Predictive value of persistent antibodies at 6 months for relapse in neuronal surface antibody-associated autoimmune encephalitis.

BACKGROUND: For patients with neuronal surface antibody-associated autoimmune encephalitis (NSAE) whose clinical symptoms gradually improve, the recommended course of immunotherapy in China is about 6 months. We aim to explore the relationship between persistent antibody positivity when immunotherapy is discontinued at 6 months and subsequent relapse. METHODS: Prospective inclusion of NSAE patients with clinical remission after 6-month immunotherapy. Their antibody titers and other clinical data were collected at onset and 6 months later. Based on the antibody test results at 6 months, patients were divided into an antibody-persistent group and an antibody-negative conversion group, and then the rate of relapse between the two groups were compared. RESULTS: The study included 28 NSAE patients who were antibody-positive at diagnosis. After 6-month immunotherapy, there were 16 (57.1%) cases with persistent antibodies and 12 (42.9%) cases with antibody-negative conversion. In the acute phase of onset, seizures were more common in patients with persistent antibodies (87.5% vs. 50.0%, p = 0.044). During a mean follow-up period of 22 months, patients with persistent antibodies were more likely to experience relapse than those with antibody-negative conversion (37.5% vs. 0.0%, p = 0.024). There were no significant differences in antibody types, CSF findings, results of MRI and EEG, tumor combination, immunotherapy, and long-term outcome between the two groups (p > 0.05). CONCLUSIONS: For patients with persistent antibodies when immunotherapy is discontinued at 6 months, persistent antibody positivity was associated with a higher relapse rate.

Origin and significance of leucine-rich glioma-inactivated 1 antibodies in cerebrospinal fluid.

BACKGROUND: Whether antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) in cerebrospinal fluid (CSF) are partially transferred from serum and the impact of CSF-LGI1-Ab positivity on clinical features and prognosis are unclear. Therefore, we aim to investigate the differences in serum titers, clinical features, and outcomes between LGI1-Ab CSF-positive and LGI1-Ab CSF-negative patients. METHODS: Retrospective analysis of serum titers and clinical features according to CSF LGI1-Ab status. In addition, univariate and multivariate logistic regression were performed to identify predictors of worse outcomes. RESULTS: A total of 60 patients with anti-LGI1 encephalitis and positive serum LGI1-Abs were identified, of whom 8 (13.3%) patients were excluded due to the absence of CSF LGI1-Ab testing. Among the remaining 52 patients, 33 (63.5%) were positive for LGI1-Abs in CSF. CSF-positive patients were more likely to have high serum titers (≥ 1:100) than CSF-negative patients (p = 0.003), and Spearman's correlation analysis showed a positive correlation between CSF and serum titers in CSF-positive patients (r2 = 0.405, p = 0.019). Psychiatric symptoms and hyponatremia were more frequent in CSF-positive patients (p < 0.05). Both univariate and multivariate logistic regression analyses showed that CSF LGI1-Ab positivity and delayed immunotherapy are independent risk factors for incomplete recovery (modified Rankin Scale (mRS) > 0 at last follow-up). CONCLUSIONS: LGI1-Ab CSF-positive patients have higher serum titers, and their CSF titers are positively correlated with serum titers, indicating a possible peripheral origin of CSF LGI1-Abs. CSF-positive patients more often present with psychiatric symptoms, hyponatremia, and worse outcomes, suggesting more severe neuronal damage.

The Role of Decreased Levels of Neuronal Autophagy in Increased Susceptibility to Post-traumatic Epilepsy.

Post-traumatic epilepsy (PTE) caused by mild TBI (mild traumatic brain injury, mTBI) has a high incidence and poor prognosis, but its mechanisms are unclear. Herein, we investigated the role of reduced levels of neuronal autophagy during the latency period in the increased susceptibility to PTE. In the study, a gentle whole-body mechanical trauma rat model was prepared using Noble-Collip drums, and the extent of injury was observed by cranial CT and HE staining of hippocampal tissue. The incidence of epilepsy and its seizure form were observed 7-90 days after mTBI, and electroencephalography (EEG) was recorded during seizures in rats. Subcortical injection of non-epileptogenic dose of ferrous chloride (FeCl2) was used to observe the changes of PTE incidence after mTBI. Western blot and Real-time PCR were used to detect the level of autophagy in hippocampal cells at different time points during the latency period of PTE, and its incidence was observed after up-regulation of autophagy after administration of autophagy agonist-rapamycin. The results showed that mTBI was prepared by Noble-Collip drum, which could better simulate the clinical mTBI process. There was no intracerebral hemorrhage and necrosis in rats, no early-onset seizures, and the incidence of PTE after mTBI was 26.7%. The incidence of PTE was 56.7% in rats injected cortically with FeCl2 at a dose lower than the epileptogenic dose 48 h after mTBI, and the difference was significant compared with no FeCl2 injection, suggesting an increased susceptibility to PTE after mTBI. Further study of neuronal autophagy during PTE latency revealed that autophagy levels were reduced, and the incidence of PTE was significantly reduced after administration of rapamycin to upregulate autophagy. Taken together, the decreased level of neuronal autophagy during the latency period may be a possible mechanism for the increased susceptibility to PTE after mTBI.

Genotype-Phenotype Correlation Reanalysis in 83 Chinese Cases with OCRL Mutations.

Background: Both Lowe syndrome and Dent-2 disease are caused by variants in the OCRL gene. However, the reason why patients with similar OCRL gene mutations presented with different phenotypes remains uncertain. Methods: Children with hemizygous pathogenic or likely pathogenic variants in OCRL were compiled from published and unpublished consecutive cases from China. Furthermore, a Chi-square test was employed to analyze the correlation of the location and types of mutations on the phenotype of children with Lowe syndrome or Dent-2 disease. Results: Among the total 83 patients, 70.8% (34/48) cases of Lowe syndrome presented with truncating mutations, while only 31.4% (11/35) cases of Dent-2 disease presented with truncating mutation (Χ2 = 12.662; P < 0.001). Meanwhile, the majority of mutations in Dent-2 disease are located in Exon 2-12 (21/35, 60.0%), while the majority of mutations in Lowe syndrome are located in Exon 13-23 (39/48, 81.3%; Χ2 = 14.922; P < 0.001). Conclusions: Truncating mutations of the OCRL gene were more common in patients with Lowe syndrome than in Dent-2 disease, while mutation is more likely located at exon 2-12 in Dent-2 disease than that in Lowe syndrome. The type and location of mutation are important indicators for the phenotypes in patients with OCRL mutation. This is a large cohort study analyzing the genotype-phenotype correlation in patients with Lowe syndrome and Dent-2 disease in China. Our data may improve the interpretation of new OCRL variants and genetic counseling. Furthermore, a large international study would be necessary to illustrate the genotype-phenotype correlation in patients with OCRL mutations.

Clinical and genetic characteristics of concomitant Mucopolysaccharidosis type IVA and neurogenic bladder in children: two case reports and literature review.

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder. Up to now, reports on the clinical characteristics of MPS IVA mainly focused on patients with progressive bone dysplasia and multiple organ damage, while the effects of this disorder on neurogenic bladder have not been reported. Therefore, the aim of the present study is to report two cases of nocturnal enuresis finally diagnosed as neurogenic bladder in MPS IVA. CASE PRESENTATION: Both children were characterized by the presence of pectus carinatum, kyphoscoliosis, nocturnal enuresis, urinary incontinence, normal intelligence, and loss of strength in the legs, diagnosed as neurogenic bladder in association with MPS IVA through the analysis of the clinical characteristics, enzyme activity and genetic testing. In addition, the terminator codon mutation c.1567T > G (p.X523E) and a novel missense mutation c.575A > G (p.E192G) were found in the coding region of the GALNS gene of the 1st patient, while the missense mutation c.488C > A (p.P163H) was found in the coding region of the GALNS gene of the 2nd patient. CONCLUSIONS: Neurogenic bladder may occur in patients with MPS IVA after spinal cord injury. It is necessary to screen for the diagnosis of MPS IVA in patients with atypical enuresis and skeletal abnormalities through the analysis of the clinical characteristics, enzyme activity and genetic testing.

Reduced anogenital distance, hematuria and left renal hypoplasia in a patient with 13q33.1-34 deletion: case report and literature review.

BACKGROUND: 13q33-q34 microdeletions are rare chromosomal aberrations associated with a high risk of developmental disability, facial dysmorphism, cardiac defects and other malformation of organs. It is necessary to collect and report evidence of this rare chromosome mutation to improve the prognosis of this rare disease. CASE PRESENTATION: We report a patient harboring an 11.56 Mb microdeletion at 13q33.1-34 region, which contains about 30 OMIM genes. Besides the common clinical manifestations such as facial dysmorphism, developmental delay, intellectual disability, epilepsy, and congenital heart disease, she also suffered from a reduced anogenital distance, hematuria and left renal hypoplasia. Most related cases were characterized by facial deformity and heart defects, but there were few reports on renal malformation, especially regarding renal hypoplasia with hematuria. CONCLUSION: We have reported a patient suffering from a reduced anogenital distance, hematuria and left renal hypoplasia. A de novo 11.56 Mb deletion ranging from 13q33.1 to 13q34 (Chr13:103542220-115,106,996) was found by SNP-array analysis. It might be the first time for hematuria and renal hypoplasia to be reported as symptoms of 13q33-q34 deletion syndrome Neurodevelopmental disability, heart defects and urogenital/anorectal anomalies may be resulted from common or overlapping regions of deletion in chromosome bands 13q33.1-q34 and may share a common molecular mechanism.

LncRNA SNHG5/miR-26a/SOX2 signal axis enhances proliferation of chondrocyte in osteoarthritis.

Chondrocyte is involved in the destruction of joints in osteoarthritis (OA) patients. The aim of this study was to explore the expression level of small nucleolar RNA host gene 5 (SNHG5) and evaluate its function in chondrocyte. In our current study, the expression levels of SNHG5, miR-26a, and SOX2 in 17 pairs of articular cartilage tissues and in the non-OA group were assessed by real-time quantitative reverse-transcription polymerase chain reaction. Results showed that the levels of SNHG5 and SOX2 were significantly downregulated in OA tissues, while the level of miR-26a was upregulated. MTT, colony formation and cell transwell assays were performed to assess the function of SNHG5 on the cell viability, growth ability, and migration capacity in CHON-001 cells. It was found that SNHG5 could promote chondrocyte cell proliferation and migration. The relationship between SNHG5 and miR-26a was confirmed by RIP and the luciferase reporter assays. SOX2 was identified as a target gene of miR-26a by the luciferase reporter assay. Rescue assay was applied to verify the relationship among SNHG5, miR-26a, and SOX2. Our current study demonstrated that SNHG5 is involved in the mechanism of OA through functioning as a ceRNA to competitively sponge miR-26a, therefore, regulating the expression of SOX2.

Leptin-Sensitive JAK2 Activation in the Regulation of Tau Phosphorylation in PC12 Cells.

BACKGROUND/AIMS: Alzheimer's disease (AD) is characterized by two major hallmarks: the deposition and accumulation of ß-amyloid (Aß) peptide and hyperphosphorylated tau in intracellular neurofibrillary tangles. Sets of evidence show that leptin reduces Aß production and tau phosphorylation. Herein, we investigated the signaling pathways activated by leptin, to extensively understand its mechanism. METHODS: Western blotting was employed to assess the protein abundance of p-tau and BAX, MTT assay to decipher the cells viability. RESULTS: Leptin decreased tau phosphorylation, an effect was dependent on the activation of JAK2. CONCLUSION: The data suggest that JAK2 is involved in AD-related pathways.

Evaluation of mycophenolate mofetil or tacrolimus in children with steroid sensitive but frequently relapsing or steroid-dependent nephrotic syndrome.

AIM: Approximately 30-40% of children with steroid sensitive nephrotic syndrome have frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Mycophenolate mofetil (MMF) and tacrolimus (TAC) are often alternative treatment choices for these patients. METHODS: A single-center prospective study was conducted to compare the efficacy of MMF or TAC in reducing relapses and maintaining remission in children with FRNS or SDNS. Of the 72 recruited patients, either MMF (20∼30 mg/kg/d, n = 34) or TAC (0.05∼0.15 mg/kg/d, n = 38) was administered for 12 months. RESULTS: The mean 6-month relapse rates decreased from 2.56 episodes before therapy to 0.76 episodes in the first 6 months after therapy (c(2) = 44.362, p < 0.001) and 0.67 in the next 6 months (c(2) = 37.817, p < 0.001) in the MMF group. In the TAC group, the mean 6-month relapse rates decreased from 2.39 episodes before therapy to 0.41 episodes in the first 6 months after therapy (c(2) = 62.242, p < 0.001) and 0.42 in next 6 months (c(2) = 67.482, p < 0.001). No significant difference in the relapse rate was found between the groups (before therapy, c(2) = 0.902, p = 0.637; first 6 months, c(2) = 5.358, p = 0.147; second 6 months, c(2) = 4.089, p = 0.252). And there was also no significant difference in cumulative sustained remission and the incidence of adverse events between two groups. CONCLUSIONS: In combination with low-dose steroids, MMF or TAC presented similar efficacy in maintaining remission in children with FRNS/SDNS in the present study. Therapy with MMF or TAC is a promising strategy with a moderate risk of side effects in children who are steroid sensitive but have FRNS/SDNS.

Serum suPAR levels help differentiate steroid resistance from steroid-sensitive nephrotic syndrome in children.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) has been regarded as a permeability factor in proteinuria, though its role in primary nephrotic syndrome remains to be elucidated further. METHODS: Plasma samples and clinical information from 176 children with primary nephrotic syndrome were collected and concentrations of suPAR were measured. We evaluated the correlation between suPAR concentrations and clinical features, and the value of the plasma suPAR level in predicting steroid-resistant nephrotic syndrome (SRNS). RESULTS: There is a significant difference in plasma suPAR concentration between SRNS and steroid-sensitive nephrotic syndrome (SSNS) groups (3,744.1 ± 2,226.0 vs. 2,153.5 ± 1,167.0, p < 0.05). The area under the curve (AUC) was 0.80, with p < 0.001 for the receiver operating characteristic (ROC) curve analysis using suPAR to predict SRNS. The suspicious range for predicting SRNS was estimated to be 1,907.0 pg/ml to 3,043.5 pg/ml (χ(2) = 14.775, p = 0.001). CONCLUSIONS: From ROC curve analysis, we demonstrated the significance of the suPAR level in predicting SRNS with a high specificity but low sensitivity. However, the clinical value of suPAR to predict steroid resistance and guide therapy remains to be investigated further.

Triple immunosuppressive therapy in steroid-resistant nephrotic syndrome children with tacrolimus resistance or tacrolimus sensitivity but frequently relapsing.

AIM: The treatment strategy for steroid-resistant nephrotic syndrome remains uncertain at present, especially in those with calcineurin inhibitor resistance or intolerance. To date, few studies have been published using multiple combination therapy of immunosuppressive reagents for children with calcineurin inhibitor-resistant or -intolerant nephrotic syndrome. METHODS: Eighteen consecutive children with steroid- and tacrolimus (TAC)-resistant (n = 10) or TAC-sensitive but frequent relapsing nephrotic syndrome (n = 8) were randomly recruited in the present study. All of them received further triple-combination therapy by cyclophosphamide (CTX, n = 6), mycophenolate mofetil (MMF, n = 5) or leflunomide (LEF, n = 7). Their clinical data were collected and efficacy of triple-combination therapy was evaluated. RESULTS: Compared with previous double-combination therapy of prednisone (Pre) and TAC, the short-term remission rate in all 18 patients was significantly improved after the triple-combination therapy, while the frequent relapse rate in the following 12 months was also significantly decreased. Among three different subgroups with CTX, MMF or LEF therapy, no significant difference was found in short-term remission rate and the relapse rate within 1 year follow up by Kaplan-Meier plot. CONCLUSION: Triple-combination therapy with Pre + TAC + CTX/MMF/LEF is effective for short-term response and 1 year remission, without significant additional side-effects seen in children with steroid-resistant and tacrolimus-resistant or tacrolimus-sensitive but frequently relapsing nephrotic syndrome. Further study for evaluating long-term efficacy and safety of triple-combination therapy with Pre + TAC + CTX/MMF/LEF would be necessary for these patients.

Overexpression of Myo1e in mouse podocytes enhances cellular endocytosis, migration, and adhesion.

Podocytes are a terminally differentiated and highly specialized cell type in the glomerulus that forms a crucial component of the glomerular filtration barrier. Recently, Myo1e was identified in the podocytes of glomeruli. Myo1e podocyte-specific knockout mice exhibit proteinuria, podocyte foot process effacement, glomerular basement membrane disorganization, signs of chronic renal injury, and kidney inflammation. After overexpression of Myo1e in a conditionally immortalized mouse podocyte cell line (MPC5), podocyte migration was evaluated via transwell assay, endocytosis was evaluated using FITC-transferrin, and adhesion was evaluated using a detachment assay after puromycin aminonucleoside treatment. Myo1e overexpression significantly increased the adherence of podocytes. ANOVA analysis indicated significant differences for cell adhesion between the overexpression and control groups (overexpression vs. control, t = 11.3199, P = 0.005; overexpression vs. negative control, t = 12.0570, P = 0.0006). Overexpression of Myo1e inhibited puromycin aminonucleoside-induced podocyte detachment, and the number of cells remaining on the bottom of the culture plate increased. Cell migration was enhanced in Myo1e-overexpressing podocytes in the transwell migration assay. Internalization of FITC-transferrin also increased in Myo1e-overexpressing podocytes relative to control cells. Overexpression of Myo1e can enhance podocyte migration ability, endocytosis, and attachment to the glomerular basement membrane. Restoration of Myo1e expression in podocytes may therefore strengthen their functional integrity against environmental and mechanical injury.

Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review.

BACKGROUND: Idiopathic renal hypouricemia (iRHUC) is an autosomal recessive hereditary disorder, characterized by impaired tubular uric acid transport, re-absorption insufficiency and/or the acceleration of secretions. Some patients present with severe complications, such as exercise-induced acute kidney injury (EIAKI) and nephrolithiasis. CASE PRESENTATION: Herein, we report the case of a girl with severe iRHUC (serum urate 0.05 mg/dL, fractional excretion of uric acid 295.99%) associated with recurrent EIAKI, in whom the disease was caused by a homozygous mutation (g.68G > A in exon 3) in the SLC2A9 gene. Her family members (father, mother and brother) carried the same mutation but were heterozygous, without any signs of severe hypouricemia. CONCLUSIONS: Our findings indicate that iRHUC is a rare disorder but that it should also be considered in patients with EIAKI, especially in those patients who manifest with moderately elevated or normal serum concentrations of uric acid during the acute phase of AKI. Mutational screening of the SLC2A9 gene is necessary for the diagnosis of iRHUC, and homozygous mutations of the SLC2A9 alleles can cause severe hypouricemia. Careful attention should be paid to any signs of hypouricemia during the recovery phase of AKI and long-term follow-up.

Case Report: Successful Treatment of Recurrent Candida Albicans Meningitis with Kimura's Disease Using Amphotericin B Colloidal Dispersion Combined with Fluconazole.

Background: Candida albicans meningitis is a fungal infectious disease of the central nervous system that most often occurs in immunodeficient populations. Kimura's disease is an IgE-mediated inflammatory reactive disease that is a chronic immune disorder with predominantly lymph node, soft tissue, and salivary gland damage, the treatment of which is hormone-based. The combination of Kimura's disease with C. albicans meningitis is relatively uncommon. Herein, we report a case of C. albicans meningitis in combination with Kimura's disease. Case Presentation: The case is a 26-year-old male with a medical history of Kimura, who presented with symptoms of dizziness, headache, and double vision. Lumbar puncture and cerebrospinal fluid examination revealed an increased white blood cell count. Further analysis through cerebrospinal fluid culture and metagenomic second-generation sequencing (mNGS) led to the final diagnosis of C. albicans meningitis. The patient was treated with fluconazole after the onset of C. albicans meningitis and had a good response. During the treatment, changes in the pathogen genome sequences were monitored dynamically using metagenomic next-generation sequencing. After 1 year, the patient had a recurrence of Candida meningitis. Treatment with fluconazole alone was ineffective, while antifungal treatment with amphotericin B colloidal dispersion was effective with no detectable renal injury. Conclusion: Candida meningitis can occur in the context of Kimura disease. In patients with mild disease, the possibility of recurrence exists with fluconazole treatment alone, and the efficacy of amphotericin B colloidal dispersion combined with fluconazole is better than fluconazole alone in patients with a recurrence. No nephrotoxicity was observed during amphotericin B colloidal dispersion treatment. The mNGS allows dynamic monitoring of pathogen sequencing reads, and for Candida meningitis, there may be a mismatch between peak sequencing reads and disease during treatment, the basis for which is unclear.

Treatment of tacrolimus or cyclosporine A in children with idiopathic nephrotic syndrome.

BACKGROUND: Cyclosporine A (CsA) and tacrolimus (TAC) are often alternative treatment choices for patients with nephrotic syndrome. METHODS: In this prospective study, the efficacy and safety of CsA and TAC in inducing and maintaining remission in 74 children with idiopathic nephrotic syndrome (INS) were evaluated. RESULTS: In terms of short-term efficacy, TAC was more effective than CsA in children with steroid-resistant nephrotic syndrome (χ(2) = 13.75, P = 0.001), although no significant difference in number of episodes of relapse were found in patients with complete remission between the two treatment groups (first year: χ(2) = 0.261, P = 0.88; second year: χ(2) = 2.685, P = 0.26). In patients with frequently relapsing or steroid-dependent nephrotic syndrome, no significant difference in short-term remission (χ(2) = 1.908, P = 0.39) or in relapse frequency during follow-up (within first year: χ(2) = 1.046, P = 0.59; within second year: χ(2) = 0.587, P = 0.75) were found between the two groups. There was a difference in the rate of adverse effects between the two treatment groups [nephrotoxicity: 4/24 (CsA) vs .0/50 (TAC), P = 0.002; hirsutism: 8/24 (CsA) vs. 0/50 (TAC), P < 0.001]. CONCLUSIONS: In our pediatric patient cohort, the treatment of steroid-resistant nephrotic syndrome with tacrolimus was associated with higher efficacy and lower renal toxicity in comparison to CsA, although no favorable outcome in relapse rate during long-term follow-up was seen. On the other hand, tacrolimus was not always the better choice to replace CsA in the treatment of severe frequently relapsing or steroid-dependent nephrotic syndrome.

Case Report: Cryptococcal eosinophilic meningitis in a patient with Hodgkin lymphoma.

Cryptococcal meningitis is the most common fungal meningitis in clinical practice. It primarily occurs in immunocompromised people and is typically associated with human immunodeficiency virus (HIV) infection. In rare cases, it is associated with Hodgkin lymphoma (HL). Eosinophilic meningitis (EM) is characterized by increased eosinophils in the cerebrospinal fluid (CSF) and is often caused by a parasitic infection of the central nervous system (CNS). EM caused by cryptococcal infection is rare; only four cases have been reported in the past 30 years. Here, we report a case of cryptococcal meningitis in a patient with HL who presented with an atypical eosinophil-predominant CSF cytology response. The patient's eosinophil proportion reached 91%; a proportion this high has not been reported previously and may be associated with HL. After antifungal therapy and tumor chemotherapy, the proportion of eosinophils decreased significantly. This case shows that cryptococcal meningitis and HL may be simultaneously contributing to CSF eosinophilia. HL should be considered in patients with eosinophilic cryptococcal meningitis and multiple adenopathies.

Description of the Molecular and Phenotypic Spectrum of Lesch-Nyhan Disease in Eight Chinese Patients.

Background: Lesch-Nyhan disease (LND) is a rare disorder involving pathogenic variants in the HPRT1 gene encoding the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) that result in hyperuricemia, intellectual disability, dystonic movement disorder, and compulsive self-mutilation. The purpose of the present study was to characterize the genetic basis of LND and describe its phenotypic heterogeneity by identifying the variation in the HPRT1 gene in a cohort of Chinese LND patients. Results: The median age at diagnosis was 31 mo (interquartile range (IQR): 7-76 mo), and the initial manifestations were mainly head control weakness and motor development delay. The median age of self-mutilation behavior onset was 19 mo (IQR: 17-24 mo), and all patients were required to travel in a wheelchair and fall into the predicament of compulsive self-harm behavior. There were two patients whose blood uric acid levels were normal for their high urinary acid excretion fraction without taking uric acid-lowering drugs. Seven different pathogenic variants of the HPRT1 gene were identified among eight independent pedigrees, including four novel mutations [c.299 (exon 3) T > A; loss (exon: 6) 84 bp; c.277_281delATTGC; c.468_470delGAT]. The pathogenic variant sites were mainly concentrated in exon 3, and truncating mutations (including frameshift mutations and nonsense mutations) were the most common genetic variant types (5/7, 71.4%). Conclusion: The present study described the phenotypic and molecular spectrum of LND in eight Chinese families, including four novel mutations, which expands our understanding of LND.

Identification of cerebrospinal fluid biomarker candidates for anti-N-methyl-D-aspartate receptor encephalitis: High-throughput proteomic investigation.

Background: Although the diagnosis is mainly dependent on the detection of anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in cerebrospinal fluid (CSF) and/or serum, there was no direct correlations between anti-NMDAR antibody titers in CSF and disease severity and prognosis in anti-NMDAR encephalitis patients. Here, we aimed to extensively identify CSF biomarkers related to the occurrence, development, and prognosis of anti-NMDAR encephalitis using a high-throughput proteomic approach. Methods: A CSF cytokine antibody array containing 80 cytokines and inflammatory mediators related to immune and inflammatory responses was applied to identify biomarker candidates in individual CSF samples from a well-characterized cohort comprising patients with anti-NMDAR encephalitis (n = 6) and controls (n = 6). Validation and specific detection were performed in an extended cohort consisting of anti-NMDAR encephalitis patients (n = 13), controls (n = 13), and viral encephalitis (n = 13) by enzyme-linked immunosorbent assay (ELISA). Additionally, the levels of some inflammatory proteins in three groups in cohort 2 reported in previous literatures that may be involved in the development of anti-NMDAR encephalitis were also tested by ELISA. Correlations between candidate biomarkers and clinical characteristics of anti-NMDAR encephalitis patients were analyzed. Results: Three differentially expressed cytokines and inflammatory mediators were screened from the 80-cytokine array in cohort 1. Functional enrichment analysis results suggested that these differentially expressed proteins were related to autophagy, immune/inflammatory responses, cell death, and other processes. In cohort 2, the elevations of cellular inhibitor of apoptosis protein-1 (cIAP-1), macrophage colony-stimulating factor (MCSF), CXC chemokine ligand 13 (CXCL13), and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) in anti-NMDAR encephalitis were validated by ELISA. Linear regression revealed that the levels of CSF CXCL13 and cIAP-1 were positively correlated with the highest modified Rankin scale (mRS) score in the acute phase (p < 0.05). The level of cIAP-1 was positively correlated with the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score (p < 0.05). Conclusion: These biomarkers show promising functions to evaluate severity or prognosis of anti-NMDAR encephalitis. The biological processes of immune/inflammatory responses, altered levels of autophagy, and the tumor necrosis factor (TNF) signal pathway may be involved in the pathophysiology of anti-NMDAR encephalitis to some extent.