described as a subtype of NIID in a few patients, most NIID patients predominantly show involvements of the central nervous system (CNS). It is necessary to further explore whether these patients have subclinical peripheral neuropathy.Twenty-eight NIID patients, clinically characterized by CNS-dominant involvements, were recruited from two tertiary hospitals. Standard nerve conduction studies were performed in all patients. Skin and sural nerve biopsies were performed in 28 and 15 patients, respectively. Repeat-primed polymerase chain reaction and amplicon length polymerase chain reaction were used to screen the CGG repeat expansion in NOTCH2NLC.All 28 patients can be diagnosed with NIID based on skin pathological and genetic changes. All patients predominantly showed CNS symptoms mainly characterized by episodic encephalopathy and cognitive impairments, but no clinical symptoms of peripheral neuropathy could be observed initially. Electrophysiological abnormalities were found in 96.4% (27/28) of these patients, indicating that subclinical peripheral neuropathy is common in NIID patients with CNS-dominant type. Electrophysiological and neuropathological studies revealed that demyelinating degeneration was the main pathological pattern in these patients, although mild axonal degeneration was also observed in some patients. No significant association between CGG repeat size and the change of nerve conduction velocity was found in these patients.This study demonstrated that most patients with CNS-dominant NIID had subclinical peripheral neuropathy. Electrophysiological examination should be the routinely diagnostic workflow for every NIID patient.
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- 2022
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