Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.

Primary central nervous system lymphoma (PCNSL) is a malignant tumor known to cause direct mass effects and various paraneoplastic syndromes. However, paraneoplastic vasculitic peripheral neuropathy is rarely associated with PCNSL. In this case report, we describe a patient with PCNSL who presented with probable paraneoplastic vasculitic peripheral neuropathy. The patient initially experienced recurrent pain and weakness in bilateral lower limbs for two years, followed by a sudden decline in consciousness over two days. A biopsy of the right sural nerve revealed probable vasculitic peripheral neuropathy, and the diagnosis of PCNSL was confirmed through brain biopsy.

BackgroundOculopharyngodistal myopathy (OPDM) is a rare hereditary muscle disease characterized by progressive ptosis, ophthalmoplegia, dysphagia, dysarthria, and distal muscle weakness. The genetic basis was identified in 2019 with CGG repeat expansions in the noncoding region of LRP12. Similar expansions in GIPC1, NOTCH2NLC, and RILPL1 were later linked to OPDM, classifying the disease into OPDM1-4. OPDM4, associated with RILPL1, was discovered in 2022 with a few confirmed cases worldwide, leaving its clinical features and pathogenic mechanisms largely unexplored.Case presentationWe present a patient with OPDM4 who had suffered progressive ptosis, external ophthalmoplegia, pharyngeal weakness, facial muscle weakness, and distal limb weakness over the past 20 years. Electromyography (EMG) revealed myogenic damage and normal H-reflex latency. A biopsy of the left biceps brachii revealed myogenic changes with atypical rimmed vacuoles in some muscle fibers. Screening for extra-muscular system involvement revealed no obvious involvement of the heart or central nervous system. Genetic analysis confirmed 126 CGG repeat expansions in RILPL1 and excluded abnormal CGG repeat expansions in LRP12, GIPC1, and NOTCH2NLC.ConclusionThis case broadens the spectrum of CGG repeat numbers in the RILPL1 gene associated with OPDM4. In addition, systematic medical examinations revealed several new characteristics of OPDM4, which have not been reported previously, such as normal H reflex, potential mild cognitive impairment, etc. These findings expand our knowledge of the phenotypic spectrum of diseases caused by repeat CGG expansions in RILPL1.

STUDY DESIGN:A prospective case-control study. PURPOSE:This prospective case-control study aimed to analyze the paravertebral muscle changes in patients with adolescent idiopathic scoliosis (AIS) and determine paravertebral myopathological changes associated with the clinical progression of AIS. OVERVIEW OF LITERATURE:The incidence of AIS is significant globally and worsens before bone maturation, causing a serious effect. Many studies have investigated its causes-such as genetic, epigenetic, and hormonal factors-but more research remains warranted. METHODS:This study enrolled 40 patients with AIS, 20 patients with congenital scoliosis (CS), and 20 patients with spinal degenerative disease (SDD). All patients underwent open posterior surgery in our hospital, and a paravertebral muscle (multifidus muscle) biopsy was performed intraoperatively. This study included many indexes that describe muscle, especially dystrophin staining. The above pathological results were compared among the AIS, CS, and SDD groups. The correlation between the Cobb angle and Nash-Moe classification and the above pathological results was analyzed in patients with AIS. RESULTS:Significant reductions in the dystrophin staining of dystrophin-1 (p<0.001), dystrophin-2 (p<0.001), and dystrophin-3 (p<0.001) were observed in the AIS group than in the CS and SDD groups. The higher the Nash-Moe classification in the AIS group, the more significant the loss of dystrophin-2 (p=0.042) in the convex paraspinal muscles. Additionally, a significantly positive correlation was observed between the reductions of dystrophin-2 on the concave side of the AIS group and Cobb angle (p=0.011). CONCLUSIONS:Dystrophin protein deficiency in the paraspinal muscles plays a crucial role in AIS formation and progression. The severity of scoliosis in patients with AIS is correlated with the extent of dystrophin loss in the paravertebral muscles. Therefore, dystrophin dysfunction may be relevant to AIS occurrence and development.

Objective Summarize the pathological and clinical characteristics of muscle disorder cases with nemaline-shaped structure,to improve the diagnosis and differential diagnosis of the disease.Methods and Results A total of 22 cases with nemaline-shaped structure underwent muscle biopsy were selected from May 2021 to May 2024.As to final diagnosis,there were 3 cases(13.64%)of congenital nemaline myopathy,12 cases(54.54%)of amyotrophic lateral sclerosis(ALS),2 cases(9.09%)of limb-girdle muscular dystrophy(LGMD),one case(1.45%)of desminopathy,one case(1.45%)of charcot-marie-tooth disease(CMT),one case(1.45%)of non-specific myositis,one case(1.45%)of frontotemporal dementia(FTO)caused by GRN,and one case(1.45%)of hypothyroid myopathy.The muscle biopsy of all 22 cases revealed various granular,rod-shape or flaky purplish-red depositions in the sarcoplasm as nemaline-shaped structure in modified Gomori trichrome(MGT)staining and positive immunohistochemistry staining of myotilin and/or α-actin.Under electron microscopy,some cases had the ultrastructural characteristics of nemaline body or nemaline-shaped structure.Muscle biopsy that confirmed congenital nemaline myopathy had more typical nemaline,besides myotilin and α-actin were both immunopositively.Besides nemaline myopathy,the pathological changes of other muscle diseases also had specific characteristics,such as neurogenic atrophy was often present in ALS;abnormal aggregation of desmin protein was often present in desminopathy;circular atrophy,large amount internalized nuclei and interstitial fibrosis were often present in LGMD;in addition,obvious inflammatory cell infiltration was common in non-specific myositis.Therefore,the diagnosis of nemaline myopathy could not be relied on HE staining and electron microscopy alone.Apart from 14 patients that diagnosed with ALS,non-specific myositis and hypothyroid myopathy,NEB gene mutation(3 cases),CAPN3 gene mutation(one case),DYSF gene mutation(one case),SH3TC2 gene mutation(one case),GRN gene mutation(one case),and DES gene heterozygous mutation(one case)were detected by whole exome sequencing(WES)in the remaining 8 cases.Conclusions Nemaline-shaped structure can appear in a variety of muscular disorder and neurodegenerative diseases.Combined with clinicopathological characteristics are contribute to recognize nemaline myopathy,and the genetic test by WES is strong evidence for nemaline myopathy.

Objective: To test the new method of iMAX (the minimum stimulus current that elicits the maximum compound muscle action potential amplitude) electrodiagnosis, verify the feasibility of this method in evaluating the excitability of peripheral motor axons, and preliminarily explore the clinical application value. Methods: This study was a cross-sectional study. A total of 50 healthy subjects were recruited from the outpatient department of Peking University Third Hospital from June 2022 to March 2023, including 25 males and 25 females, aged 25-68 (48±8) years. Eleven patients with Charcot-Marie-Pain-1A (CMT1A), 7 males and 4 females, aged 19-55 (41±13) years and 21 patients with diabetic peripheral neuropathy (DPN), 10 males and 11 females, aged 28-79 (53±16) years were enrolled in this study. iMAX of bilateral median nerves, ulnar nerves and peroneal nerves were detected in all patients. Repeatable motor responses with minimum motor threshold and amplitude of at least 0.1 mV and the minimum stimulus current intensity, at which the maximum compound muscle action potential amplitude is elicited, were measured respectively [1 mA increment is called (iUP) and, 0.1 mA adjustment is called (iMAX)].Comparison of the parameters: the parameters of threshold, iUP and iMAX were compared among different age groups, genders and sides, body mass index(BMI) values and detection time , as well as between CMT1A patients, DPN patients and healthy subjects. Results: In healthy subjects, the threshold, iUP value and iMAX value were (1.8±0.7) mA, (4.4±1.2) mA, and (4.2±1.3) mA respectively; ulnar nerve (3.1±1.6) mA, (6.8±3.2) mA, (6.4±3.2) mA; peroneal nerve (3.7±2.0) mA, (7.8±2.8) mA, (7.4±2.9) mA. There were statistically significant differences in threshold, iUP value and iMAX value among different age groups (all P<0.001).With the increase of age, there was a trend of increasing threshold, iUP, and iMAX values in different nerves, and the differences are statistically significant (all P<0.001). There were no significant differences in gender, side and detection time threshold, iUP value and iMAX value (all P>0.05). The parameters of healthy subjects with high BMI value were higher than those of healthy subjects with low BMI value(all P<0.05). Compared with the healthy subjects, the parameters of 11 CMT1A patients were significantly increased (all P<0.05), and the parameters of 21 DPN patients were slightly increased (P<0.05). Conclusion: The new iMAX method reflects the excitability of motor axons and early axonal dysfunction, which is an important supplement to the traditional nerve conduction, and can be used to monitor motor axon excitability disorders.

BACKGROUND:Smell loss significantly impacts the quality of life in patients. However, there is limited research on smell loss in individuals with amyotrophic lateral sclerosis (ALS), and the correlation between smell loss and cognitive impairment is unclear. This study aimed to investigate the correlation between smell loss and cognition impairment in ALS patients. METHODS:The study included 216 ALS patients. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and smell identification test specifically for the Chinese population (CSIT) were administered to evaluate participants' cognitive and olfactory function, respectively. RESULTS:After covarying for age, sex, BMI, education level, degree of hunger, dietary bias, eagerness for food, stress, smoking status, alcohol consumption, and upper respiratory tract infection (URTI) or rhinitis, CSIT scores were significantly correlated with ECAS scores (r = 0.162, p = 0.028), especially the ALS-specific scores (r = 0.158, p = 0.031). Even after excluding patients with URTI or rhinitis, the results were similar. CSIT scores were significantly correlated with ECAS scores (r = 0.224, p = 0.011), especially the ALS-specific scores (r = 0.205, p = 0.019). CONCLUSION:In patients with ALS, smell loss is significantly correlated with cognitive impairment, particularly frontotemporal dysfunction. Cognitive dysfunction may lead to worse olfactory performance in ALS patients.

BackgroundUpper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).ResultsAmong the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.ConclusionUMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.

Cytoplasmic aggregation of the transactive response DNA-binding protein-43 (TDP-43) in neurons, a pathological feature common to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, has been found in some Alzheimer’s patients. Protein disulfide isomerase (PDI) functions as both an enzyme and a molecular chaperone to correct or eliminate misfolded proteins under pathological conditions. Here, we report that TDP-43 is mislocalized to the cytoplasm and colocalizes with PDI in the brain and spinal cord of two ALS patients and the brain of six Alzheimer’s patients compared to controls. TDP-43 selectively recruits wild-type PDI into its phase-separated condensate, which in turn slows down in vitro liquid–liquid phase separation of TDP-43, shifting the equilibrium phase boundary to higher protein concentrations. Importantly, wild-type PDI decreases oxidative stress-induced interaction between TDP-43 and G3BP1 to disassemble stress granules containing TDP-43 in neuronal cells. Wild-type PDI blocks the oxidative stress-induced mislocalization of TDP-43 to the cytoplasm, and blocks subsequent pathological phosphorylation and aggregation of TDP-43. We demonstrate that under pathological stress conditions, wild-type PDI disassembles stress granules, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppresses mitochondrial damage and TDP-43 toxicity. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS patients and some Alzheimer’s patients. Teaser PDI disassembles SGs, blocks cytoplasmic mislocalization and aggregation of TDP-43, and suppress TDP-43 toxicity in ALS. ### Competing Interest Statement The authors have declared no competing interest.

Undergraduate medical education in China has shifted from educator-centered learning to self-directed learning (SDL) over the past few decades. Careful design of public engagement activities can enable SDL and empower medical students to pioneer public health and patient safety education. In this study, we aimed to innovate nervous system education by implementing a public engagement model that empowers students to learn about the nervous system by teaching the public. Our goal was to generate greater interest in the nervous system at the undergraduate stage, inspire students’ enthusiasm to pursue a career in neurology, and ultimately, contribute to health promotion. During the nervous system module of the second year of the undergraduate curriculum, students were given the option to participate in the public engagement model. Participants were tasked with the creation of educational videos focusing on knowledge, attitudes, and behaviors associated with the prevention and management of neurological diseases and their complications. The videos were made accessible to the general public through the university’s official channel at the end of the semester. A total of 117 students (67.24% of all students) chose to participate in the public engagement model. Female students and those with higher Grade Point Averages in the present semester were more likely to participate. The model received strong positive feedback from participants, as students found the public engagement task helpful in learning about the nervous system module as well as in enhancing their public engagement skills. Despite the time and effort consumption, participating in the public engagement task did not affect students’ exam scores. The public engagement task is an innovative model in the nervous system curriculum and has the potential to be integrated into a broader range of undergraduate courses. It empowers medical students to pioneer public health and patient safety education.

BackgroundNeuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions and the GGC repeats in the 5'-untranslated region of NOTCH2NLC. The prevalent presence of high-intensity signal along the corticomedullary junction on diffusion-weighted imaging (DWI) helps to recognize this heterogeneous disease despite of highly variable clinical manifestations. However, patients without the typical sign on DWI are often misdiagnosed. Besides, there are no reports of NIID patients presenting with paroxysmal peripheral neuropathy-like onset to date.Case presentationWe present a patient with NIID who suffered recurrent transient numbness in arms for 17 months. Magnetic resonance imaging (MRI) showed diffuse, bilateral white matter lesions without typical subcortical DWI signals. Electrophysiological studies revealed mixed demyelinating and axonal sensorimotor polyneuropathies involving four extremities. After excluding differential diagnosis of peripheral neuropathy through body fluid tests and a sural nerve biopsy, NIID was confirmed by a skin biopsy and the genetic analysis of NOTCH2NLC.ConclusionThis case innovatively demonstrates that NIID could manifest as paroxysmal peripheral neuropathy-like onset, and addresses the electrophysiological characteristics of NIID in depth. We broaden the clinical spectrum of NIID and provide new insights into its differential diagnosis from the perspective of peripheral neuropathy.

OBJECTIVE:To analyze and compare the characteristics and causes of F wave changes in patients with Charcot-Marie-Tooth1A (CMT1A) and chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS:Thirty patients with CMT1A and 30 patients with CIDP were enrolled in Peking University Third Hospital from January 2012 to December 2018. Their clinical data, electrophysiological data(nerve conduction velocity, F wave and H reflex) and neurological function scores were recorded. Some patients underwent magnetic resonance imaging of brachial plexus and lumbar plexus, and the results were analyzed and compared. RESULTS:The average motor conduction velocity (MCV) of median nerve was (21.10±10.60) m/s in CMT1A and (31.52±12.46) m/s in CIDP. There was a significant difference between the two groups (t=-6.75, P < 0.001). About 43.3% (13/30) of the patients with CMT1A did not elicit F wave in ulnar nerve, which was significantly higher than that of the patients with CIDP (4/30, 13.3%), χ2=6.65, P=0.010. Among the patients who could elicit F wave, the latency of F wave in CMT1A group was (52.40±17.56) ms and that in CIDP group was (42.20±12.73) ms. There was a significant difference between the two groups (t=2.96, P=0.006). The occurrence rate of F wave in CMT1A group was 34.6%±39%, and that in CIDP group was 70.7%±15.2%. There was a significant difference between the two groups (t=-5.13, P < 0.001). The MCV of median nerve in a patient with anti neurofascin 155 (NF155) was 23.22 m/s, the latency of F wave was 62.9-70.7 ms, and the occurrence rate was 85%-95%. The proportion of brachial plexus and lumbar plexus thickening in CMT1A was 83.3% (5/6) and 85.7% (6/7), respectively. The proportion of brachial plexus and lumbar plexus thickening in the CIDP patients was only 25.0% (1/4, 2/8). The nerve roots of brachial plexus and lumbar plexus were significantly thickened in a patient with anti NF155 antibody. CONCLUSION:The prolonged latency of F wave in patients with CMT1A reflects the homogenous changes in both proximal and distal peripheral nerves, which can be used as a method to differentiate the CIDP patients characterized by focal demyelinating pathology. Moreover, attention should be paid to differentiate it from the peripheral neuropathy caused by anti NF155 CIDP. Although F wave is often used as an indicator of proximal nerve injury, motor neuron excitability, anterior horn cells, and motor nerve myelin sheath lesions can affect its latency and occurrence rate. F wave abnormalities need to be comprehensively analyzed in combination with the etiology, other electrophysiological results, and MRI imaging.

The patient was a 55-year-old man who was admitted to hospital with "progressive myalgia and weakness for 4 months, and exacerbated for 1 month". Four months ago, he presented with persistent shoulder girdle myalgia and elevated creatine kinase (CK) at routine physical examination, which fluctuated from 1 271 to 2 963 U/L after discontinuation of statin treatment. Progressive myalgia and weakness worsened seriously to breath-holding and profuse sweating 1 month ago. The patient was post-operative for renal cancer, had previous diabetes mellitus and coronary artery disease medical history, had a stent implanted by percutaneous coronary intervention and was on long-term medication with aspirin, atorvastatin and metoprolol. Neurological examination showed pressure pain in the scapularis and pelvic girdle muscles, and V- grade muscle strength in the proximal extremities. Strongly positive of anti-HMGCR antibody was detected. Muscle magnetic resonance imaging (MRI) T2-weighted image and short time inversion recovery sequences (STIR) showed high signals in the right vastus lateralis and semimembranosus muscles. There was a small amount of myofibrillar degeneration and necrosis, CD4 positive inflammatory cells around the vessels and among myofibrils, MHC-Ⅰ infiltration, and multifocal lamellar deposition of C5b9 in non-necrotic myofibrils of the right quadriceps muscle pathological manifestation. According to the clinical manifestation, imageological change, increased CK, blood specific anti-HMGCR antibody and biopsy pathological immune-mediated evidence, the diagnosis of anti-HMGCR immune-mediated necrotizing myopathy was unequivocal. Methylprednisolone was administrated as 48 mg daily orally, and was reduced to medication discontinuation gradually. The patient's complaint of myalgia and breathlessness completely disappeared after 2 weeks, the weakness relief with no residual clinical symptoms 2 months later. Follow-up to date, there was no myalgia or weakness with slightly increasing CK rechecked. The case was a classical anti-HMGCR-IMNM without swallowing difficulties, joint symptoms, rash, lung symptoms, gastrointestinal symptoms, heart failure and Raynaud's phenomenon. The other clinical characters of the disease included CK as mean levels >10 times of upper limit of normal, active myogenic damage in electromyography, predominant edema and steatosis of gluteus and external rotator groups in T2WI and/or STIR at advanced disease phase except axial muscles. The symptoms may occasionally improve with discontinuation of statins, but glucocorticoids are usually required, and other treatments include a variety of immunosuppressive therapies such as methotrexate, rituximab and intravenous gammaglobulin.

Background: Hereditary spastic paraplegia (HSP) constitutes a group of clinically and genetically rare neurodegenerative diseases characterized by progressive corticospinal tract degeneration. The phenotypes and genotypes of HSP are still expanding. In this study, we aimed to analyse the differential diagnosis, clinical features, and genetic distributions of a Chinese HSP patients in a 14-year cohort and to improve our understanding of the disease.Methods: The clinical data of patients with a primary diagnosis of HSP at the initial visit to the Department of the Neurology, Peking University Third Hospital, from 2008 to 2022 were retrospectively collected. Next-generation sequencing gene panels (NGS) combined with a multiplex ligation-amplification assay (MLPA) were conducted. Epidemiological and clinical features and candidate variants in HSP-related genes were analyzed and summarized.Results: 54 cases (probands from 25 different pedigrees and 29 sporadic cases) from 95 patients with a primary diagnosis of HSP were finally confirmed to have a clinical diagnosis of HSP based on clinical criteria, including their clinical findings, family history and long-term follow-up. Earlier disease onset was associated with longer diagnostic delay and longer disease duration and was associated with a lower risk of loss of ability to walk independently. In addition, 20 candidate variants in reported HSP-related genes were identified in these clinically diagnosed HSP patients, including variants in SPAST, ALT1, WASHC5, SPG11, B4GALNT1, and REEP1. The genetic diagnostic rate in these 54 patients was 35.18%.Conclusion: Hereditary spastic paraplegia has high clinical and genetic heterogeneity and is prone to misdiagnosis. Long-term follow-up and genetic testing can partially assist in diagnosing HSP. Our study summarized the clinical features of Chinese HSP patients in a 14-year cohort, expanded the genotype spectrum, and improved our understanding of the disease.

Parkinson's disease (PD), a progressive and incurable neurodegenerative disease, has taken a huge economic toll and medical burden on our society. Increasing evidence has shown a strong link between PD and the gut microbiome, but studies on the relationship between the gut microbiome and the severity of PD are limited. In this study, 90 fecal samples were collected from newly diagnosed and untreated patients with PD (n = 47) and matched healthy control subjects (n = 43). The 16S rRNA amplicon and shotgun metagenomic sequencing was performed, aiming to uncover the connection between the gut microbiome and disease severity in PD. The results showed that Desulfovibrio was significantly increased in PD compared to healthy controls and positively correlated with disease severity. The increase in Desulfovibrio was mainly driven by enhanced homogeneous selection and weakened drift. Moreover, through metagenome-assembled genomes (MAGs) analysis, a Desulfovibrio MAG (MAG58) was obtained which was also positively correlated with disease severity. MAG58 possesses a complete assimilatory sulfate reduction pathway and a near-complete dissimilatory sulfate reduction pathway to produce hydrogen sulfide which may influence the development of PD. Based on these results, a potential pathogenic mechanism was presented to illustrate how the increased Desulfovibrio accelerates the development of PD by producing excessive hydrogen sulfide. The present study highlighted the vital role of Desulfovibrio in the development of PD, which may provide a new target for the diagnosis and treatment of PD. KEY POINTS: • The evidence for the link between increased Desulfovibrio and disease severity in PD • A Desulfovibrio MAG was obtained which was correlated with PD • A model was presented to illustrate how increased Desulfovibrio causes PD.

OBJECTIVE:To characterize the paraspinal muscles of adolescent idiopathic scoliosis (AIS) patients, and to further explore its etiology.METHODS:Clinical records and paraspinal muscle biopsies at the apex vertebra region during posterior scoliosis correction surgery of 18 AIS were collected from November 2018 to August 2019. Following standardized processing of fresh muscle tissue biopsy, serial sections with conventional hematoxylin-eosin (HE) and histochemical and immunohistochemical (IHC) with antibody Dystrophin-1 (R-domain), Dystrophin-2 (C-terminal), Dystrophin-3 (N-terminal), Dystrophin-total, Myosin (fast), major histocompatibility complex 1 (MHC-1), CD4, CD8, CD20, and CD68 staining were obtained. Biopsy samples were grouped according to the subjects' median Cobb angle (Cobb angle ≥ 55° as severe AIS group and Cobb angle < 55° as mild AIS group) and Nash-Moe's classification respectively, and the corresponding pathological changes were compared between the groups statistically.RESULTS:Among the 18 AIS patients, 8 were in the severe AIS group (Cobb angle ≥55°) and 10 in the mild AIS group (Cobb angle < 55°). Both severe and mild AIS groups presented various of atrophy and degeneration of paraspinal muscles, varying degrees and staining patterns of immune-expression of Dystrophin-3 loss, especially Dystrophin-2 loss in severe AIS group with significant differences, as well as among the Nash-Moe classification subgroups. Besides, infiltration of CD4+ and CD8+ cells in the paraspinal muscles and tendons was observed in all the patients while CD20+ cells were null. The expression of MHC-1 on myolemma was present in some muscle fibers.CONCLUSION:The histologic of paraspinal muscle biopsy in AIS had similar characteristic changes, the expression of Dystrophin protein was significantly reduced and correlated with the severity of scoliosis, suggesting that Dystrophin protein dysfunctions might contribute to the development of scoliosis. Meanwhile, the inflammatory changes of AIS were mainly manifested by T cell infiltration, and there seemed to be a certain correlation between inflammatory cell infiltration, MHC-1 expression and abnormal expression of Dystrophin. Further research along the lines of this result may open up new ideas for the diagnosis of scoliosis and the treatment of paraspinal myopathy.

Background GNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases. Results The absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family. Conclusions These rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.

认知功能障碍是帕金森病(Parkinson's disease,PD)常见的非运动症状之一,本文综述相关文献,从丘脑底核(subthalamic nucleus,STN)的解剖结构、神经纤维连接、神经递质,以及STN深部脑刺激后认知功能的变化情况等方面介绍STN在皮质基底节认知环路中的重要作用,分析STN与PD认知功能障碍的相关联系,提出PD的认知功能障碍与STN密切相关.

Objective:To investigate the genetic distribution of pathogenic genes of Charcot-Marie-Tooth diseases (CMT) in Chinese Han population, and compare the similarity and difference with the data in Peking University Third Hospital in 2013.Methods:Five hundred and twenty families with CMT and related diseases in Peking University Third Hospital and China-Japan Friendship Hospital from January 2007 to March 2021 were collected. After peripheral myelin protein 22 (PMP22) gene duplication and deletion mutations were initially detected by multiple ligation probe amplification, the probands of these families were sequenced by next-generation sequencing (NGS) gene panel or whole exome sequencing, and validated by Sanger sequencing.Results:Among the 520 families, 336 CMT families were genetically confirmed, and the mutation detection rate increased from 48.6% (51/105) in 2013 to 64.6% (336/520) in 2021 (χ 2=9.54, P=0.003). Among them, 139 families had PMP22 gene duplication mutation (139/520, 26.7%), 46 families had gap junction beta-1 (GJB1) gene mutation (46/520, 8.8%), 26 families had mitofusin-2 (MFN2) gene mutation (26/520, 5.0%), 12 families had myelin protein zero (MPZ) gene mutation (12/520, 2.3%), 11 families had PMP22 gene point mutation (11/520, 2.1%), and 10 families had heat shock protein B1 gene mutation (10/520, 1.9%). There were 10 families with ganglioside induced differentiation associated protein 1 (GDAP1) gene mutation (10/520, 1.9%), 8 families with SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene mutation (8/520, 1.5%), 7 families with immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene mutation (7/520, 1.3%), 6 families with MORC family CW-type zinc finger 2 (MORC2) gene mutation (6/520, 1.2%), 5 families with sorbitol dehydrogenase (SORD) gene mutation (5/520, 1.0%), 16 families with very rare gene mutation (16/520, 3.1%) and 184 families without genetic diagnosis (184/520, 35.4%). Conclusions:Compared with the results in 2013, the 3 most common genes affecting CMT were still PMP22, GJB1 and MFN2 genes, but the proportion difference of patients with MPZ gene mutation gradually decreased with other genes such as SH3TC2 and GDAP1 genes. The proportion of newly discovered CMT genes, such as MORC2 and SORD genes, was similar with IGHMBP2 gene, which should be paid more attention. NGS greatly improved the detection rate of CMT, especially for patients with autosomal recessive-CMT.

Parkinson's disease (PD) is one of the common neurodegenerative diseases that is characterized by selective degeneration of dopaminergic neurons in the substantia nigra, and misfolding of α-synuclein into aggregates is thought to contribute to its pathology. Studies have shown that immune-inflammatory responses are involved in the development of PD and play an important role in α-synuclein scavenge. Natural killer (NK) cells are first responders in immune cells and can directly promote immune defense mechanisms by cytotoxicity and by secreting cytokines. Recent discoveries suggest that NK cells are increasingly recognized in the pathological features of PD. However, the mechanisms underlying it have not been fully understood. In this review, we systematically retrieved and evaluated published evidence about the functions of NK cells in PD. We find alterations in the number of NK cells and cytotoxicity during the progression of PD, and it seems that NK cells play a neuroprotective role in PD pathogenesis, which may further reveal novel targets for the management and treatment of PD.