Immune characteristics of children with autoimmune encephalitis and the correlation with a short-term prognosis.

BACKGROUND: Autoimmune encephalitis (AE) is a type of encephalopathy mediated by an antigenic immune response in the central nervous system. Most research related to autoimmune encephalitis (AE) is focused on early diagnosis, treatment and prognosis analysis; there has been little research conducted on the characteristics of immune function, and the relationship between immune function and prognoses of patients with autoimmune encephalitis needs to be studied further. METHODS: A total of 33 children with autoimmune encephalitis were identified through the clinic database and inpatient consults at Tianjin Children's Hospital from January 2013 to January 2021. Based on the one-year follow-up and the modified Rankin Scale (mRS) prognosis score, they were divided into a good prognosis group and a poor prognosis group. The immune function characteristics of the two groups of children with autoimmune encephalitis (AE) were compared using Spearman correlation to analyse the mRS score and immune function indicators (IgA, IgG, IgM, CD4, CD8, CD4/CD8), and binary logistic regression was used to analyse the independent risk factors of the prognoses in patients with autoimmune encephalitis (AE). RESULTS: The differences in abnormal mental disorders and limb dyskinesia, cognitive impairment, onset types, modified Rankin Scale (mRS) scores at admission, and immune function status during remission between the two groups were statistically significant (p < 0.05). CONCLUSION: There is a close correlation between modified Rankin Scale (mRS) scores and the immune function index CD4/CD8 in children with autoimmune encephalitis (AE) when they are admitted to the hospital. A young age, disturbance of consciousness, limb dyskinesia, abnormal immune function in remission and anti-NMDAR encephalitis are risk factors for poor prognoses in children with autoimmune encephalitis (AE). Clinical treatment requires more attention.

The Clinical and Imaging Characteristics Associated With Neurological Sequelae of Pediatric Patients With Acute Necrotizing Encephalopathy.

Background: Acute necrotizing encephalopathy of childhood (ANE) is a rare but rapidly progressing encephalopathy. Importantly, the exact pathogenesis and evidence-based treatment is scarce. Thus, we aimed to identify the clinical, imaging, and therapeutic characteristics that associated with prognosis of pediatric ANE patients. Methods: A retrospective study was conducted on pediatric patients with ANE who were admitted to Wuhan Children's Hospital between January 2014 and September 2019. All cases met the diagnostic criteria for ANE proposed by Mizuguchi in 1997. The clinical information and follow-up data were collected. The prognostic factors were analyzed by trend chi-square test and Goodman-Kruskal gamma test. Results: A total of 41 ANE patients ranging in age from 8.9 to 142 months were included in this study. Seven cases (17%) died, and the other 34 survivors had different degrees of neurological sequelae. Factors tested to be significantly correlated with the severity of neurological sequelae were the intervals from prodromal infection to acute encephalopathy (G = -0.553), conscious disturbance (r = 0.58), endotracheal intubation (r = 0.423), elevation of alanine aminotransferase (r = 0.345), aspartate aminotransferase (r = 0.393), and cerebrospinal fluid protein (r = 0.490). In addition, dynamic magnetic resonance imaging (MRI) evaluation on follow-up revealed that the total numbers of brain lesion location (χ2 = 6.29, P < 0.05), hemorrhage (r = 0.580), cavitation (r = 0.410), and atrophy (r = 0.602) status were significantly correlated with the severity of neurological sequelae, while early steroid therapy (r = -0.127 and 0.212, respectively) and intravenous immunoglobulin (IVIG) (r = 0.111 and -0.023, respectively) within 24 h or within 72 h after onset showed no association. Conclusions: Intervals from prodromal infection to acute encephalopathy (≤1 day), total numbers of brain lesion location (≥3), the recovery duration of hemorrhage and atrophy (>3 months), and the presence of cavitation predict severe neurological sequelae in pediatric patients with ANE. Early treatments, including steroid therapy and IVIG, had no correlation with better outcomes. Further studies are needed to establish a consensus guideline for the management of ANE.

Ginsenoside Rg3 inhibits pulmonary fibrosis by preventing HIF-1α nuclear localisation.

BACKGROUND: Excessive fibroblast proliferation during pulmonary fibrosis leads to structural abnormalities in lung tissue and causes hypoxia and cell injury. However, the mechanisms and effective treatment are still limited. METHODS: In vivo, we used bleomycin to induce pulmonary fibrosis in mice. IHC and Masson staining were used to evaluate the inhibitory effect of ginsenoside Rg3 in pulmonary fibrosis. In vitro, scanning electron microscopy, transwell and wound healing were used to evaluate the cell phenotype of LL 29 cells. In addition, biacore was used to detect the binding between ginsenoside Rg3 and HIF-1α. RESULTS: Here, we found that bleomycin induces the activation of the HIF-1α/TGFß1 signalling pathway and further enhances the migration and proliferation of fibroblasts through the epithelial mesenchymal transition (EMT). In addition, molecular docking and biacore results indicated that ginsenoside Rg3 can bind HIF-1α. Therefore, Ginsenoside Rg3 can slow down the progression of pulmonary fibrosis by inhibiting the nuclear localisation of HIF-1α. CONCLUSIONS: This finding suggests that early targeted treatment of hypoxia may have potential value in the treatment of pulmonary fibrosis.

Discovery of specific mutations in spinal muscular atrophy patients by next-generation sequencing.

Spinal muscular atrophy (SMA) is a type of autosomal recessive genetic disease, which seriously threatens the health and lives of children and adolescents. We attempted to find some genes and mutations related to the onset of SMA. Eighty-three whole-blood samples were collected from 28 core families, including 28 probands with clinically suspected SMA (20 SMA patients, 5 non-SMA children, and 3 patients with unknown etiology) and their parents. The multiplex ligation probe amplification (MLPA) was performed for preliminary diagnosis. The high-throughput sequencing technology was used to conduct the whole-exome sequencing analysis. We analyzed the mutations in adjacent genes of SMN1 gene and the unique mutations that only occurred in SMA patients. According to the MLPA results, 20 probands were regarded as experimental group and 5 non-SMA children as control group. A total of 10 mutations were identified in the adjacent genes of SMN1 gene. GUSBP1 g.[69515863G>A], GUSBP1 g.[69515870C>T], and SMA4 g.[69515738C>A] were the top three most frequent sites. SMA4 g.[69515726A>G] and OCLN c.[818G>T] have not been reported in the existing relevant researches. Seventeen point mutations in the DYNC1H1 gene were only recognized in SMA children, and the top two most common mutations were c.[2869-34A>T] and c.[345-89A>G]; c.[7473+105C>T] was the splicing mutation that might change the mRNA splicing site. The mutations of SMA4 g.[69515726A>G], OCLN c.[818G>T], DYNC1H1 c.[2869-34A>T], DYNC1H1 c.[345-89A>G], and DYNC1H1 c.[7473+105C>T] in the adjacent genes of SMN1 gene and other genes might be related to the onset of SMA.

Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

A novel mutation in a common pathogenic gene (SETD5) associated with intellectual disability: A case report.

Intellectual disability (ID) is a non-specific phenotype present in a genetically heterogeneous group of disorders. The genetic cause of ID remains elusive in the majority of patients due to this extreme heterogeneity. Whole exome sequencing technology has been applied to identify pathogenic gene variants responsible for ID. The present report described a 1.7-year-old female patient who had severe ID with the specific features of delayed motor development, language disorders and abnormal facial features. Exome analysis identified a novel pathogenic variant of the SETD5 gene [c.2025_2026delAG (p.Gly676Valfs*2)]. The variant was a frameshift mutation, causing termination of the protein in advance. These findings indicated that this mutation of the SETD5 gene may be a genetic cause for ID. The present study aimed to provide a meaningful exploration of ID and the identification of clinical core genetic pedigrees.

Immature teratoma of the posterior fossa in an infant: case report.

Teratoma is a rare tumor of the central nervous system that belongs to intracranial germ cell tumors. We report a 2-month-old male child with an immature teratoma of the posterior fossa. Physical and laboratory examinations were normal. Though a radiologic examination was characteristic for this neoplasm, it was insufficient to make a definite diagnosis. Combining the radiologic findings with a histopathologic examination contributed to diagnosing immature teratoma and differentiating it from other subtypes of intracranial germ cell tumors. Our aim was to provide a greater understanding of immature teratoma by reporting this case.

Teratom, merkezi sinir sisteminin nadir görülen bir tümörü olup intrakranial germ hücreli tümörlerden birisidir. Bu makalede, posterior fossanin immatür teratomu bulunan 2 aylik bir erkek çocugu sunmaktayiz. Fizik baki ve laboratuvar bulgulari normal saptandi. Radyolojik inceleme bu neoplazma açisindan belirgin bulunmasina ragmen, kesin tani koymak için yetersizdi. Radyolojik bulgularin histopatolojik inceleme ile birlestirilmesi, immatür teratomun tanisina ve immatür teratomun intrakraniyal germ hücreli tümörlerinin diger alt türlerinden ayirt edilmesine katkida bulunmustur. Bu olguyu sunarak, immatür teratomun daha iyi anlasilmasini saglamayi amaçladik.

Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway.

BACKGROUND: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring. METHODS: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones. RESULTS: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308). CONCLUSION: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.

Intracranial Medulloepithelioma in a Child: A Case Report.

Intracranial medulloepithelioma is an extremely rare and highly malignant fast-growing tumor that shows a propensity to spread widely throughout the central nervous system. It most commonly occurs in infants and young children. We report a rare case of 2-year-old female patient with a large mass lesion diagnosed as medulloepithelioma. Although radiological examination was characteristic for the neoplasm, it was not sufficient to make a definite diagnosis. However, when it was combined with histopathological examination, we could diagnose medulloepithelioma and differentiate it from other central nervous system tumors. We intend to provide greater understanding and knowledge of intracranial medulloepithelioma by reporting this case.

Choroid Plexus Papilloma of Bilateral Lateral Ventricle in an Infant Conceived by in vitro Fertilization.

Choroid plexus papilloma (CPP) is a rare benign tumor of the central nervous system. Bilateral lateral ventricle CPP is extremely uncommon. In this case report, we described a case of bilateral lateral ventricle CPP in a 4-month-old female patient conceived by in vitro fertilization (IVF). Neurological examination and imaging were performed. In neurological examination, meningeal irritation signs and sunset phenomenon were positive. Brain computed tomography (CT) and magnetic resonance imaging (MRI) displayed masses located in the trigone of the bilateral lateral ventricle with hydrocephalus. Contrast-enhanced MRI showed intense homogeneous enhancement. The diagnoses of bilateral lateral ventricle CPP related to hydrocephalus and extravasation of cerebrospinal fluid (CSF) were made. Repeated surgical procedures via parietotemporal craniotomy were performed, and the diagnosis was confirmed by histopathology examination. The patient presented with delayed development during a follow-up period of 1 year. In conclusion, imaging is an effective approach of investigation. CPP could be highly suspected according to the features of hydrocephalus, lobulated appearance, and homogeneous enhancement on imaging. Total surgical removal is a valid curative method for CPP.

A unique methylation pattern co-segregates with neural tube defect statuses in Han Chinese pedigrees.

Neural tube defects (NTDs) are a complex trait associated with gene-environment interactions. Folic acid deficiency and planar cell polarity gene mutations account for some NTD cases; however, the etiology of NTDs is still little understood. In this study, in three Han Chinese NTD pedigrees (two with multiple affected children), with no information on folic acid deficiency or supplement, we examined genome-wide methylation profiles of each individual in these families. We further compared methylation status among cases and normal individuals within the pedigrees. A unique methylation pattern co-segregated with affected status: NTD cases had more hypermethylated than hypomethylated CpG islands; genes with different methylations clustered in pathways associated with epithelial-to-mesenchymal transition (ZEB2, SMAD6, and CDH23), folic acid/homocysteine metabolism (MTHFD1L), transcription/nuclear factors (HDAC4, HOXB7, SOX18), cell migration/motility/adhesion, insulin and cell growth, and neuron/axon development. Although the genetics of NTD are likely complex, epigenetic changes may concentrate in certain key pathways.

Polymorphisms in FZD3 and FZD6 genes and risk of neural tube defects in a northern Han Chinese population.

Neural tube defects (NTDs) are the most common and severe malformations of the central nervous system. The association of single nucleotide polymorphisms (SNPs) of the Frizzled 3 (FZD3) and Frizzled 6 (FZD6) genes and NTDs in the Han population of northern China was principally studied. One synonymous SNP (rs2241802) in FZD3 gene and three nonsynonymous SNPs (rs827528, rs3808553 and rs12549394) in FZD6 gene were analyzed by polymerase chain reaction (PCR) and sequencing methods in 135 NTD patients and 135 normal controls. The allele, genotype and haplotype frequencies were calculated and analyzed to examine the relationship between FZD3/FZD6 SNPs and NTDs. Both T allele and TT genotype frequencies of the FZD6 rs3808553 loci in the NTDs group were significantly higher than those in the controls, and children with T allele and TT genotype were associated with increased NTDs risk (OR = 1.575, 95 % CI 1.112-2.230, P = 0.010 and OR = 2.811, 95 % CI 1.325-5.967, P = 0.023, respectively). There were no differences among different genotypes or alleles in other three SNPs. Haplotypes A-G-C and A-T-C in FZD6 were found associated with NTDs in the case-control study (OR = 0.560, 95 % CI 0.378-0.830, P = 0.004 and OR = 1.670, 95 % CI 1.126-2.475, P = 0.011, respectively). The rs3808553 of FZD6 is obviously associated with NTDs in Han population of northern China. The TT genotype may increase risk for NTDs.

Identification of novel rare mutations of DACT1 in human neural tube defects.

Neural tube defects (NTDs) constitute the second most frequent cause of human congenital abnormalities. Complex multigenetic causes have been suggested to contribute to NTDs. The planar cell polarity (PCP) pathway plays a critical role in neural tube closure in model organisms and in human. Knockout of Dact1 (Dapper, Frodo) leads to deregulated PCP signaling with defective neural tube in mice. Here, we report that five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. Our biochemical analyses revealed that among the five mutations, N356K and R45W show loss-of-function or reduced activities in inducing Dishevelled2 (DVL2) degradation and inhibiting jun-N-terminal kinase (JNK) phosphorylation, implicating mutated DACT1 as a risk factor for human NTDs. Our findings, together with early reports, suggest that rare mutations of the PCP-related genes may constitute a great contribution to human NTDs.

Dermoid cyst of the posterior fossa associated with congenital dermal sinus in a child.

BACKGROUND: Intracranial dermoid cysts are congenital benign neoplasms. Hydrocephalus and abscess as the principal manifestations of the posterior fossa dermoid cyst are rare. We present a case of obstructive hydrocephalus and abscess induced by an adjacent dermoid cyst with occipital dermal sinus. METHODS: A 2-year-old girl presented with headache and vomiting. Physical examination showed nothing abnormal except for a small subcutaneous nodule above the occipital protuberance with a small skin opening. She had no neurological deficits. Neuroradiological studies including CT and MRI showed a cyst located in the posterior fossa. The cyst in the posterior fossa with occipital dermal sinus was diagnosed. She was treated by radical excision of the occipital cyst through a suboccipital approach, and was followed up. RESULTS: Histopathologic examination suggested a dermoid cyst with an abscess. Bacterial investigation revealed Staphylococcus epidermidis, and appropriate systemic antibiotic therapy was given. The child recovered and a 2-year follow-up was uneventful. CONCLUSIONS: Posterior fossa dermoid cyst should be considered in all children with occipital skin lesions, especially dermal sinus. CT and MRI scan are helpful in the diagnosis of the lesion. Neurosurgical treatment of the lesion should be planned early to prevent infections such as abscess and meningitis.