Gp78 regulates PMP22 and causes ER stress and autophagy in EV71-VP1-overexpressing mouse Schwann cells

Background:During Enterovirus type 71(EV71)infection,the structural viral protein 1(VP1)activates endoplasmic reticulum(ER)stress associated with peripheral myelin protein 22(PMP22)accumulation and induces autophagy.However,the specific mechanism behind this process remains elusive.Methods:In this research,we used the VP1-overexpressing mouse Schwann cells(SCs)models co-transfected with a PMP22 silencing or Autocrine motility factor receptor(AMFR/gp78)overexpressing vector to explore the regulation of gp78 on PMP22 and its relationship with autophagy and apoptosis.Results:The activity of gp78 could be influenced by EV71-VP1,leading to a decrease in the ubiquitination and degradation of PMP22,resulting in PMP22 accumulation in ER.In VP1-overexpressing mouse SCs,all three ER stress sensors,including pancreatic endoplasmic reticulum kinase(PERK),activating transcription factor 6(ATF6)and inositol-requiring enzyme 1(IRE1)and the related downstream signals(C/EBP-homologous protein(CHOP)and Caspase 12)were activated,as well as the ER-resident chaperone Glucose-regulated protein 78(GRP78).In addition,VP1 upregulated the autophagy marker Microtubule-associated protein 1 light chain 3 beta(LC3B),while PMP22 silencing or gp78 overexpression reversed the phenomenon.Meanwhile,PMP22 silencing or gp78 overexpression increased proliferation of EV71-VP1-transfected mouse SCs.Conclusion:Gp78 could regulate PMP22 accumulation through ubiquitination degradation and cause ER stress and autophagy in EV71-VP1-overexpressing mouse SCs.Therefore,the gp78/PMP22/ER stress axis might emerge as a promising therapeutic target for myelin and neuronal damage induced by EV71 infection.

Voltage gated calcium channel antibody-related neurological diseases

Voltage gated calcium channel(VGCC) antibodies are generally associated with Lambert-Eaton myasthenic syndrome. However the presence of this antibody has been associated with paraneoplastic as well as nonparaneoplastic cerebellar degeneration. Most patients with VGCC-antibody-positivity have small cell lung cancer(SCLC). Lambert-Eaton myasthenic syndrome(LEMS)is an autoimmune disease of the presynaptic part of the neuromuscular junction. Its classical clinical triadis proximal muscle weakness, areflexia and autonomic dysfunction. Fifty to sixty percent of LEMS patients have a neoplasia, usually SCLC. The co-occurrence of SCLC and LEMS causes more severe and progressive disease and shorter survival than non-paraneoplastic LEMS. Treatment includes 3,4 diaminopyridine for symptomatic purposes and immunotherapy with prednisolone, azathioprine or intravenous immunoglobulin in patients unresponsive to 3,4 diaminopyridine. Paraneoplastic cerebellar degeneration(PCD) is a syndrome characterized with severe, subacute pancerebellar dysfunction. Serum is positive for VGCC antibody in 41%-44% of patients, usually with the co-occurrence of SCLC. Clinical and electrophysiological features of LEMS are also present in 20%-40% of these patients. Unfortunately, PCD symptoms do not improve with immunotherapy. The role of VGCC antibody in the immunopathogenesis of LEMS is well known whereas its role in PCD is still unclear. All patients presenting with LEMS or PCD must be investigated for SCLC.

Risk Factors of Influenza-Associated Necrotizing Encephalopathy in Children

Objective: A case-control study of Influenza-Associated Necrotizing Encephalopathy (IANE) in children was conducted to explore the risk factors for the diagnosis of IANE, and to provide a predictive reference for the diagnosis of IANE. Methods: The children with IANE who received treatment in our hospital from January 2016 to December 2020 were selected as the study group, and the children with Influenza-Associated Encephalopathy (IAE) group who received treatment in the same period were selected as the control group. The blood biochemical, coagulation function and cerebrospinal fluid test results of the two groups were analyzed by univariate analysis. Receiver Operating Characteristic curve (ROC) analysis was used to determine the optimal threshold point of each index for the indicators with statistically significant differences in univariate analysis results, and multivariate Logistic stepwise regression analysis was performed according to the optimal threshold points. Results: In the IANE group, there were 32 children, including 20 males and 12 females, aged 60 (35, 84) months. There were 40 children in IAE group, including 26 males and 14 females, aged 58 (23, 97) months. Univariate results showed that serum Lactate Dehydrogenase (LDH), Cerebrospinal Fluid Lactate Dehydrogenase (CSF LDH) and Cerebrospinal Fluid Protein (CSF PRO) in the IANE group were significantly higher than those in the IAE group, and the difference between the two groups was statistically significant (P < 0.001). The optimal threshold points of blood LDH, CSF LDH and CSF PRO by ROC curve analysis were 535 U/L, 67 U/L and 0.49 g/L, respectively. Further Multivariate Logistic stepwise regression analysis showed that LDH > 535 U/L (OR = 31.264, 95% CI: 5.892 - 165.878, P < 0.001) and CSF PRO > 0.49 g/L (OR = 7.695, 95% CI: 1.052 - 56.305, P = 0.044) were independent risk factors for IANE. Conclusion: For children with influenza whose neurological symptoms appear rapidly and persist in the early stages of the disease, blood LDH > 535 U/L and CSF PRO > 0.49 g/L are independent risk factors for IANE.

Clinico-Radiological Correlation in Children with Ataxia Telangiectasia in Qatar

Introduction: Ataxia telangiectasia (AT) is a rare disease characterized by immunodeficiency and neurological manifestations. Ataxia, resulting from cerebella atrophy, runs a progressive incapacitating course. Clinical monitoring of the disease course is mandatory for early treatment. Aim: To study clinical severity of AT and correlate it with the degree of cerebellar atrophy. Patients and Methods: We retrospectively studied all children (less than 14 years) with AT seen at Hamad General Hospital Clinics between 1998-2013. We collected basic demographic data, parental consan-guinity, family history, AT clinical severity scores, and reviewed CBC with differential counts;alpha-fetoprotein, serum immunoglobulins and lymphocyte subsets. Cranial MRI scans of each subject were reviewed by a neuroradiologist. Cerebellar atrophy was visually and semi-quantitatively scored. Results: We analyzed data on 18 AT children (10 males and 8 females), mean age of 76.9 months. 77.8% had a positive family history of AT and 41.7% parental consanguinity. Lymphopenia was observed in 77.8% and high serum alpha-fetoprotein in 87.5% of children. Clinical severity of ataxia was 17.1 ± 8.4 (mean ± SD);86.7% of patients were moderate-severe. MRI cerebellar atrophy score was 1.9 ± 1.3 (mean ± SD), and moderate in 51% of patients. AT clinical severity score correlated (coefficient r = 0.566) but not statistically significant p = 0.088) with MRI cerebellar atrophy scores. Conclusions: Moderate to severe ataxia and marked cerebellar atrophy are quite common in AT children. There is a correlation between AT clinical severity and cerebellar atrophy. Larger prospective studies might further determine the significance of our observations and help practicing practitioners monitor the progression of the disease.

帕-罗综合征(进行性一侧面萎缩)涉及致命的脑干系统

We report the case of a 4 year- old boy with Parry- Romberg syndrome who ha d intractable seizures, progressive cerebral hemisphere atrophy, and fatal brain stem involvement.

A survey on pediatric anti-N-methyl-D-aspartate-receptor encephalitis treatment strategies in China

To the Editor:Currently,there is no standardized treatment protocol for the pediatric anti-N-methyl-D-aspartate receptor(NMDAR).There are two surveys by Kahn et al[1]and Bartolini et al[2]that aimed at determining the treatment strategies that are used for pediatric NMDAR encephalitis in other parts of the world rather than China.Bartolini et al[2]performed a worldwide survey involving 199 participants:61 adult neurologists,86 pediatric neurologists,and 52 pediatric rheumatologists.Their survey investigated the differences in anti-NMDAR encephalitis treatment strategies,according to medical specialty,years in practice,and geographical location.[2]The survey of Kahn et al[1]involved 151 pediatric neurologists and focused on identifying the indications for the initiation of immunotherapy,type of the used immunotherapy,length of the first-line immunotherapy,time for the initiation of the second-line immunotherapy,and the preferable options for the second-line immunotherapy.Additionally,they investigated the indications and time for adding a disease-modifying therapy,and how long should patients continue with the immunotherapy once returned to their neurologic baseline.[1]Both surveys did not sufficiently focus on identifying the utility of the modified Rankin Scale(mRS),dosages and duration of the treatments(including the duration of oral prednisone),the utility of Cluster of Differentiation 19 positive(CD19+)B cells in adjusting the dosages of rituximab,the necessity of long-term immunosuppressive treatment(for relapse prevention),and the indications for stopping the immunotherapy.

Towards creation of national cerebral palsy registries in Arab countries:what is missing?

Cerebral palsy(CP)is a global,complex and lifelong health issue with a relatively high disease burden in low-resource countries.The benefits of a national disease registry in general and a national CP registry in particular are twofold,namely the public health and the clinical disease-related benefits.A national CP quality registry has the potential to inform health planning and spending at national,regional and continental levels.In turn,this can help allocate and manage the relevant material and human resources in a more predictable and efficient manner.

SARS-CoV-2 infection in children requiring hospitalization: the experience of Navarra, Spain

Background Coronavirus disease 2019 in children,or pediatric COVID-19,initially was described as an acute respiratory syndrome similar to the adult presentation but with less severe manifestations.Methods We describe the clinical characteristics,disease presentation,treatments and outcomes of all pediatric cases with COVID-19 admitted to the reference hospitals in Navarra,Spain during the first wave of the COVID-19 outbreak(February-May 2020).Results We found a low number of hospitalized cases in infants and children compared to adults with a hospitalization ratio of 1:180.Most of these hospitalized cases did not suffer from severe disease.Over 80%of infections reported household contacts,and the mother was the known-contact in 83%of these cases.72%of hospitalized cases were previously healthy children.We describe how symptoms in pediatric cases are nonspecific and how COVID-19 can be presented with a wide range and variety of symptoms.Respiratory symptoms are not always present,and severe neurological and cardiac features can occur in previously healthy children.Conclusion Epidemiological description and case reports will be key to a better recognition and to adequate treatment of pediatric patients with COVID-19.